Synthesis of novel, DNA binding heterocyclic dehydroabietylamine derivatives as potential antiproliferative and apoptosis-inducing agents
Identifieur interne : 000495 ( Pmc/Corpus ); précédent : 000494; suivant : 000496Synthesis of novel, DNA binding heterocyclic dehydroabietylamine derivatives as potential antiproliferative and apoptosis-inducing agents
Auteurs : Fengyi Zhao ; Xu Sun ; Wen Lu ; Li Xu ; Jiuzhou Shi ; Shilong Yang ; Mengyi Zhou ; Fan Su ; Feng Lin ; Fuliang CaoSource :
- Drug Delivery [ 1071-7544 ] ; 2020.
Abstract
Several dehydroabietylamine derivatives containing heterocyclic moieties such as
thiophene and pyrazine ring were successfully synthesized. The antiproliferative
activities of these thiophene-based Schiff-bases, thiophene amides, and pyrazine amides
were investigated
Url:
DOI: 10.1080/10717544.2020.1716879
PubMed: 31984809
PubMed Central: 7034089
Links to Exploration step
PMC:7034089Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Synthesis of novel, DNA binding heterocyclic dehydroabietylamine derivatives
as potential antiproliferative and apoptosis-inducing agents</title><author><name sortKey="Zhao, Fengyi" sort="Zhao, Fengyi" uniqKey="Zhao F" first="Fengyi" last="Zhao">Fengyi Zhao</name><affiliation><nlm:aff id="AF0001"><institution>Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University</institution>, Nanjing,<country>PR China</country>;</nlm:aff></affiliation><affiliation><nlm:aff id="AF0002"><institution>College of Forestry, Nanjing Forestry University</institution>, Nanjing,<country>PR China</country>;</nlm:aff></affiliation><affiliation><nlm:aff id="AF0003"><institution>College of Science, Nanjing Forestry University</institution>, Nanjing,<country>PR China</country>;</nlm:aff></affiliation></author><author><name sortKey="Sun, Xu" sort="Sun, Xu" uniqKey="Sun X" first="Xu" last="Sun">Xu Sun</name><affiliation><nlm:aff id="AF0003"><institution>College of Science, Nanjing Forestry University</institution>, Nanjing,<country>PR China</country>;</nlm:aff></affiliation><affiliation><nlm:aff id="AF0004"><institution>College of Information Science and Technology, Nanjing Forestry University</institution>, Nanjing,<country>PR China</country>;</nlm:aff></affiliation></author><author><name sortKey="Lu, Wen" sort="Lu, Wen" uniqKey="Lu W" first="Wen" last="Lu">Wen Lu</name><affiliation><nlm:aff id="AF0003"><institution>College of Science, Nanjing Forestry University</institution>, Nanjing,<country>PR China</country>;</nlm:aff></affiliation></author><author><name sortKey="Xu, Li" sort="Xu, Li" uniqKey="Xu L" first="Li" last="Xu">Li Xu</name><affiliation><nlm:aff id="AF0001"><institution>Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University</institution>, Nanjing,<country>PR China</country>;</nlm:aff></affiliation><affiliation><nlm:aff id="AF0003"><institution>College of Science, Nanjing Forestry University</institution>, Nanjing,<country>PR China</country>;</nlm:aff></affiliation></author><author><name sortKey="Shi, Jiuzhou" sort="Shi, Jiuzhou" uniqKey="Shi J" first="Jiuzhou" last="Shi">Jiuzhou Shi</name><affiliation><nlm:aff id="AF0003"><institution>College of Science, Nanjing Forestry University</institution>, Nanjing,<country>PR China</country>;</nlm:aff></affiliation></author><author><name sortKey="Yang, Shilong" sort="Yang, Shilong" uniqKey="Yang S" first="Shilong" last="Yang">Shilong Yang</name><affiliation><nlm:aff id="AF0005"><institution>Advanced Analysis and Testing Center, Nanjing Forestry University</institution>, Nanjing,<country>PR China</country></nlm:aff></affiliation></author><author><name sortKey="Zhou, Mengyi" sort="Zhou, Mengyi" uniqKey="Zhou M" first="Mengyi" last="Zhou">Mengyi Zhou</name><affiliation><nlm:aff id="AF0005"><institution>Advanced Analysis and Testing Center, Nanjing Forestry University</institution>, Nanjing,<country>PR China</country></nlm:aff></affiliation></author><author><name sortKey="Su, Fan" sort="Su, Fan" uniqKey="Su F" first="Fan" last="Su">Fan Su</name><affiliation><nlm:aff id="AF0005"><institution>Advanced Analysis and Testing Center, Nanjing Forestry University</institution>, Nanjing,<country>PR China</country></nlm:aff></affiliation></author><author><name sortKey="Lin, Feng" sort="Lin, Feng" uniqKey="Lin F" first="Feng" last="Lin">Feng Lin</name><affiliation><nlm:aff id="AF0005"><institution>Advanced Analysis and Testing Center, Nanjing Forestry University</institution>, Nanjing,<country>PR China</country></nlm:aff></affiliation></author><author><name sortKey="Cao, Fuliang" sort="Cao, Fuliang" uniqKey="Cao F" first="Fuliang" last="Cao">Fuliang Cao</name><affiliation><nlm:aff id="AF0001"><institution>Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University</institution>, Nanjing,<country>PR China</country>;</nlm:aff></affiliation><affiliation><nlm:aff id="AF0002"><institution>College of Forestry, Nanjing Forestry University</institution>, Nanjing,<country>PR China</country>;</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31984809</idno><idno type="pmc">7034089</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7034089</idno><idno type="RBID">PMC:7034089</idno><idno type="doi">10.1080/10717544.2020.1716879</idno><date when="2020">2020</date><idno type="wicri:Area/Pmc/Corpus">000495</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000495</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Synthesis of novel, DNA binding heterocyclic dehydroabietylamine derivatives
as potential antiproliferative and apoptosis-inducing agents</title><author><name sortKey="Zhao, Fengyi" sort="Zhao, Fengyi" uniqKey="Zhao F" first="Fengyi" last="Zhao">Fengyi Zhao</name><affiliation><nlm:aff id="AF0001"><institution>Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University</institution>, Nanjing,<country>PR China</country>;</nlm:aff></affiliation><affiliation><nlm:aff id="AF0002"><institution>College of Forestry, Nanjing Forestry University</institution>, Nanjing,<country>PR China</country>;</nlm:aff></affiliation><affiliation><nlm:aff id="AF0003"><institution>College of Science, Nanjing Forestry University</institution>, Nanjing,<country>PR China</country>;</nlm:aff></affiliation></author><author><name sortKey="Sun, Xu" sort="Sun, Xu" uniqKey="Sun X" first="Xu" last="Sun">Xu Sun</name><affiliation><nlm:aff id="AF0003"><institution>College of Science, Nanjing Forestry University</institution>, Nanjing,<country>PR China</country>;</nlm:aff></affiliation><affiliation><nlm:aff id="AF0004"><institution>College of Information Science and Technology, Nanjing Forestry University</institution>, Nanjing,<country>PR China</country>;</nlm:aff></affiliation></author><author><name sortKey="Lu, Wen" sort="Lu, Wen" uniqKey="Lu W" first="Wen" last="Lu">Wen Lu</name><affiliation><nlm:aff id="AF0003"><institution>College of Science, Nanjing Forestry University</institution>, Nanjing,<country>PR China</country>;</nlm:aff></affiliation></author><author><name sortKey="Xu, Li" sort="Xu, Li" uniqKey="Xu L" first="Li" last="Xu">Li Xu</name><affiliation><nlm:aff id="AF0001"><institution>Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University</institution>, Nanjing,<country>PR China</country>;</nlm:aff></affiliation><affiliation><nlm:aff id="AF0003"><institution>College of Science, Nanjing Forestry University</institution>, Nanjing,<country>PR China</country>;</nlm:aff></affiliation></author><author><name sortKey="Shi, Jiuzhou" sort="Shi, Jiuzhou" uniqKey="Shi J" first="Jiuzhou" last="Shi">Jiuzhou Shi</name><affiliation><nlm:aff id="AF0003"><institution>College of Science, Nanjing Forestry University</institution>, Nanjing,<country>PR China</country>;</nlm:aff></affiliation></author><author><name sortKey="Yang, Shilong" sort="Yang, Shilong" uniqKey="Yang S" first="Shilong" last="Yang">Shilong Yang</name><affiliation><nlm:aff id="AF0005"><institution>Advanced Analysis and Testing Center, Nanjing Forestry University</institution>, Nanjing,<country>PR China</country></nlm:aff></affiliation></author><author><name sortKey="Zhou, Mengyi" sort="Zhou, Mengyi" uniqKey="Zhou M" first="Mengyi" last="Zhou">Mengyi Zhou</name><affiliation><nlm:aff id="AF0005"><institution>Advanced Analysis and Testing Center, Nanjing Forestry University</institution>, Nanjing,<country>PR China</country></nlm:aff></affiliation></author><author><name sortKey="Su, Fan" sort="Su, Fan" uniqKey="Su F" first="Fan" last="Su">Fan Su</name><affiliation><nlm:aff id="AF0005"><institution>Advanced Analysis and Testing Center, Nanjing Forestry University</institution>, Nanjing,<country>PR China</country></nlm:aff></affiliation></author><author><name sortKey="Lin, Feng" sort="Lin, Feng" uniqKey="Lin F" first="Feng" last="Lin">Feng Lin</name><affiliation><nlm:aff id="AF0005"><institution>Advanced Analysis and Testing Center, Nanjing Forestry University</institution>, Nanjing,<country>PR China</country></nlm:aff></affiliation></author><author><name sortKey="Cao, Fuliang" sort="Cao, Fuliang" uniqKey="Cao F" first="Fuliang" last="Cao">Fuliang Cao</name><affiliation><nlm:aff id="AF0001"><institution>Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University</institution>, Nanjing,<country>PR China</country>;</nlm:aff></affiliation><affiliation><nlm:aff id="AF0002"><institution>College of Forestry, Nanjing Forestry University</institution>, Nanjing,<country>PR China</country>;</nlm:aff></affiliation></author></analytic><series><title level="j">Drug Delivery</title><idno type="ISSN">1071-7544</idno><idno type="eISSN">1521-0464</idno><imprint><date when="2020">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>Abstract</title><p>Several dehydroabietylamine derivatives containing heterocyclic moieties such as
thiophene and pyrazine ring were successfully synthesized. The antiproliferative
activities of these thiophene-based Schiff-bases, thiophene amides, and pyrazine amides
were investigated <italic>in vitro</italic> against Hela (cervix), MCF-7 (breast), A549
(lung), HepG2 (liver), and HUVEC (umbilical vein) cells by MTT assay. The toxicity of
<bold>L<sup>1</sup></bold>−<bold>L<sup>10</sup></bold>(IC<sub>50</sub> = 5.92− >100 μM) was lower than <bold>L<sup>0</sup></bold>(1.27 μM) and DOX (4.40 μM) in every case. Compound <bold>L<sup>1</sup></bold> had higher
anti-HepG2 <bold>(</bold>0.66 μM), anti-MCF-7 (5.33 μM), and anti-A549 (2.11 μM) and
compound <bold>L<sup>3</sup></bold> had higher anti-HepG2 (1.63 μM) and anti-MCF-7
(2.65 μM) activities. Both of these compounds were recognized with high efficiency in
apoptosis induction in HepG2 cells and intercalated binding modes with DNA. Moreover, with
average IC<sub>50</sub> values of 0.66 and 5.98 μM, <bold>L<sup>1</sup></bold> was nine
times more effective at suppressing cultured HepG2 cells viability than normal cells (SI =
9). The relative tumor proliferation rate (T/C) was 38.6%, the tumor inhibition rate was
up to 61.2%, which indicated that <bold>L<sup>1</sup></bold> had no significant toxicity
but high anti-HepG2 activity <italic>in vivo</italic>. Thus, it may be a potential
antiproliferation drug with nontoxic side effects.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Ahmed, Hea" uniqKey="Ahmed H">HEA Ahmed</name></author><author><name sortKey="Ihmaid, Sk" uniqKey="Ihmaid S">SK Ihmaid</name></author><author><name sortKey="Omar, Am" uniqKey="Omar A">AM Omar</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Aissi, Re" uniqKey="Aissi R">RE Aissi</name></author><author><name sortKey="Liu, J" uniqKey="Liu J">J Liu</name></author><author><name sortKey="Besse, S" uniqKey="Besse S">S Besse</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Arjmand, F" uniqKey="Arjmand F">F Arjmand</name></author><author><name sortKey="Aziz, M" uniqKey="Aziz M">M Aziz</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Auxiliadora, Mda" uniqKey="Auxiliadora M">MDA Auxiliadora</name></author><author><name sortKey="Pablo, Br" 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Drug Deliv</journal-id><journal-id journal-id-type="iso-abbrev">Drug Deliv</journal-id><journal-id journal-id-type="publisher-id">IDRD</journal-id><journal-id journal-id-type="publisher-id">idrd20</journal-id><journal-title-group><journal-title>Drug Delivery</journal-title></journal-title-group><issn pub-type="ppub">1071-7544</issn><issn pub-type="epub">1521-0464</issn><publisher><publisher-name>Taylor & Francis</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31984809</article-id><article-id pub-id-type="pmc">7034089</article-id><article-id pub-id-type="doi">10.1080/10717544.2020.1716879</article-id><article-id pub-id-type="publisher-id">1716879</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group></article-categories><title-group><article-title>Synthesis of novel, DNA binding heterocyclic dehydroabietylamine derivatives
as potential antiproliferative and apoptosis-inducing agents</article-title><alt-title alt-title-type="running-authors">F. Zhao et al.</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Zhao</surname><given-names>Fengyi</given-names></name><xref ref-type="aff" rid="AF0001"><sup>a</sup></xref><xref ref-type="aff" rid="AF0002"><sup>b</sup></xref><xref ref-type="aff" rid="AF0003"><sup>c</sup></xref></contrib><contrib contrib-type="author"><name><surname>Sun</surname><given-names>Xu</given-names></name><xref ref-type="aff" rid="AF0003"><sup>c</sup></xref><xref ref-type="aff" rid="AF0004"><sup>d</sup></xref></contrib><contrib contrib-type="author"><name><surname>Lu</surname><given-names>Wen</given-names></name><xref ref-type="aff" rid="AF0003"><sup>c</sup></xref></contrib><contrib contrib-type="author"><name><surname>Xu</surname><given-names>Li</given-names></name><xref ref-type="aff" rid="AF0001"><sup>a</sup></xref><xref ref-type="aff" rid="AF0003"><sup>c</sup></xref><xref ref-type="corresp" rid="AN0001"></xref></contrib><contrib contrib-type="author"><name><surname>Shi</surname><given-names>Jiuzhou</given-names></name><xref ref-type="aff" rid="AF0003"><sup>c</sup></xref></contrib><contrib contrib-type="author"><name><surname>Yang</surname><given-names>Shilong</given-names></name><xref ref-type="aff" rid="AF0005"><sup>e</sup></xref></contrib><contrib contrib-type="author"><name><surname>Zhou</surname><given-names>Mengyi</given-names></name><xref ref-type="aff" rid="AF0005"><sup>e</sup></xref></contrib><contrib contrib-type="author"><name><surname>Su</surname><given-names>Fan</given-names></name><xref ref-type="aff" rid="AF0005"><sup>e</sup></xref></contrib><contrib contrib-type="author"><name><surname>Lin</surname><given-names>Feng</given-names></name><xref ref-type="aff" rid="AF0005"><sup>e</sup></xref></contrib><contrib contrib-type="author"><name><surname>Cao</surname><given-names>Fuliang</given-names></name><xref ref-type="aff" rid="AF0001"><sup>a</sup></xref><xref ref-type="aff" rid="AF0002"><sup>b</sup></xref></contrib><aff id="AF0001"><label>a</label><institution>Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University</institution>, Nanjing,<country>PR China</country>;</aff><aff id="AF0002"><label>b</label><institution>College of Forestry, Nanjing Forestry University</institution>, Nanjing,<country>PR China</country>;</aff><aff id="AF0003"><label>c</label><institution>College of Science, Nanjing Forestry University</institution>, Nanjing,<country>PR China</country>;</aff><aff id="AF0004"><label>d</label><institution>College of Information Science and Technology, Nanjing Forestry University</institution>, Nanjing,<country>PR China</country>;</aff><aff id="AF0005"><label>e</label><institution>Advanced Analysis and Testing Center, Nanjing Forestry University</institution>, Nanjing,<country>PR China</country></aff></contrib-group><author-notes><fn id="AUFN1"><p>Supplemental data for this article can be accessed <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1080/10717544.2020.1716879"><underline>here</underline></ext-link>.</p></fn><corresp id="AN0001">CONTACT Li Xu <email>2016qlsz@njfu.edu.cn</email><institution>Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing
Forestry University</institution>, Nanjing, 210037, <country>PR
China</country></corresp></author-notes><pub-date pub-type="collection"><year>2020</year></pub-date><pub-date pub-type="epub"><day>27</day><month>1</month><year>2020</year></pub-date><volume>27</volume><issue>1</issue><fpage seq="19">216</fpage><lpage>227</lpage><history><date date-type="received"><day>27</day><month>11</month><year>2019</year></date><date date-type="rev-recd"><day>05</day><month>1</month><year>2020</year></date><date date-type="accepted"><day>13</day><month>1</month><year>2020</year></date></history><permissions><copyright-statement>© 2020 The Author(s). Published by Informa UK Limited, trading as
Taylor & Francis Group.</copyright-statement><copyright-year>2020</copyright-year><copyright-holder>The Author(s)</copyright-holder><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>), which permits unrestricted
use, distribution, and reproduction in any medium, provided the original work is
properly cited.</license-p></license></permissions><self-uri content-type="pdf" xlink:href="IDRD_27_1716879.pdf"></self-uri><abstract><title>Abstract</title><p>Several dehydroabietylamine derivatives containing heterocyclic moieties such as
thiophene and pyrazine ring were successfully synthesized. The antiproliferative
activities of these thiophene-based Schiff-bases, thiophene amides, and pyrazine amides
were investigated <italic>in vitro</italic> against Hela (cervix), MCF-7 (breast), A549
(lung), HepG2 (liver), and HUVEC (umbilical vein) cells by MTT assay. The toxicity of
<bold>L<sup>1</sup></bold>−<bold>L<sup>10</sup></bold>(IC<sub>50</sub> = 5.92− >100 μM) was lower than <bold>L<sup>0</sup></bold>(1.27 μM) and DOX (4.40 μM) in every case. Compound <bold>L<sup>1</sup></bold> had higher
anti-HepG2 <bold>(</bold>0.66 μM), anti-MCF-7 (5.33 μM), and anti-A549 (2.11 μM) and
compound <bold>L<sup>3</sup></bold> had higher anti-HepG2 (1.63 μM) and anti-MCF-7
(2.65 μM) activities. Both of these compounds were recognized with high efficiency in
apoptosis induction in HepG2 cells and intercalated binding modes with DNA. Moreover, with
average IC<sub>50</sub> values of 0.66 and 5.98 μM, <bold>L<sup>1</sup></bold> was nine
times more effective at suppressing cultured HepG2 cells viability than normal cells (SI =
9). The relative tumor proliferation rate (T/C) was 38.6%, the tumor inhibition rate was
up to 61.2%, which indicated that <bold>L<sup>1</sup></bold> had no significant toxicity
but high anti-HepG2 activity <italic>in vivo</italic>. Thus, it may be a potential
antiproliferation drug with nontoxic side effects.</p></abstract><kwd-group kwd-group-type="author"><title>Keywords</title><kwd>Dehydroabietylamine derivatives</kwd><kwd>antiproliferative</kwd><kwd>lower toxicity</kwd><kwd>apoptosis</kwd></kwd-group><funding-group><award-group><funding-source><named-content content-type="funder-name">National Key Research and Development Program
of China</named-content><named-content content-type="funderidentifier">10.13039/501100002852</named-content></funding-source><award-id>706</award-id></award-group><award-group><funding-source><named-content content-type="funder-name">Sate Key Laboratory for Chemistry and
Molecular Engineering of Medicinal Resources (Guangxi Normal
University)</named-content></funding-source><award-id>-B06</award-id></award-group><funding-statement>This work was supported by the National Key Research and Development
Program of China [grant number 2017YFD0600706] and Sate Key Laboratory for Chemistry and
Molecular Engineering of Medicinal Resources (Guangxi Normal University) [grant number
CMEMR2017-B06].</funding-statement></funding-group><counts><fig-count count="7"></fig-count><table-count count="4"></table-count><page-count count="12"></page-count><word-count count="8137"></word-count></counts></article-meta></front><body><sec id="s0001"><label>1.</label><title>Introduction</title><p>Currently, various chemotherapy drugs have been developed for the treatment of different
cancers; however, undesirable side effects may greatly impede their use in clinical
progression. Among a variety of cancer cures, the antiproliferative approach plays a crucial
role in controlling this deadly disease (Xin et al., <xref rid="CIT0056" ref-type="bibr">2018</xref>; Lei et al., <xref rid="CIT0024" ref-type="bibr">2019b</xref>). Up to now,
numerous molecules containing heterocyclic rings have showed great antiproliferative
potential, particularly those with thiophene and pyrazine rings.</p><p>Thiophene derivatives are ubiquitous in nature and can be found in the structure of various
drugs and medicines, produced by combustion of fossil fuels or by the general cooking
process (Dyreborg et al., <xref rid="CIT0009" ref-type="bibr">1996</xref>; Dalvie et al.,
<xref rid="CIT0008" ref-type="bibr">2002</xref>; Medower et al., <xref rid="CIT0035" ref-type="bibr">2008</xref>). Thiophenes bear extensive pharmacological properties such as
analgesic, antipyretic, and antiandrogenic activities (Hana et al., <xref rid="CIT0014" ref-type="bibr">2008</xref>; Huang et al., <xref rid="CIT0017" ref-type="bibr">2012</xref>;
Iványi et al., <xref rid="CIT0019" ref-type="bibr">2012</xref>). Furthermore, a great number
of thiophene derivatives are used as antitumor agents (Lesyk et al., <xref rid="CIT0026" ref-type="bibr">2006</xref>; Kulandasamy et al., <xref rid="CIT0021" ref-type="bibr">2009</xref>; Khalil et al., <xref rid="CIT0020" ref-type="bibr">2010</xref>; Ye et al.,
<xref rid="CIT0057" ref-type="bibr">2010</xref>). For instance, OSI-930 is an
investigational anticancer agent which contains thiophene moiety (Petti et al., <xref rid="CIT0040" ref-type="bibr">2005</xref>; Garton et al., <xref rid="CIT0012" ref-type="bibr">2006</xref>). Ghorab et al. (<xref rid="CIT0013" ref-type="bibr">2016</xref>) reported a series of thiophene derivatives with high anti-MCF-7 (breast
adenocarcinoma) cancer activity (half maximal inhibitory concentration
[IC<sub>50</sub>] = 33.1–66.3 μM). Mohareb and Al-Omran (<xref rid="CIT0036" ref-type="bibr">2012</xref>) have studied three thiophene derivatives exhibited much higher inhibitory
effects toward three tumor cell lines, MCF-7, NCI-H460 (non-small cell lung cancer), and
SF-268 (CNS cancer) with GC<sub>50</sub> value in the range of 0.01–16.2 μM than the
reference drug, doxorubicin (DOX).</p><p>Recently, nitrogen heterocycles have also been reported to exhibit therapeutics anticancer
(Azuine et al., <xref rid="CIT0005" ref-type="bibr">2004</xref>; Lei et al., <xref rid="CIT0023" ref-type="bibr">2019a</xref>,<xref rid="CIT0025" ref-type="bibr">c</xref>)
and anti-microbial (Nomiya et al., <xref rid="CIT0039" ref-type="bibr">2000</xref>; Mathew
et al., <xref rid="CIT0034" ref-type="bibr">2006</xref>) activities. Among them, the
pyrazine heterocycles have widespread application in food science, materials, and medicinal
chemistry (Mondal et al., <xref rid="CIT0037" ref-type="bibr">2010</xref>; Saito et al.,
<xref rid="CIT0044" ref-type="bibr">2010</xref>; Badrinarayanan & Sperry, <xref rid="CIT0006" ref-type="bibr">2011</xref>; Zitko et al., <xref rid="CIT0060" ref-type="bibr">2011</xref>). For example, pyrazinamide, a pyrazine derivative, is an
antimicrobial agent that is most commonly used for treatment of active tuberculosis during
the initial phase of therapy in combination with other agents. Quinoxaline compounds have
been reported to possess a wide range of interesting biological properties such as
anticancer, antiviral, antimicrobial, antifungal, antitubercular, anti-inflammatory, and
anti-angiogenesis agents (Seitz et al., <xref rid="CIT0045" ref-type="bibr">2002</xref>;
Smits et al., <xref rid="CIT0048" ref-type="bibr">2008</xref>; Vicente et al., <xref rid="CIT0052" ref-type="bibr">2009</xref>; Lee et al., <xref rid="CIT0022" ref-type="bibr">2010</xref>; Sridevi et al., <xref rid="CIT0050" ref-type="bibr">2010</xref>; Ingle
et al., <xref rid="CIT0018" ref-type="bibr">2013</xref>; Aissi et al., <xref rid="CIT0002" ref-type="bibr">2014</xref>; Soozani et al., <xref rid="CIT0049" ref-type="bibr">2018</xref>), containing pyrazine motif. Ahmed et al. (<xref rid="CIT0001" ref-type="bibr">2018</xref>) have synthesized several compounds and evaluated anticancer effects against
three cancer lines (HCT-116, MCF-7, and HepG2), and the results revealed that pyrazine
derivatives were the most active compounds with IC<sub>50</sub> value of 1.89 and 2.05 Μm.
Another pyrazine derivative, pyrazin-2(1H)-one, has attracted considerable attention due to
its biological activities, such as anti-viral, antibacterial, anti-inflammatory, and
anticancer (colon cancer therapies) activities (Lindsley et al., <xref rid="CIT0030" ref-type="bibr">2005</xref>).</p><p>Recently, dehydroabietylamine (<bold>L<sup>0</sup></bold>), which is one of the most vital
modified products of rosin, has attracted considerable attention due to the broad spectrum
of biological properties (Singh et al., <xref rid="CIT0047" ref-type="bibr">2014</xref>; Lin
et al., <xref rid="CIT0029" ref-type="bibr">2015</xref>; Auxiliadora et al., <xref rid="CIT0004" ref-type="bibr">2016</xref>; Bahekar et al., <xref rid="CIT0007" ref-type="bibr">2016</xref>; Fei et al., <xref rid="CIT0010" ref-type="bibr">2016</xref>;
Liu et al., <xref rid="CIT0031" ref-type="bibr">2016</xref>; Wang et al., <xref rid="CIT0053" ref-type="bibr">2016</xref>; Huang et al., <xref rid="CIT0016" ref-type="bibr">2017</xref>; Liu et al., <xref rid="CIT0032" ref-type="bibr">2017</xref>).
In general, a focus of research on dehydroabietylamine derivatives with their anticancer,
antibacterial, antifungal, and cytotoxic activities has been paid their attention in forest
chemistry too. Rao et al. (<xref rid="CIT0043" ref-type="bibr">2012</xref>) screened a
series of imines, amides, and ureas with a dehydroabietyl skeleton for their anticancer
activities against SMMC7721 (liver), A549 (lung), C6 (glioma), and MCF-7 cancer cell lines
with smallest IC<sub>50</sub> values of 6.65, 0.75, 0.81, and 10.65 μM. Lately, our group
has found that several Schiff-bases and amide compounds displayed highly potent inhibitory
activities against HepG2 (liver), MCF-7 and A549 cells with smallest IC<sub>50</sub> values
of 0.14, 0.24, 2.58, and 3.17 μM (Zhao et al., <xref rid="CIT0058" ref-type="bibr">2018</xref>).</p><p>Up until this day, finding new molecules with more effective, less toxic, and
target-specific DNA binding properties is one of the most important interest in medicinal
chemistry. Cisplatin, a well-known active anticancer drug, can covalently bind to DNA, but
its usage is limited with side effects and acquired cellular resistance (Rajendiran et al.,
<xref rid="CIT0042" ref-type="bibr">2007</xref>). The aforementioned thiophene, pyrazine,
and dehydroabietylamine analogs are all recognized as excellent antiproliferative agents;
thus, our group was interested in the further investigation of these derivatives. Our goal
was to achieve high anticancer activity, low toxicity, and target-specific DNA binding
properties with the dehydroabietylamine derivatives including thiophene Schiff-bases
(<bold>L<sup>1</sup>−L<sup>3</sup></bold>), thiophene amides
(<bold>L<sup>4</sup>−L<sup>6</sup></bold>), and pyrazine amides
(<bold>L<sup>7</sup>−L<sup>10</sup></bold>). These new compounds were screened for
antiproliferative activities against Hela (cervix), MCF-7, A549, HepG2 human cancer cell
lines <italic>in vitro</italic> by MTT assay, in addition to <bold>L<sup>1</sup></bold><italic>in vivo</italic>. We have verified that several compounds owned high
antiproliferative activities against these cancer cells and some of them exhibited more
potent antiproliferative activities as compared to dehydroabietylamine. Subsequently, the
induction of apoptosis effect on <bold>L<sup>1</sup></bold>and <bold>L<sup>3</sup></bold> with HepG2 cells was also investigated and the result
suggested they could inhibit cell proliferation by inducing apoptosis. In this report, we
hope to display a simple but effective strategy that may make contributions to the
exploration of future anticancer drugs.</p></sec><sec id="s0002"><label>2.</label><title>Results and discussion</title><sec id="s0003"><label>2.1.</label><title>Chemistry</title><p>All compounds were synthesized by the facile and efficient synthetic route from the
commercially available (+)-Dehydroabietylamine, [α]20 D = +55.1 (c 2.4 pyridine) (<xref ref-type="scheme" rid="SCH0001">Scheme 1</xref>). To explore the relationship between
the compound’s structures and biological activities, three thiophene aldehydes with
different functional groups, three carboxylic acids, and four pyrazine carboxylic acids
with various substituents were designed to react with dehydroabietylamine to prepare
thiophene Schiff-bases (<bold>L<sup>1</sup>−L<sup>3</sup></bold>), thiophene amides
(<bold>L<sup>4</sup>−L<sup>6</sup></bold>), and pyrazine amides
(<bold>L<sup>7</sup>−L<sup>10</sup></bold>). <bold>L<sup>1</sup>−L<sup>10</sup></bold>were obtained under neutral to slightly alkaline conditions (pH = 7.0–7.4) during the
experimental process.</p><fig id="SCH0001" orientation="portrait" position="float"><label>Scheme 1.</label><caption><p>Synthesis of <bold>L<sup>1</sup>−L<sup>10</sup></bold>.</p></caption><graphic content-type="color" xlink:href="IDRD_A_1716879_SCH0001_C"></graphic></fig><p>Both of the thiophene Schiff-bases <bold>L<sup>3</sup></bold> and thiophene amides
<bold>L<sup>4</sup></bold>owned novel structural features with two aromatic rings (thiophene ring and benzene
ring) and two aliphatic rings from dehydroabietylamine. For <bold>L<sup>3</sup></bold>,
its faint yellow block-shaped single crystal was found to be a monoclinic crystal in a
chiral space group <italic>P</italic>2<sub>1</sub> with a Flack parameter of 0.009(8). The
thiophene ring with C5, N1, and C6 was coplanar (<xref ref-type="fig" rid="F0001">Figure
1(a)</xref>). The molecules are stably connected by slightly weak
C1 − H1⋅⋅⋅S1<sup>#</sup> hydrogen bond to assemble an infinite one-dimensional chain
structure along <italic>b</italic> axis (<xref ref-type="fig" rid="F0001">Figure
1(b)</xref>). The distance of H1⋅⋅⋅S1 (2.8019(18) Å) and C1⋅⋅⋅S1 (3.6459(64) Å) is
corresponding to Shi’s report (H16⋅⋅⋅S2 2.95 Å and C16⋅⋅⋅S2 3.61 Å), which is slightly
shorter than the sum of van der Waals radii, proving that a weak interaction existed
between H1⋅⋅⋅S1 (Shi & Wen, <xref rid="CIT0046" ref-type="bibr">1998</xref>). The
length of the new imine double bond C5 − N1 (1.2520(7) Å) is in accordance with the report
from Lu (C10 − N2 1.2913(3) Å) (Lu et al., <xref rid="CIT0033" ref-type="bibr">2016</xref>) and our previous result of C7 − N1 1.2690(4) Å (Zhao et al., <xref rid="CIT0059" ref-type="bibr">2018</xref>). For <bold>L<sup>4</sup></bold>, its
colorless block-shaped single crystal was obtained as orthorhombic crystal system in a
chiral space group <italic>P</italic>2<sub>1</sub> with a Flack parameter of 0.08(5). The
molecules are connected by N1 − H1⋅⋅⋅O1<sup>#</sup> hydrogen bond to assemble an infinite
one-dimensional chain structure along <italic>b</italic> axis (<xref ref-type="fig" rid="F0002">Figure 2(b)</xref>). The hydrogen-bond parameters of
<bold>L<sup>3</sup></bold> and <bold>L<sup>4</sup></bold> are shown in <xref rid="t0001" ref-type="table">Table 1</xref>. Selected bond lengths and angles of
<bold>L<sup>3</sup></bold> and <bold>L<sup>4</sup></bold>are shown in <xref rid="t0002" ref-type="table">Table 2</xref>. The
crystallographic data are shown in <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1080/10717544.2020.1716879">Table S1</ext-link> in
<ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1080/10717544.2020.1716879">Supplementary Material</ext-link>.</p><fig id="F0001" orientation="portrait" position="float"><label>Figure 1.</label><caption><p>(a) Molecular structure of <bold>L<sup>3</sup></bold> (hydrogen atoms omitted for
clarity). (b) The 1D chain structure formed by intermolecular hydrogen bonds.</p></caption><graphic content-type="color" xlink:href="IDRD_A_1716879_F0001_C"></graphic></fig><fig id="F0002" orientation="portrait" position="float"><label>Figure 2.</label><caption><p>(a) Molecular structure of <bold>L<sup>4</sup></bold> (hydrogen atoms omitted for
clarity). (b) The 1D chain structure formed by intermolecular hydrogen bonds.</p></caption><graphic content-type="color" xlink:href="IDRD_A_1716879_F0002_C"></graphic></fig><table-wrap id="t0001" orientation="portrait" position="float"><label>Table 1.</label><caption><p>Hydrogen bonds of <bold>L<sup>3</sup></bold> and <bold>L<sup>4</sup></bold>.</p></caption><pmc-comment>OASIS TABLE HERE</pmc-comment>
<table frame="hsides" rules="groups"><colgroup><col width="1*"></col><col width="1*"></col><col width="1*"></col><col width="1*"></col><col width="1*"></col><col width="1*"></col></colgroup><thead><tr><th align="left">Compd.</th><th align="center">D–H⋅⋅⋅A</th><th align="center">d(D–H)(Å)</th><th align="center">d(H⋅⋅⋅A)(Å)</th><th align="center">d(D⋅⋅⋅A)(Å)</th><th align="center">∠DHA( ° )</th></tr></thead><tbody valign="top"><tr><td align="left"><bold>L<sup>3</sup></bold></td><td align="char" char="."><bold>C1–H1⋅⋅⋅S1</bold><sup>a</sup></td><td align="char" char=".">0.9304(62)</td><td align="char" char=".">2.8019(18)</td><td align="char" char=".">3.6459(64)</td><td align="char" char=".">151.365(379)</td></tr><tr><td align="left"><bold>L<sup>4</sup></bold></td><td align="char" char="."><bold>N1–H1⋅⋅⋅O1</bold><sup>b</sup></td><td align="char" char=".">0.8579(30)</td><td align="char" char=".">2.2648(30)</td><td align="char" char=".">3.0015(42)</td><td align="char" char=".">143.759(209)</td></tr></tbody></table><table-wrap-foot><fn id="TF1"><p>Symmetry code: <sup>a</sup><italic>x</italic>, –2 + <italic>y</italic>, <italic>z</italic>; <sup>b</sup><italic>x</italic>, –1 + <italic>y</italic>, <italic>z</italic>.</p></fn></table-wrap-foot></table-wrap><table-wrap id="t0002" orientation="portrait" position="float"><label>Table 2.</label><caption><p>Selected bond lengths (Å) and angles (deg) for <bold>L<sup>3</sup></bold> and
<bold>L<sup>4</sup></bold>.</p></caption><pmc-comment>OASIS TABLE HERE</pmc-comment>
<table frame="hsides" rules="groups"><colgroup><col width="1*"></col><col width="1*"></col><col width="1*"></col><col width="1*"></col><col width="1*"></col><col width="1*"></col></colgroup><thead><tr><th colspan="4" align="left">L<sup>3</sup></th><th colspan="2" align="center">L<sup>4</sup></th></tr></thead><tbody valign="top"><tr><td align="left">Br1 − C3</td><td align="char" char=".">1.866(7)</td><td align="char" char=".">N1–C6</td><td align="char" char=".">1.471(7)</td><td align="left">C5 − O1</td><td align="char" char=".">1.226(5)</td></tr><tr><td align="left">S1 − C4</td><td align="char" char=".">1.706(6)</td><td align="left">C4 − S1 − C3</td><td align="char" char=".">91.6(3)</td><td align="left">N1 − C5</td><td align="char" char=".">1.346(5)</td></tr><tr><td align="left">S1 − C3</td><td align="char" char=".">1.709(6)</td><td align="left">C5 − N1 − C6</td><td align="char" char=".">115.7(5)</td><td align="left">O1 − C5 − N1</td><td align="char" char=".">123.7(4)</td></tr><tr><td align="left">N1 − C5</td><td align="char" char=".">1.252(7)</td><td align="left">S1 − C3 − Br1</td><td align="char" char=".">120.1(4)</td><td align="left">C1 − S1 − C4</td><td align="char" char=".">91.3(2)</td></tr></tbody></table></table-wrap></sec><sec id="s0004"><label>2.2.</label><title>Biological evaluation</title><sec id="s0005"><label>2.2.1.</label><title>Antiproliferative activities</title><p>Compounds <bold>L<sup>1</sup></bold>−<bold>L<sup>10</sup></bold> were evaluated against
human cancer cell lines Hela, HepG2, MCF-7, A549, and the normal cell HUVEC with the
antiproliferative activities <italic>in vitro</italic> by MTT assay, and results are
summarized as IC<sub>50</sub> values in <xref rid="t0003" ref-type="table">Table
3</xref>. DMSO was used as negative control and DOX (Doxorubicin) as positive control,
which is a common chemotherapy medication used to cure cancer (Wang et al., <xref rid="CIT0054" ref-type="bibr">2004</xref>).</p><table-wrap id="t0003" orientation="portrait" position="float"><label>Table 3.</label><caption><p>Cytotoxicity of <bold>L<sup>1</sup></bold>−<bold>L<sup>10</sup></bold> and DOX
against certain axenic cancer cells and normal cell.</p></caption><pmc-comment>OASIS TABLE HERE</pmc-comment>
<table frame="hsides" rules="groups"><colgroup><col width="1*"></col><col width="1*"></col><col width="1*"></col><col width="1*"></col><col width="1*"></col><col width="1*"></col></colgroup><thead><tr><th colspan="6" align="left"><bold>IC<sub>50</sub> ± SE</bold><sup>a</sup><bold>( <italic>μ</italic>M )</bold><hr></hr></th></tr><tr><th align="left">Compd.</th><th align="center">Hela</th><th align="center">HepG2</th><th align="center">MCF-7</th><th align="center">A549</th><th align="center">HUVEC</th></tr></thead><tbody valign="top"><tr><td align="left"><bold>L<sup>0</sup></bold></td><td align="char" char="±">2.02 ± 0.02</td><td align="char" char="±">2.56 ± 0.04</td><td align="char" char="±">19.45 ± 0.39</td><td align="char" char="±">5.02 ± 0.19</td><td align="char" char="±">1.27 ± 0.03</td></tr><tr><td align="left"><bold>L<sup>1</sup></bold></td><td align="char" char="±">9.02 ± 0.25<xref ref-type="table-fn" rid="TF6">***</xref></td><td align="char" char="±">0.66 ± 0.02<xref ref-type="table-fn" rid="TF6">***</xref></td><td align="char" char="±">5.33 ± 0.16<xref ref-type="table-fn" rid="TF6">***</xref></td><td align="char" char="±">2.11 ± 0.06<xref ref-type="table-fn" rid="TF6">***</xref></td><td align="char" char="±">5.92 ± 0.17<xref ref-type="table-fn" rid="TF6">***</xref></td></tr><tr><td align="left"><bold>L<sup>2</sup></bold></td><td align="char" char="±">59.52 ± 0.27<xref ref-type="table-fn" rid="TF6">***</xref></td><td align="char" char="±">28.78 ± 0.19<xref ref-type="table-fn" rid="TF6">***</xref></td><td align="char" char="±">14.48 ± 2.48<xref ref-type="table-fn" rid="TF6">*</xref></td><td align="char" char="±">>100</td><td align="char" char="±">34.02 ± 1.57<xref ref-type="table-fn" rid="TF6">***</xref></td></tr><tr><td align="left"><bold>L<sup>3</sup></bold></td><td align="char" char="±">54.38 ± 0.38<xref ref-type="table-fn" rid="TF6">***</xref></td><td align="char" char="±">1.63 ± 0.39<xref ref-type="table-fn" rid="TF6">***</xref></td><td align="char" char="±">2.65 ± 0.07<xref ref-type="table-fn" rid="TF6">***</xref></td><td align="char" char="±">95.48 ± 2.48<xref ref-type="table-fn" rid="TF6">***</xref></td><td align="char" char="±">16.65 ± 1.08<xref ref-type="table-fn" rid="TF6">*</xref></td></tr><tr><td align="left"><bold>L<sup>4</sup></bold></td><td align="char" char="±">14.80 ± 0.22<sup>ns</sup></td><td align="char" char="±">45.99 ± 1.13<sup>ns</sup></td><td align="char" char="±">8.21 ± 0.65<xref ref-type="table-fn" rid="TF6">***</xref></td><td align="char" char="±">>100</td><td align="char" char="±">>100</td></tr><tr><td align="left"><bold>L<sup>5</sup></bold></td><td align="char" char="±">>100</td><td align="char" char="±">53.14 ± 1.95<xref ref-type="table-fn" rid="TF6">***</xref></td><td align="char" char="±">8.27 ± 0.21<xref ref-type="table-fn" rid="TF6">***</xref></td><td align="char" char="±">>100</td><td align="char" char="±">>100</td></tr><tr><td align="left"><bold>L<sup>6</sup></bold></td><td align="char" char="±">>100</td><td align="char" char="±">51.44 ± 2<xref ref-type="table-fn" rid="TF6">***</xref></td><td align="char" char="±">55.56 ± 2.56<xref ref-type="table-fn" rid="TF6">***</xref></td><td align="char" char="±">94.39 ± 2.56<xref ref-type="table-fn" rid="TF6">***</xref></td><td align="char" char="±">75.45 ± 12.44<xref ref-type="table-fn" rid="TF6">***</xref></td></tr><tr><td align="left"><bold>L<sup>7</sup></bold></td><td align="char" char="±">43.53 ± 1.34<xref ref-type="table-fn" rid="TF6">***</xref></td><td align="char" char="±">24.01 ± 1.33<xref ref-type="table-fn" rid="TF6">***</xref></td><td align="char" char="±">11.82 ± 0.54<xref ref-type="table-fn" rid="TF6">**</xref></td><td align="char" char="±">83.60 ± 15.65<xref ref-type="table-fn" rid="TF6">***</xref></td><td align="char" char="±">66.77 ± 2.60<xref ref-type="table-fn" rid="TF6">***</xref></td></tr><tr><td align="left"><bold>L<sup>8</sup></bold></td><td align="char" char="±">20.22 ± 0.89<xref ref-type="table-fn" rid="TF6">**</xref></td><td align="char" char="±">17.06 ± 0.07<xref ref-type="table-fn" rid="TF6">**</xref></td><td align="char" char="±">8.81 ± 0.54<xref ref-type="table-fn" rid="TF6">***</xref></td><td align="char" char="±">36.02 ± 2.18<xref ref-type="table-fn" rid="TF6">**</xref></td><td align="char" char="±">95.11 ± 0.97<xref ref-type="table-fn" rid="TF6">***</xref></td></tr><tr><td align="left"><bold>L<sup>9</sup></bold></td><td align="char" char="±">52.46 ± 0.54<xref ref-type="table-fn" rid="TF6">***</xref></td><td align="char" char="±">44.94 ± 0.75<xref ref-type="table-fn" rid="TF6">***</xref></td><td align="char" char="±">6.66 ± 0.24<xref ref-type="table-fn" rid="TF6">***</xref></td><td align="char" char="±">>100</td><td align="char" char="±">18.91 ± 1.72<xref ref-type="table-fn" rid="TF6">**</xref></td></tr><tr><td align="left"><bold>L<sup>10</sup></bold></td><td align="char" char="±">>100</td><td align="char" char="±">56.08 ± 6.11<xref ref-type="table-fn" rid="TF6">***</xref></td><td align="char" char="±">88.81 ± 3.46<xref ref-type="table-fn" rid="TF6">***</xref></td><td align="char" char="±">39.63 ± 1.74<xref ref-type="table-fn" rid="TF6">**</xref></td><td align="char" char="±">29.38 ± 2.35<xref ref-type="table-fn" rid="TF6">***</xref></td></tr><tr><td align="left"><bold>DOX</bold></td><td align="char" char="±">3.55 ± 0.17<sup>ns</sup></td><td align="char" char="±">1.20 ± 0.04<sup>ns</sup></td><td align="char" char="±">14 ± 1.03<xref ref-type="table-fn" rid="TF6">*</xref></td><td align="char" char="±">3.35 ± 0.69<sup>ns</sup></td><td align="char" char="±">4.40 ± 0.55***</td></tr></tbody></table><table-wrap-foot><fn id="TF2"><p>ns: not significant, complexes compared with <bold>L<sup>0</sup></bold>,
respectively.</p></fn><fn id="TF3"><p><sup>a</sup>Average IC<sub>50</sub> values from at least three independent
experiments.</p></fn><fn id="TF4"><p>***<italic>p</italic> < .001.</p></fn><fn id="TF5"><p>**<italic>p</italic> < .01.</p></fn><fn id="TF6"><p>*<italic>p</italic> < .05.</p></fn></table-wrap-foot></table-wrap><p>A histogram was drawn more distinctly to compare the antiproliferative activity of
<bold>L<sup>0</sup>−L<sup>10</sup></bold> against axenic cancer cells and
cytotoxicity based on IC<sub>50</sub> values (<xref rid="t0003" ref-type="table">Table
3</xref>). We used DOX as positive control, <bold>L<sup>0</sup></bold> also as control
to compare the antiproliferative activity among its modified products for the reasoned
that the antiproliferative activity of <bold>L<sup>0</sup></bold> was slightly lower
than DOX (except Hela cells), whereas that was better than a variety of pharmaceutical
products. The values of <italic>p</italic> > 0.05 were considered that the
antiproliferative activity of <bold>L<sup>0</sup></bold> and DOX in statistics
difference were insignificant, except for MCF-7 cells. The result is shown in <xref ref-type="fig" rid="F0003">Figure 3</xref>.</p><fig id="F0003" orientation="portrait" position="float"><label>Figure 3.</label><caption><p>The comparison of antiproliferative effects and cytotoxicity of DOX,
<bold>L<sup>0</sup></bold>−<bold>L<sup>10</sup></bold>.</p></caption><graphic content-type="color" xlink:href="IDRD_A_1716879_F0003_C"></graphic></fig><p>From <xref ref-type="fig" rid="F0003">Figure 3</xref>, the result showed quite clearly
that <bold>L<sup>1</sup></bold> and <bold>L<sup>3</sup></bold> had higher
antiproliferative activity against HepG2 cells while <bold>L<sup>2</sup></bold> had
higher antiproliferative activity against A549 cells.
<bold>L<sup>1</sup></bold>−<bold>L<sup>10</sup></bold> were low toxic as their
toxicity (IC<sub>50</sub> = 5.92− >100 μM) was all lower than
<bold>L<sup>0</sup></bold> (1.27 μM) and DOX (4.40 μM) for HUVEC cells. For further
observation, for HepG2 cells, the IC<sub>50</sub> values of <bold>L<sup>1</sup></bold>(0.66 μM) and <bold>L<sup>3</sup></bold> (1.63 μM) were much smaller than those of
<bold>L<sup>0</sup></bold>. Moreover, with average IC<sub>50</sub> values of 0.66
and 5.92 μM, <bold>L<sup>1</sup></bold> was nine times more effective at suppressing
cultured HepG2 cells viability than normal cells, and <bold>L<sup>3</sup></bold> as well
with average IC<sub>50</sub> values of 1.63 and 16.65 μM. For MCF-7 cells, most
compounds had higher anti-MCF-7 activity than both <bold>L<sup>0</sup></bold> and DOX
with their smaller IC<sub>50</sub> value compared to <bold>L<sup>0</sup></bold>(excluding <bold>L<sup>6</sup></bold> and <bold>L<sup>10</sup></bold>), particularly,
<bold>L<sup>1</sup></bold> (5.33 μM) and <bold>L<sup>3</sup></bold> (2.65 μM). For
A549 cells, the IC<sub>50</sub> value of <bold>L<sup>1</sup></bold> (2.11 μM) was
smaller than <bold>L<sup>0</sup></bold>, which meant <bold>L<sup>1</sup></bold> had
higher anti-A549 activity than <bold>L<sup>0</sup></bold>; in especial, the
IC<sub>50</sub> value of <bold>L<sup>1</sup></bold> was smaller than DOX. The security
index (SI) value of <bold>L<sup>1</sup></bold> is 9.0 and <bold>L<sup>3</sup></bold> is
10.2, which suggested they had higher anticancer activity and lower toxicity compared
with L<bold><sup>0</sup>（</bold>0.5）and DOX (3.7). Actually, among these investigated
compounds, <bold>L<sup>1</sup></bold> had the smallest IC<sub>50</sub> value of 0.66 μM
against HepG2 cells and lower toxicity, which shows that <bold>L<sup>1</sup></bold> may
be a promising anticancer drug.</p><p>Furthermore, by contrast with the structure and cytotoxicity <italic>in vitro</italic>on the cancer cell lines of <bold>L<sup>1</sup>−L<sup>10</sup></bold>, compounds
owned − CH<sub>3</sub> electron-donating group (<bold>L<sup>2</sup></bold>,
<bold>L<sup>5</sup></bold>, <bold>L<sup>9</sup></bold>) had relatively lower
antiproliferative activity than those without electron-donating group
(<bold>L<sup>1</sup></bold>, <bold>L<sup>4</sup></bold>,
<bold>L<sup>7</sup></bold>). As reported by Hande, introduction of a polar group
containing a hydrogen-bond donor resulted to enhanced anticancer activity (Hande, <xref rid="CIT0015" ref-type="bibr">1998</xref>). Although the correspondingly better
solubility of Schiff-bases and the special structure of Schiff-base (−CH = N−), which
can conjugate with the thiophene ring and grant it with higher stability and
bioactivity, these Schiff-base compounds
(<bold>L<sup>1</sup></bold>−<bold>L<sup>3</sup></bold>) had higher antiproliferative
activity against HepG2 and MCF-7 cells. As a whole, all these synthetic compounds could
inhibit the proliferation of cancer cells by penetrating into cytoplasm with
endocytosis, we reasoned that the strong chelating ability of ‘S’ and ‘N’ may lead to
the easy formation of hydrogen bonds with carboxyl and amino groups in the cancer cell
lines through their unique lone pair electrons.</p></sec><sec id="s0006"><label>2.2.2.</label><title>Induction of apoptosis</title><p>As a routine chemotherapeutic agent for a broad range of malignancies, DOX can prevent
tumor proliferation via inducing apoptosis. Apoptosis, known as programed cell death, is
a crucial process related to the regulation of development and homeostasis (Arjmand
& Aziz, <xref rid="CIT0003" ref-type="bibr">2009</xref>; Qi et al., <xref rid="CIT0041" ref-type="bibr">2019</xref>). It plays an important role in cancer, as
its induction in cancer cells is significant to a successful therapy, thereby carrying
out apoptosis assay can afford meaningful information to the study of the mode of
action. In this paper, we have estimated the potential mechanism of cell proliferation
inhibitory activity of <bold>L<sup>1</sup></bold> and <bold>L<sup>3</sup></bold> through
the assay apoptosis with Annexin V-FITC/PI and flow cytometry in HepG2 cells. The
flow-cytometric analysis is shown in <xref ref-type="fig" rid="F0004">Figure
4</xref>.</p><fig id="F0004" orientation="portrait" position="float"><label>Figure 4.</label><caption><p>Apoptosis assay of HepG2 cells treated with <bold>L<sup>1</sup></bold> and
<bold>L<sup>3</sup></bold>. C was DMSO (negative control), others were
<bold>L<sup>1</sup></bold> at 0.26, 2.6, 13 μM, and <bold>L<sup>3</sup></bold>at 0.22, 2.2, 11 μM, respectively.</p></caption><graphic content-type="color" xlink:href="IDRD_A_1716879_F0004_C"></graphic></fig><p>According to <xref ref-type="fig" rid="F0004">Figure 4</xref>, after
<bold>L<sup>1</sup></bold> and <bold>L<sup>3</sup></bold> incubated with HepG2 cells
with the concentration range from 0.22 to 13 μM, respectively, live cells reduced and
apoptotic cells increased; herein, they obviously exhibited the dosage-dependent manner.
When the concentrations of <bold>L<sup>1</sup></bold> were 0.26, 2.6, and 13 μM, the
apoptotic ratios of <bold>L<sup>1</sup></bold> were 12.67%, 36.76%, and 80.60%,
respectively. Simultaneously, when the concentrations of <bold>L<sup>1</sup></bold> were
0.22, 2.2, and 11 μM, the apoptotic ratios of <bold>L<sup>3</sup></bold> were 8.55%,
12.97%, and 39.21%, respectively. Compared to the apoptotic ratio of these two
compounds, <bold>L<sup>1</sup></bold>had obviously higher ability to induce apoptosis at the similar concentration.
During the induction of apoptosis process, live cells trend to develop toward apoptotic
cells with the enhanced concentration. Herein the reported results distinctly
illustrated that <bold>L<sup>1</sup></bold> and <bold>L<sup>3</sup></bold>could inhibit cell proliferation by inducing apoptosis.</p><p>For further investigation, the logP values of all compounds were calculated by
hyperchem 8.0 (<xref rid="t0004" ref-type="table">Table 4</xref>). Compared with DOX
(1.50), the values of logP of <bold>L<sup>1</sup></bold> (0.98),
<bold>L<sup>2</sup></bold> (1.17) and <bold>L<sup>3</sup></bold> (1.32) were smaller
with stronger hydrophily, which implied they had better solubility and may be in favor
of excellent cytotoxic activities. According to a report, the ideal drug potency and
satisfied pharmacokinetic profiles required good water solubility to achieve the desired
therapeutic efficacy (Li et al., <xref rid="CIT0027" ref-type="bibr">2014</xref>). Any
drug to be absorbed should exist in the form of solution at the site of absorption
(Muhammad & Bashir, <xref rid="CIT0038" ref-type="bibr">2017</xref>). The value of
logP of <bold>L<sup>4</sup></bold>−<bold>L<sup>10</sup></bold> (>3) was larger, which
suggested they had stronger lipophicity and its slightly poor solubility might lead to
relatively worse effects on cancer cells. All compounds herein had been next examined
with p<italic>K</italic><sub>b</sub> in the range of 9.00–14.96; thus, they seemed no
regular effect on cytotoxic activities.</p><table-wrap id="t0004" orientation="portrait" position="float"><label>Table 4.</label><caption><p>Physicochemical data (logP and p<italic>K</italic><sub>b</sub>) of
<bold>L<sup>1</sup>−L<sup>10</sup></bold>, DOX.</p></caption><pmc-comment>OASIS TABLE HERE</pmc-comment>
<table frame="hsides" rules="groups"><colgroup><col width="1*"></col><col width="1*"></col><col width="1*"></col><col width="1*"></col><col width="1*"></col><col width="1*"></col><col width="1*"></col><col width="1*"></col><col width="1*"></col><col width="1*"></col><col width="1*"></col><col width="1*"></col><col width="1*"></col></colgroup><thead><tr><th align="left">Compd.</th><th align="center"><bold>L<sup>0</sup></bold></th><th align="center"><bold>L<sup>1</sup></bold></th><th align="center"><bold>L<sup>2</sup></bold></th><th align="center"><bold>L<sup>3</sup></bold></th><th align="center"><bold>L<sup>4</sup></bold></th><th align="center"><bold>L<sup>5</sup></bold></th><th align="center"><bold>L<sup>6</sup></bold></th><th align="center"><bold>L<sup>7</sup></bold></th><th align="center"><bold>L<sup>8</sup></bold></th><th align="center"><bold>L<sup>9</sup></bold></th><th align="center"><bold>L<sup>10</sup></bold></th><th align="center"><bold>DOX</bold></th></tr></thead><tbody valign="top"><tr><td align="left"><bold>logP</bold></td><td align="char" char=".">0.40</td><td align="char" char=".">0.98</td><td align="char" char=".">1.17</td><td align="char" char=".">1.32</td><td align="char" char=".">3.46</td><td align="char" char=".">3.48</td><td align="char" char=".">4.90</td><td align="char" char=".">3.65</td><td align="char" char=".">4.35</td><td align="char" char=".">3.68</td><td align="char" char=".">4.79</td><td align="char" char=".">1.50</td></tr><tr><td align="left"><bold>p<italic>K</italic><sub>b</sub></bold></td><td align="char" char=".">7.00</td><td align="char" char=".">9.00</td><td align="char" char=".">10.18</td><td align="char" char=".">9.90</td><td align="char" char=".">14.30</td><td align="char" char=".">14.16</td><td align="char" char=".">14.96</td><td align="char" char=".">11.12</td><td align="char" char=".">10.36</td><td align="char" char=".">13.38</td><td align="char" char=".">11.50</td><td align="char" char=".">5.80</td></tr></tbody></table></table-wrap></sec><sec id="s0007"><label>2.2.3.</label><title>DNA binding modes</title><p>Intercalation is well known to strongly influence the properties of the DNA and has
been reported as a preliminary step in mutagenesis. It was reported that DOX had the
ability to remain inside nucleated cells because of its lipophilic characteristics and
DNA intercalating or binding properties (Arjmand & Aziz, <xref rid="CIT0003" ref-type="bibr">2009</xref>; Sun et al., <xref rid="CIT0051" ref-type="bibr">2019</xref>). We further investigated whether <bold>L<sup>1</sup></bold> and
<bold>L<sup>3</sup></bold> had similar activity to DOX; herein we studied DNA
binding properties of them. The DNA (Salmon Sperm DNA) binding modes were evaluated by
ethidium bromide (EB) fluorescence displacement experiments. Actually, EB had no
perceptible emission in buffer solution; after adding DNA, the fluorescence intensity
improved obviously, which was considered of its strongly intercalation with DNA base
pairs. The intercalation of the compound with the base pairs of DNA can be confirmed
when the DNA − EB emission can be decreased or quenched upon adding a compound (Li
et al., <xref rid="CIT0028" ref-type="bibr">1996</xref>; Gao et al., <xref rid="CIT0011" ref-type="bibr">2010</xref>). As expected, the emission intensity
apparently reduced (shown in <xref ref-type="fig" rid="F0005">Figure 5</xref>) by adding
<bold>L<sup>1</sup></bold> and <bold>L<sup>3</sup></bold> to DNA-EB, which exhibits
that <bold>L<sup>1</sup></bold> and <bold>L<sup>3</sup></bold> can bind to DNA at the
sites occupied by EB, and it can interact with DNA by intercalation.</p><fig id="F0005" orientation="portrait" position="float"><label>Figure 5.</label><caption><p>Emission spectra of DNA − EB in the absence and presence of increasing amounts of
<bold>L<sup>1</sup></bold> and <bold>L<sup>3</sup></bold> at room temperature,
respectively ([EB] = 2 × 10<sup>−5</sup> M, [DNA] = 1 × 10<sup>−4</sup> M, and
[<bold>L<sup>1</sup></bold>,
<bold>L<sup>3</sup></bold>] = 1.5 × 10<sup>−5 </sup>M).</p></caption><graphic content-type="color" xlink:href="IDRD_A_1716879_F0005_C"></graphic></fig><p>The DNA binding modes of <bold>L<sup>1</sup></bold> and <bold>L<sup>3</sup></bold> were
detected by the application of Absorption Spectral as well (shown in <xref ref-type="fig" rid="F0006">Figure 6</xref>). Normally, a compound binding to DNA can
generate hypochromism and bathochromism by intercalation. The absorption spectra
exhibited a hypochromic shift after promoting added amounts of DNA to solution of
<bold>L<sup>3</sup></bold>, which illustrated an intercalative binding mode. The
result was in coincidence with that of fluorescence studies. To sum up, the absorption
and fluorescence spectral all verified that <bold>L<sup>1</sup></bold> and
<bold>L<sup>3</sup></bold> with the same as DOX could bind with DNA through
intercalation.</p><fig id="F0006" orientation="portrait" position="float"><label>Figure 6.</label><caption><p>Absorption spectra of <bold>L<sup>1</sup></bold> and <bold>L<sup>3</sup></bold>(5 × 10<sup>−5 </sup>M) in the absence and presence of increasing amounts of DNA
(5 × 10<sup>−5 </sup>M to 10<sup>−3</sup> M) at room temperature in Tris-NaCl-HCl
buffer (pH = 7.3). The arrow shows the absorbance change when increasing the DNA
concentration.</p></caption><graphic content-type="color" xlink:href="IDRD_A_1716879_F0006_C"></graphic></fig><p>In view of aforementioned findings, these synthetic dehydroabietylamine derivatives had
relatively high potential antiproliferative activity and low toxicity, some of them also
could induce apoptosis at low concentration. Moreover, to understand the cytotoxicity
and the DNA binding modes was significative for designing new and potential drugs.</p></sec><sec id="s0008"><label>2.2.4.</label><title>Antiproliferation activity in vivo</title><p>Herein, we have intravenously injected compound <bold>L<sup>1</sup></bold>(dose:
0.6 mg/kg) into the mice with HepG2 cells during 25 days with every 3 days
<italic>in vivo</italic> experiment for further investigation.</p><p>As shown in <xref ref-type="fig" rid="F0007">Figure 7(a–f)</xref>, it is obvious that
the volume and weight of tumor mice were decreased after injected with compound
<bold>L<sup>1</sup></bold> (0.6 mg/kg) as compared with PBS control. The average
volume of tumor (HepG2) was 0.739 cm<sup>3</sup> when the PBS control was
1.876 cm<sup>3</sup>. In addition, the weight of tumor was 0.84 g compared with PBS
control was 2.16 g. The relative tumor proliferation rate (T/C) was 38.6% and the tumor
inhibition rate was up to 61.2%. Moreover, no obvious toxicity was also observed in the
heart, liver, spleen, lung, kidney, and brain tissues of the mice injected with compound
<bold>L<sup>1</sup></bold> in <xref ref-type="fig" rid="F0007">Figure 7(f)</xref>,
which exhibited no significant changes in morphology of these organs. In <xref ref-type="fig" rid="F0007">Figure 7(g)</xref>, CD31 immumohistochemical staining with
mice was taken on the 25th day after an intravenous injection of compound
<bold>L<sup>1</sup></bold> (0.6 mg/kg) showed tumor angiogenesis rate was decreased
compared with PBS control, which demonstrated compound <bold>L<sup>1</sup></bold> could
suppress tumor growth. In general, these findings suggested that
<bold>L<sup>1</sup></bold> had high anti-HepG2 activity both <italic>in vitro</italic>and <italic>in vivo</italic>, and <bold>L<sup>1</sup></bold> had great promising future
as nontoxic side effects and effective antiproliferation drug.</p><fig id="F0007" orientation="portrait" position="float"><label>Figure 7.</label><caption><p>(a) Whole appearance and (b) the volume of tumor mice injected with PBS (control)
and compound <bold>L<sup>1</sup></bold> after 25 days. (c) Change in tumor volume of
mice injected with compound <bold>L<sup>1</sup></bold> (0.6 mg/kg) compared with PBS
control. (d) Change in body weight of mice injected with compound
<bold>L<sup>1</sup></bold> (0.6 mg/kg) and PBS. (e) The tumor weight of mice
injected with compound <bold>L<sup>1</sup></bold> (0.6 mg/kg) and PBS control after
25 days. (f) H&E staining of the brain, heart, liver, spleen, lung, and kidney
tissues collected from mice on the 25th day after an intravenous injection of
compound <bold>L<sup>1</sup></bold> (0.6 mg/kg) and PBS control. (g) CD31
immumohistochemical staining with mice on the 25th day after an intravenous
injection of compound <bold>L<sup>1</sup></bold> (0.6 mg/kg) and PBS control. Scale
bar = 20 μm; error bars are based on standard errors of the mean
(<italic>n</italic> = 5).</p></caption><graphic content-type="color" xlink:href="IDRD_A_1716879_F0007_C"></graphic></fig></sec></sec></sec><sec id="s0009"><label>3.</label><title>Conclusions</title><p>In conclusion, our formulation has shown thiophene Schiff-bases
(<bold>L<sup>1</sup></bold>−<bold>L<sup>3</sup></bold>), thiophene amides
(<bold>L<sup>4</sup></bold>−<bold>L<sup>6</sup></bold>) and pyrazine amides
(<bold>L<sup>7</sup></bold>−<bold>L<sup>10</sup></bold>) with high antiproliferative
activity, relatively low toxicity and DNA binding modes. The toxicity of
<bold>L<sup>1</sup></bold>−<bold>L<sup>10</sup></bold>(IC<sub>50</sub> = 5.92− >100 μM) was all lower than <bold>L<sup>0</sup></bold>(1.27 μM) and DOX (4.40 μM). Compound <bold>L<sup>1</sup></bold> had higher anti-HepG2
<bold>(</bold>0.66 μM), anti-MCF-7 (5.33 μM) and anti-A549 (2.11 μM) activity. Compound
<bold>L<sup>3</sup></bold> had higher anti-HepG2 (1.63 μM) and anti-MCF-7 (2.65 μM)
activity. Additionally, <bold>L<sup>1</sup></bold> and <bold>L<sup>3</sup></bold> were
verified with high efficiency apoptosis induction in HepG2 cells and intercalated modes of
binding with DNA. <bold>L<sup>1</sup></bold> had no significant toxicity but high anti-HepG2
activity both <italic>in vitro</italic> and <italic>in vivo</italic>; it may be an effective
antiproliferation drug with nontoxic side effects.</p><p>These findings can provide a convenient procedure of the rational design in new and
potential cellular targeting compounds, which may help to explore the future selective
anticancer drugs directly toward cellular targets. However, the possible cellular and
structural mechanisms are still unclear and its investigation is currently ongoing.</p></sec><sec id="s0010"><label>4.</label><title>Experimental section</title><sec id="s0011"><label>4.1.</label><title>General experimental procedures</title><p>All reagents and solvents were analytical reagent (AR) grade and used as received unless
otherwise indicated. The IR spectra were recorded on a Bruker Vectex 80 FT − IR
spectrometer with KBr discs in the 4000–500 cm<sup>−1</sup> range. The <sup>1 </sup>H NMR
spectra were measured on a Bruker Avance III 600 MHz NMR spectrometer (Billerica, MA,
USA). <sup>1 </sup>H and <sup>13 </sup>C {<sup>1 </sup>H} NMR spectra were recorded in
CDCl<sub>3</sub> as solvent unless otherwise stated. Chemical shifts
(<italic>δ</italic>) were given as parts per million (ppm) relative to the NMR solvent
signals (CDCl<sub>3</sub> 7.26 and 77.00 ppm for <sup>1 </sup>H and
<sup>13 </sup>C{<sup>1</sup>H} NMR, respectively). <italic>J</italic> values were given
in Hz. HRMS were measured to determine purity of all tested compounds by LTQ Orbitrap XL
mass spectrometer (Thermo Electron, USA). Reactions were monitored by TLC using silica gel
60 F–254 in 0.25 mm thick plates. Compounds on TLC plates were detected under UV light at
254 nm. Purifications were performed by flash chromatography on silica gel (300–400 mesh).
The DNA binding modes were investigated by Lambda 950 (Perkin Elmer, USA) and LS55
Fluorescence Spectrophotometer (Perkin Elmer, USA).</p></sec><sec id="s0012"><label>4.2.</label><title>Synthesis of compound L<sup>1</sup>−L<sup>10</sup></title><p>Thiophene Schiff-bases (<bold>L<sup>1</sup></bold>−<bold>L<sup>3</sup></bold>), thiophene
amides (<bold>L<sup>4</sup></bold>−<bold>L<sup>6</sup></bold>), and pyrazine amides
(<bold>L<sup>7</sup></bold>−<bold>L<sup>10</sup></bold>) were synthesized by the
following methods.</p><sec id="s0013"><label>4.2.1.</label><title>Synthesis of 2-thiophene-dehydroabietylamine-Schiff-base (L<sup>1</sup>)</title><p><bold>L<sup>0</sup></bold> (1.43 g, 5.0 mmol), 2-thiopehne-formaldehyde (0.56 g
5.0 mmol) with acetic acid as the catalyst was dissolved in ethanol (50 mL) and refluxed
for 24 h. When reaction mixture was cooled to the room temperature, lots of white
needlelike crystal precipitation appeared. Then white needlelike crystals were obtained
by recrystallization from ethanol solution. (1.58 g, 83%), mp: 83.6-85.4 °C; IR (neat)
<italic>ν</italic><sub>max</sub>/cm<sup>−1</sup> 3423, 2929, 2861, 1649, 1598, 1450,
1375, 1036, 977, 747, 637; <sup>1 </sup>H-NMR (CDCl<sub>3</sub>, 600 MHz)
<italic>δ</italic> 1.04 (3 H, s), 1.21-1.23 (9 H, t, <italic>J</italic> = 7.2 Hz),
1.30-1.50 (3 H, m), 1.60-1.66 (2 H, m), 1.71–1.79 (2 H, m), 1.88–1.90 (1 H, m),
2.24–2.26 (1 H, d, <italic>J</italic> = 12 Hz); 2.79–2.81 (2 H, m), 2.81–2.86 (1 H, m),
3.40 (2 H, m), 6.86 (1 H, s), 6.98 (1 H, d, <italic>J</italic> = 7.8 Hz), 7.02 (1 H, dd,
<italic>J</italic> = 3.6 Hz), 7.17 (1 H, d, <italic>J</italic> = 8.4 Hz), 7.25 (1 H,
d, <italic>J</italic> = 3.0 Hz), 7.31–7.32 (1 H, m), 8.30 (1 H, s);
<sup>13 </sup>C{<sup>1</sup>H} (CDCl<sub>3</sub>, 151 MHz) <italic>δ</italic> 18.95,
19.45, 24.04, 24.05, 25.72, 30.58, 33.46, 36.72, 37.73, 38.27, 38.48, 46.11, 123.83,
124.48, 126.88, 127.26, 128.52, 129.70, 135.01, 143.02, 145.39, 147.51, 153.95; MS
[M + H]<sup>+</sup><italic>m/z</italic> 380.2419 (calcd for C<sub>25</sub>H<sub>33</sub>NS 379.2334). Anal.
calcd for C<sub>25</sub>H<sub>33</sub>NS: C, 79.10; H, 8.76; N, 3.69; S, 8.45. Found: C,
79.21; H, 8.62; N, 3.81; S, 8.36.</p></sec><sec id="s0014"><label>4.2.2.</label><title>Synthesis of 3-methyl-2-thiophene-dehydroabietylamine-Schiff-base
(L<sup>2</sup>)</title><p>When the mixture was cooled to the room temperature, removed the solvent by reduced
pressure distillation, and received the brown oil compound. Finally, the brown products
were obtained by recrystallization from methanol solution and dried in vacuum. (1.34 g,
68%), mp: 38.2–39.1 °C; IR (neat) <italic>ν</italic><sub>max</sub>/cm<sup>−1</sup> 3428,
2929, 2868, 1629, 1447, 1378, 1207, 1050, 825, 716, 620; <sup>1 </sup>H–NMR
(CDCl<sub>3</sub>, 600 MHz) <italic>δ</italic> 1.02 (3 H, s), 1.21–1.24 (9 H, t,
<italic>J</italic> = 7.2 Hz), 1.38–1.52 (3 H, m), 1.60–1.66 (2 H, m), 1.69–1.80 (2 H,
m), 1.91–1.95 (1 H, m), 2.25–2.27 (1 H, d, <italic>J</italic> = 11.4 Hz), 2.37(3 H, s),
2.80–2.87 (3 H, m), 3.41 (2 H, m), 6.83 (1 H, s), 6.98 (1 H, d,
<italic>J</italic> = 7.2 Hz), 7.17 (1 H, dd, <italic>J</italic> = 8.4 Hz), 7.22 (1 H, d,
<italic>J</italic> = 4.8 Hz), 7.24–7.25 (1 H, m), 8.36 (1 H, s);
<sup>13 </sup>C{<sup>1</sup>H} ((CD<sub>3</sub>)<sub>2</sub>SO, 151 MHz)
<italic>δ</italic> 15.79, 18.50, 18.69, 24.37, 24.45, 25.45, 29.46, 33.38, 35.02,
36.08, 37.40, 38.01, 40.41, 44.88, 50.04, 123.96, 124.36, 126.03, 126.81, 129.54,
134.89, 141.97, 142.87, 145.45, 147.28, 165.57; MS [M + H]<sup>+</sup><italic>m/z</italic> 394.5419 (calcd for C<sub>26</sub>H<sub>35</sub>NS 393.2490). Anal.
calcd for C<sub>26</sub>H<sub>35</sub>NS: C, 79.33; H, 8.96; N, 3.56; S, 8.15. Found: C,
79.02; H, 8.69; N, 3.75; S, 8.54.</p></sec><sec id="s0015"><label>4.2.3.</label><title>Synthesis of 5-bromine-2-thiophene-dehydroabietylamine-Schiff-base
(L<sup>3</sup>)</title><p>After the reaction mixture cooling to the room temperature, lots of pale yellow
needlelike crystal precipitation appeared. Then faint yellow block-shaped single
crystals were obtained by recrystallization from ethanol solution. (1.99 g, 87%), mp:
132.9–134.3 °C; IR (neat) <italic>ν</italic><sub>max</sub>/cm<sup>−1</sup> 3394, 2977,
2922, 1630, 1427, 1378, 1085, 1044, 879, 797, 620; <sup>1 </sup>H–NMR (CDCl<sub>3</sub>,
600 MHz) <italic>δ</italic> 1.04 (3 H, s), 1.21–1.23 (9 H, t,
<italic>J</italic> = 7.2 Hz), 1.30–1.50 (3 H, m), 1.60–1.66 (2 H, m), 1.71–1.79 (2 H,
m),1.88–1.90 (1 H, m), 2.24–2.26 (1 H, d, <italic>J</italic> = 12 Hz); 2.79–2.81 (2 H,
m), 2.81–2.86 (1 H, m), 3.40 (2 H, dd, <italic>J</italic> = 12 Hz), 6.89 (1 H, s),
6.99–7.01 (3 H, m), 7.19–7.20 (1 H, d, <italic>J</italic> = 8.4 Hz), 8.19 (1 H, s);
<sup>13 </sup>C{<sup>1</sup>H} (CDCl<sub>3</sub>, 151 MHz) <italic>δ</italic> 18.92,
18.95, 19.40, 24.00, 25.63, 30.54, 33.45, 36.74, 37.70, 38.24, 38.49, 46.15, 72.94,
116.61, 123.83, 124.43, 126.86, 129.52, 130.19, 134.89, 144.72, 145.39, 147.42, 153.02;
MS [M + H]<sup>+</sup><italic>m/z</italic> 458.1526 (calcd for C<sub>25</sub>H<sub>32</sub>BrNS 457.1439).
Anal. calcd for C<sub>25</sub>H<sub>32</sub>BrNS: C, 65.49; H, 7.03; N, 3.05; S, 6.99.
Found: C, 65.34; H, 7.12; N, 3.11; S, 6.90.</p></sec><sec id="s0016"><label>4.2.4.</label><title>Synthesis of 2–thiophene-acyl-dehydroabietylamine (L<sup>4</sup>)</title><p>Equal 2-thiophene-carboxylic acid (0.64 g, 5.0 mmol) and HOBT (0.68 g, 5.0 mmol) were
dissolved in ethyl acetate (40 mL), stirred for 0.5 h at 0 °C. Then DCC (1.03 g,
5.0 mmol) was slowly added, stirred for 2.5 h at 0 °C. The ethyl acetate solution
(10 mL) of <bold>L<sup>0</sup></bold> (1.43 g, 5.0 mmol) was added to the reaction
system slowly, the mixture was stirred at room temperature for 8 h. Filter to remove
DCU, filtrate was diluted to 200 mL and washed with 5% NaHCO<sub>3</sub> (3*20 mL), 10%
citric acid (2*20 mL) and saturated salt water. Ethyl acetate layer was dried with
anhydrous Na<sub>2</sub>SO<sub>4</sub> for 2 h, and solvents were evaporated to get
milky white powders. Then colorless block-shaped single crystals were obtained by
recrystallization from ethanol solution. (1.74 g, 88%), mp: 153.7–156.0 °C; IR (neat)
<italic>ν</italic><sub>max</sub>/cm<sup>−1</sup> 3428, 2922, 2860, 1638, 1561, 1439,
1371, 1044, 976, 771, 606; <sup>1 </sup>H NMR (CDCl<sub>3</sub>, 600 MHz):
<italic>δ</italic> 1.05 (3 H, s), 1.21–1.24 (9 H, s), 1.38–1.44 (2 H, m), 1.56–1.57
(1 H, m), 1.60–1.67 (2 H, m), 1.71–1.81 (2 H, m), 1.89–1.92 (1 H, m), 2.25–2.30 (1 H,
m), 2.76–2.91 (3 H, m), 3.42–3.61 (2 H, dd, <italic>J</italic> = 12 Hz), 6.87 (1 H, s),
6.98 (1 H, dd, <italic>J</italic> = 7.2 Hz), 7.14 (1 H, d, <italic>J</italic> = 7.2 Hz),
7.18 (1 H, d, <italic>J</italic> = 8.4 Hz), 7.29–7.30 (1 H, m), 7.69–7.72 (1 H, m),
8.01–8.05 (1 H, m), 8.34 (1 H, s), 8.61(1 H, d, <italic>J</italic> = 3.6 Hz);
<sup>13 </sup>C{<sup>1</sup>H} NMR (CDCl<sub>3</sub>, 151 MHz): <italic>δ</italic>18.76, 18.90, 19.64, 23.96, 25.64, 30.48, 33.40, 36.60, 37.66, 38.20, 38.42, 45.63,
58.45, 72.91, 121.16, 123.80, 124.41, 124.61, 126.87, 135.00, 136.55, 145.39, 147.47,
149.18, 154.68, 161.83; MS [M + H]<sup>+</sup><italic>m/z</italic> 375.2800 (calcd for C<sub>26</sub>H<sub>34</sub>N<sub>2</sub>374.2722). Anal. calcd for C<sub>26</sub>H<sub>34</sub>N<sub>2</sub>: C, 83.37; H, 9.15;
N, 7.48. Found: C, 83.43; H, 9.28; N, 7.29.</p></sec><sec id="s0017"><label>4.2.5.</label><title>Synthesis of 5-methyl-2-thiophene-acyl-dehydroabietylamine (L<sup>5</sup>)</title><p>The condensation reaction used HOBT and DCC like the method of
<bold>L<sup>4</sup></bold>. The solution was dried with anhydrous
Na<sub>2</sub>SO<sub>4</sub> and evaporated to get milky white powders. (1.72 g, 84%),
mp: 169.4–171.7 °C; IR (neat) <italic>ν</italic><sub>max</sub>/cm<sup>−1</sup> 3413,
2922, 2854, 1629, 1553, 1453, 1290, 1050, 1046, 811, 743, 606; <sup>1 </sup>H–NMR
((CD<sub>3</sub>)<sub>2</sub>SO, 600 MHz) <italic>δ</italic> 0.90 (3 H, s), 1.13–1.15
(9 H, t, <italic>J</italic> = 7.2 Hz), 1.32–1.36(2H, m), 1.43–1.45 (1 H, m),
1.56–1.61(2H, m), 1.69–1.71 (2 H, m), 1.96–1.99 (1 H, m), 2.24 (1 H, d,
<italic>J</italic> = 12.6 Hz), 2.42–2.44 (3 H, s), 2.73–2.78 (3 H, m), 2.90–3.40 (2 H,
dd, <italic>J</italic> = 7.2 Hz), 6.77 (1 H, s), 6.82 (1 H, d,
<italic>J</italic> = 1.8 Hz), 6.92 (1 H, dd, <italic>J</italic> = 8.4 Hz), 7.12 (1 H, d,
<italic>J</italic> = 8.4 Hz), 7.60 (1 H, d, <italic>J</italic> = 3.6 Hz), 8.09 (1 H,
s, –NH); <sup>13 </sup>C{<sup>1</sup>H} NMR ((CD<sub>3</sub>)<sub>2</sub>SO, 151 MHz)
<italic>δ</italic> 15.61, 18.74, 19.13, 19.30, 24.35, 24.40, 25.82, 30.37, 33.35,
36.35, 37.48, 38.32, 45.04, 49.72, 123.93, 124.46, 126.64, 126.88, 128.64, 135.00,
138.10, 144.73, 145.28, 147.44, 161.88; MS [M + H]<sup>+</sup><italic>m/z</italic> 410.2527, MS [M + Na]<sup>+</sup><italic>m/z</italic> 432.2346 (calcd for C<sub>26</sub>H<sub>35</sub>NOS 409.2439).
Anal. calcd for C<sub>26</sub>H<sub>35</sub>NOS: C, 76.24; H, 8.61; N, 3.42; S, 7.83.
Found: C, 76.19; H, 8.72; N, 3.36; S, 7.74.</p></sec><sec id="s0018"><label>4.2.6.</label><title>Synthesis of 5-bromine-2-thiophene-acyl-dehydroabietylamine (L<sup>6</sup>)</title><p>HOBT and DCC were used in the condensation reaction (same as
<bold>L<sup>4</sup></bold>). Ethyl acetate was dried with and evaporated to get milky
white powders. (1.92 g, 81%), mp: 170.7–173.2 °C; IR (neat)
<italic>ν</italic><sub>max</sub>/cm<sup>−1</sup> 3414, 2922, 2849, 1629, 1550, 1413,
1282, 1077, 805, 736, 620; <sup>1 </sup>H–NMR ((CD<sub>3</sub>)<sub>2</sub>SO, 600 MHz)
<italic>δ</italic> 0.90 (3 H, s), 1.13–1.15 (9 H, t, <italic>J</italic> = 6.6 Hz),
1.32–1.35 (2 H, m), 1.42–1.46 (1 H, m), 1.57–1.61(2H, m), 1.62–1.73 (2 H, m), 1.95–1.99
(1 H, m), 2.24 (1 H, d, <italic>J</italic> = 12.6 Hz), 2.72–2.79 (3 H, m), 2.92–3.41
(2 H, m), 6.82 (1 H, s), 6.92 (1 H, dd, <italic>J</italic> = 7.8 Hz), 7.12 (1 H, d,
<italic>J</italic> = 7.8 Hz), 7.22 (1 H, d, <italic>J</italic> = 3.6 Hz), 7.68 (1 H,
d, <italic>J</italic> = 4.2 Hz), 8.33 (1 H, s, –NH); <sup>13 </sup>C{<sup>1</sup>H} NMR
((CD<sub>3</sub>)<sub>2</sub>SO, 151 MHz) <italic>δ</italic> 18.71, 19.12, 19.26,
24.35, 24.40, 25.81, 30.34, 33.34, 36.35, 37.48, 38.34, 40.42, 45.78, 45.08, 49.87,
117.02, 123.94, 124.46, 126.89, 129.26, 131.81, 134.95, 142.47, 145.29, 147.40, 160.88;
MS [M + H]<sup>+</sup><italic>m/z</italic> 475.3262 (calcd for C<sub>25</sub>H<sub>32</sub>BrNOS 474.3138).
Anal. calcd for C<sub>25</sub>H<sub>32</sub>BrNOS: C, 63.28; H, 6.80; N, 2.95; S, 6.76.
Found: C, 63.19; H, 6.87; N, 2.83; S, 6.82.</p></sec><sec id="s0019"><label>4.2.7.</label><title>Synthesis of 2-pyrazine-acyl-dehydroabietylamine (L<sup>7</sup>)</title><p>After the condensation reaction of 2-pyrazine-carboxylic acid (0.62 g, 5.0 mmol) and
dehydroabietylamine (1.43 g, 5.0 mmol) used HOBT and DCC, which was same as
<bold>L<sup>4</sup></bold>, solvents were evaporated to get yellow powders. (1.53 g,
78%), mp: 159.8–162.3 °C; IR (neat) <italic>ν</italic><sub>max</sub>/cm<sup>−1</sup>3401, 2929, 2854, 1653, 1524, 1392, 1153, 1016, 873, 819, 620; <sup>1 </sup>H–NMR
(CDCl<sub>3</sub>, 600 MHz) <italic>δ</italic> 1.02 (3 H, s), 1.21–1.23 (9 H, t,
<italic>J</italic> = 7.2 Hz), 1.38–1.41 (1 H, m), 1.51–1.53 (2 H, m), 1.66–1.71(1H,
m), 1.77–1.79 (2 H, m), 1.91–2.04 (2 H, m), 2.29 (1 H, d, <italic>J</italic> = 12.6 Hz),
2.80–2.89 (2 H, m), 2.90–2.95(1H, m), 3.26–3.54 (2 H, dd, <italic>J</italic> = 7.2 Hz),
6.89 (1 H, s), 6.98 (1 H, dd, <italic>J</italic> = 8.4 Hz), 7.16 (1 H, d,
<italic>J</italic> = 7.8 Hz), 7.91 (1 H, s, –NH), 8.49 (1 H, d,
<italic>J</italic> = 1.2 Hz), 8.72 (1 H, d, <italic>J</italic> = 2.4 Hz), 9.39 (1 H, s);
<sup>13 </sup>C{<sup>1</sup>H} NMR ((CD<sub>3</sub>)<sub>2</sub>SO, 151 MHz)
<italic>δ</italic> 18.43, 18.68, 24.38, 24.44, 25.43, 29.41, 33.36, 35.02, 36.04,
37.40, 37.99, 44.89, 50.15, 123.99, 124.37, 126.79, 134.85, 143.90, 144.75, 145.50,
145.57, 147.26, 151.88, 167.45; MS [M + H]<sup>+</sup><italic>m/z</italic> 392.2721, [M + Na]<sup>+</sup><italic>m/z</italic> 414.2539 (calcd for C<sub>25</sub>H<sub>33</sub>N<sub>3</sub>O
391.2624). Anal. calcd for C<sub>25</sub>H<sub>33</sub>N<sub>3</sub>O: C, 76.69; H,
8.49; N, 10.73. Found: C, 76.57; H, 8.56; N, 10.64.</p></sec><sec id="s0020"><label>4.2.8.</label><title>Synthesis of 5-methoxyl-2-pyrazine-acyl-dehydroabietylamine (L<sup>8</sup>)</title><p>A mixture of Dehydroabietylamine (<bold>L<sup>0</sup></bold>) (10.0 mmol),
5-chloro-pyrazine-2-carboxylic acid methyl ester (10.0 mmol) was dissolved in EtOH
(150 mL) and refluxed for 24 h. Then the mixture was cooled to the room temperature,
removed the solvent by reduced pressure distillation, and received the orange powders.
Finally, the orange powders were obtained by recrystallization from ethanol solution.
(1.37 g, 65%), mp: 117.6–119.8 °C; IR (neat)
<italic>ν</italic><sub>max</sub>/cm<sup>−1</sup> 3422, 2929, 2868, 1714, 1593, 1433,
1276, 1125, 1016, 825, 620; <sup>1 </sup>H–NMR ((CD<sub>3</sub>)<sub>2</sub>SO, 600 MHz)
<italic>δ</italic> 0.92 (3 H, s), 1.11–1.21 (9 H, t, <italic>J</italic> = 7.2 Hz),
1.22–1.26 (2 H, m), 1.38–1.49 (2 H, m), 1.52–1.64 (2 H, m), 1.64–1.72 (1 H, m),
1.88–1.92 (1 H, m), 2.23 (1 H, d, <italic>J</italic> = 12.0 Hz), 2.63–2.79 (3 H, m),
3.16–3.53 (2 H, m), 3.79 (3 H, s), 6.79 (1 H, s), 6.92 (1 H, dd,
<italic>J</italic> = 7.8 Hz), 7.11 (1 H, d, <italic>J</italic> = 7.8 Hz), 7.80 (1 H, s,
–NH), 8.08 (1 H, s), 8.59 (1 H, s); <sup>13 </sup>C{<sup>1</sup>H} NMR
((CD<sub>3</sub>)<sub>2</sub>SO, 151 MHz) <italic>δ</italic> 14.49, 18.73, 19.00,
19.25, 21.13, 24.31, 25.58, 29.97, 33.35, 36.02, 37.44, 44.35, 50.62, 51.86, 60.18,
123.92, 124.40, 126.82, 129.62, 134.04, 134.78, 145.32, 147.40, 157.09, 165.16; MS
[M + H]<sup>+</sup><italic>m/z</italic> 422.2804, [M + Na]<sup>+</sup><italic>m/z</italic> 444.2620 (calcd for
C<sub>26</sub>H<sub>35</sub>N<sub>3</sub>O<sub>2</sub> 421.2729). Anal. calcd for
C<sub>26</sub>H<sub>35</sub>N<sub>3</sub>O<sub>2</sub>: C, 74.07; H, 8.37; N, 9.97.
Found: C, 74.01; H, 8.46; N, 9.89.</p></sec><sec id="s0021"><label>4.2.9.</label><title>Synthesis of 5–methyl-2-pyrazine-acyl-dehydroabietylamine (L<sup>9</sup>)</title><p><bold>L<sup>9</sup></bold> was synthesized according to the method used for
<bold>L<sup>4</sup></bold>. Obtained <bold>L<sup>9</sup></bold>is pale yellow powders. (1.66 g, 82%), mp: 130.7–133.4 °C; IR (neat)
<italic>ν</italic><sub>max</sub>/cm<sup>−1</sup> 3387, 2922, 2854, 1664, 1534, 1439,
1378, 1290, 1167, 1030, 819, 634; <sup>1 </sup>H–NMR (CDCl<sub>3</sub>, 600 MHz)
<italic>δ</italic> 1.02 (3 H, s), 1.21–1.23 (9 H, t, <italic>J</italic> = 6.6 Hz),
1.38–1.42 (2 H, m), 1.51–1.53 (2 H, m), 1.67–1.73 (1 H, m), 1.70–1.81 (2 H, m),1.97–2.01
(1 H, m), 2.28 (1 H, d, <italic>J</italic> = 12.0 Hz), 2.63 (3 H, s), 2.81–2.94 (3 H,
m), 3.25–3.49 (2 H, dd, <italic>J</italic> = 7.2 Hz), 6.88 (1 H, s), 6.98 (1 H, dd,
<italic>J</italic> = 1.8 Hz), 7.16 (1 H, d, <italic>J</italic> = 7.2 Hz), 7.85(1 H, s,
–NH), 8.34(1 H, d, <italic>J</italic> = 3.0 Hz), 9.25 (1 H, d,
<italic>J</italic> = 1.8 Hz); <sup>13 </sup>C{<sup>1</sup>H} NMR (CDCl<sub>3</sub>,
151 MHz) <italic>δ</italic> 18.92, 19.12, 21.77, 23.94, 24.92, 25.47, 30.43, 33.91,
36.31, 37.58, 37.83, 38.28, 45.42, 49.75, 123.87, 124.24, 126.95, 134.84, 141.80,
142.22, 143.39, 145.61, 147.07, 156.91, 163.28; MS [M + H]<sup>+</sup><italic>m/z</italic> 406.2879, [M + Na]<sup>+</sup><italic>m/z</italic> 428.2698 (calcd for C<sub>26</sub>H<sub>35</sub>N<sub>3</sub>O
405.2780). Anal. calcd for C<sub>26</sub>H<sub>35</sub>N<sub>3</sub>O: C, 77.00; H,
8.70; N, 10.36. Found: C, 76.92; H, 8.62; N, 10.44.</p></sec><sec id="s0022"><label>4.2.10.</label><title>Synthesis of 5-chloro-2-pyrazine-acyl-dehydroabietylamine (L<sup>10</sup>)</title><p>The condensation reaction yielded pale yellow powders, which was synthesized according
to the method used for <bold>L<sup>4</sup></bold>. (1.59 g, 75%), mp: 152.4–154.5 °C; IR
(neat) <italic>ν</italic><sub>max</sub>/cm<sup>−1</sup> 3387, 2929, 2860, 1664, 1529,
1447, 1282, 1167, 1125, 1022, 825, 620; <sup>1 </sup>H–NMR
((CD<sub>3</sub>)<sub>2</sub>SO, 600 MHz) <italic>δ</italic> 0.90 (3 H, s), 1.12–1.18
(9 H, t, <italic>J</italic> = 7.2 Hz), 1.32–1.42 (3 H, m), 1.57–1.76 (4 H, m), 2.01–2.04
(1 H, m), 2.24 (1 H, d, <italic>J</italic> = 13.8 Hz), 2.73–2.81 (3 H, m), 3.09–3.44
(2 H, dd, <italic>J</italic> = 6.6 Hz), 6.83 (1 H, s), 6.92 (1 H, dd,
<italic>J</italic> = 7.8 Hz), 7.11 (1 H, d, <italic>J</italic> = 7.8 Hz), 7.12 (1 H, d,
<italic>J</italic> = 8.4 Hz), 7.60 (1 H, d, <italic>J</italic> = 3.6 Hz), 8.60 (1 H,
s, –NH), 8.83 (1 H, s), 9.00 (1 H, s); <sup>13 </sup>C{<sup>1</sup>H} NMR
((CD<sub>3</sub>)<sub>2</sub>SO, 151 MHz) <italic>δ</italic> 18.66, 19.08, 19.20,
24.30, 25.66, 30.18, 33.27, 36.31, 37.53, 38.36, 38.47, 40.62, 45.39, 49.76, 123.94,
124.36, 126.86, 134.91, 143.47, 143.83, 144.14, 145.35, 147.44, 151.13, 162.78; MS
[M + Na]<sup>+</sup><italic>m/z</italic> 448.2146 (calcd for C<sub>25</sub>H<sub>32</sub>ClN<sub>3</sub>O
425.2234). Anal. calcd for C<sub>25</sub>H<sub>32</sub>ClN<sub>3</sub>O: C, 70.49; H,
7.57; N, 9.86. Found: C, 70.37; H, 7.48; N, 9.94.</p></sec></sec><sec id="s0023"><label>4.3.</label><title>Biological assays</title><sec id="s0024"><label>4.3.1.</label><title>Cell culture, antiproliferative activities and cytotoxicity assay</title><p>Reagents and compounds Dulbecco’s Modified Eagle’s Medium (DMEM) and
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), fetal bovine serum
(FBS) and penicillin/streptomycin were all commercially purchased.</p><p>Hela, HepG2, MCF-7, A549, and HUVEC cells were used in the antiproliferative activity
assay. Cancer cells were seeded in 96-well plates with a density of 10<sup>4</sup> cells
per well, after 12 hours of incubation at 5% CO<sub>2</sub> and 37 °C, the culture media
was removed and cells were incubated with <bold>L<sup>1</sup>−L<sup>10</sup></bold>dissolved in DMEM at different concentrations (each concentration repeated 3 times) for
36 h at 5% CO<sub>2</sub> and 37 °C. Subsequently, removed the culture media and the new
culture medium containing MTT (1 mg/mL) was added, followed by incubating for 4 h to
allow the formation of formazan dye (Xia et al., <xref rid="CIT0055" ref-type="bibr">2015</xref>; Zhao et al., <xref rid="CIT0058" ref-type="bibr">2018</xref>). After
removing the medium, 200 μL DMSO was added to each well to dissolve the formazan
crystals. Absorbance was measured at 595 nm in a microplate photometer. Cell viability
values were determined (at least three times) according to the following formulae: cell
viability (%) = the absorbance of experimental group/the absorbance of blank control
group ×100%.</p></sec><sec id="s0025"><label>4.3.2.</label><title>Induction of apoptosis by flow-cytometric analysis</title><p>Induction apoptosis assay was operated by Becton Dickinson Ultra-high speed separation
flow-cytometry instrument and Annexin V-FITC/PI was purchased from Nanjing Keygen
Biotech Co. Ltd.</p><p>We further investigated whether <bold>L<sup>1</sup></bold> and
<bold>L<sup>3</sup></bold> could induce apoptosis; DMSO was used as negative control.
HepG2 cells (1 × 10<sup>6</sup>) were cultured in 35 mm dishes and incubated at 37 °C
for 24 h. After incubation with DMSO at 5 <italic>μ</italic>g/mL,
<bold>L<sup>1</sup></bold> at 1, 2, 5 <italic>μ</italic>g/mL, and
<bold>L<sup>3</sup></bold> at 0.1, 1, 5 <italic>μ</italic>g/mL for 24 h (each
concentration repeated 3 times, the incubation time is optimum), the treated cells were
washed, trypsinized (non-EDTA), and centrifuged (2000 rpm/min). Then the cells were
collected and resuspended in 500 μL of buffer solutions loaded with Annexin V-FITC
apoptosis detection reagent (with 5 μL Annexin V-FITC and 5 μL PI). The Annexin
V-FITC-stained cells were incubated for 5–15 min in the dark, and approximate
10<sup>4</sup> cells were collected for flow-cytometry analysis with a single 488 nm
argon laser.</p></sec><sec id="s0026"><label>4.3.3.</label><title>In vivo experiment</title><p><italic>In vivo</italic> experiment was taken by Nanjing Keygen Biotech Co. Ltd. For
developing the tumor model, 1 × 10<sup>6</sup> HepG2 cells were subcutaneously injected
into the right armpit of every Balb/C nude mouse. And then two groups of
HepG2-tumor-bearing mice with five mice per group were randomly chosen in our
experiment: (1) PBS (as a control) and (2) compound <bold>L<sup>1</sup></bold>. After
the size of tumors reached 80 mm<sup>3</sup>, all agents including PBS, compound
<bold>L<sup>1</sup></bold>solutions were administrated via an intravenous injection (dose = 0.6 mg/kg),
respectively. During the next 25 days, the tumor size of every mouse in our experiments
was measured by a vernier caliper every 3 days. Moreover, to accurately evaluate the
growth inhibition of tumors, the mice were sacrificed after 25 days, and then their
tumors were collected, photographed, and weighed. In addition, the sections of tumor,
heart, kidney, liver, lung, and spleen tissues of different groups harvested on the 25th
day were observed using H&E staining, and then examined by a pathologist. The tumor
size was calculated as the volume = 0.5 × (tumor length) × (tumor width)<sup>2</sup>.
The inhibition efficiency of tumor growth was calculated according to the following
equation: <disp-formula id="M0001"><alternatives><graphic xlink:href="IDRD_A_1716879_M0001.jpg" position="float" orientation="portrait"></graphic><mml:math id="d1e3984"><mml:mrow><mml:mtext>inhibition</mml:mtext><mml:mtext> efficiency</mml:mtext><mml:mrow><mml:mo>(</mml:mo><mml:mi>%</mml:mi><mml:mo>)</mml:mo></mml:mrow><mml:mo>=</mml:mo><mml:mrow><mml:mo>(</mml:mo><mml:mrow><mml:mn>1</mml:mn><mml:mo>−</mml:mo><mml:mtext>the</mml:mtext><mml:mtext> weight</mml:mtext><mml:mtext> of</mml:mtext><mml:mtext> experimental</mml:mtext><mml:mtext> group</mml:mtext><mml:mo>/</mml:mo><mml:mtext>the</mml:mtext><mml:mtext> weight</mml:mtext><mml:mtext> of</mml:mtext><mml:mtext>control </mml:mtext><mml:mtext>group</mml:mtext></mml:mrow><mml:mo>)</mml:mo></mml:mrow><mml:mo>×</mml:mo><mml:mn>100</mml:mn><mml:mi>%</mml:mi></mml:mrow></mml:math></alternatives></disp-formula></p><p>CD31 immumohistochemical staining with mice was conducted on the 25th day after an
intravenous injection of compound <bold>L<sup>1</sup></bold> (0.6 mg/kg) and PBS
control.</p></sec></sec></sec><sec sec-type="supplementary-material"><title>Supplementary Material</title><supplementary-material content-type="local-data" id="SM4759"><caption><title>Supplemental Material</title></caption><media mimetype="application" mime-subtype="docx" xlink:href="IDRD_A_1716879_SM4759.docx" orientation="portrait" id="d37e254" position="anchor"></media></supplementary-material></sec></body><back><sec id="s0027"><title>Disclosure statement</title><p>No potential conflict of interest was reported by the authors.</p></sec><ref-list><title>References</title><ref id="CIT0001"><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Ahmed</surname><given-names>HEA</given-names></name>, <name name-style="western"><surname>Ihmaid</surname><given-names>SK</given-names></name>, <name name-style="western"><surname>Omar</surname><given-names>AM</given-names></name>, <etal>et al.</etal></person-group>(<year>2018</year>). <article-title>Design, synthesis, molecular docking of new
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