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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Theranostic Lysosomal Targeting Anticancer and Antimetastatic
Agents: Half-Sandwich Iridium(III) Rhodamine Complexes</title><author><name sortKey="Ma, Wenli" sort="Ma, Wenli" uniqKey="Ma W" first="Wenli" last="Ma">Wenli Ma</name><affiliation><nlm:aff id="aff1">Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, Department of Chemistry and Chemical Engineering,<institution>Qufu Normal University</institution>, Qufu 273165,<country>China</country></nlm:aff></affiliation></author><author><name sortKey="Ge, Xingxing" sort="Ge, Xingxing" uniqKey="Ge X" first="Xingxing" last="Ge">Xingxing Ge</name><affiliation><nlm:aff id="aff1">Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, Department of Chemistry and Chemical Engineering,<institution>Qufu Normal University</institution>, Qufu 273165,<country>China</country></nlm:aff></affiliation></author><author><name sortKey="Xu, Zhishan" sort="Xu, Zhishan" uniqKey="Xu Z" first="Zhishan" last="Xu">Zhishan Xu</name><affiliation><nlm:aff id="aff1">Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, Department of Chemistry and Chemical Engineering,<institution>Qufu Normal University</institution>, Qufu 273165,<country>China</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Department of Chemistry and Chemical Engineering,<institution>Shandong Normal University</institution>, Jinan 250014,<country>China</country></nlm:aff></affiliation></author><author><name sortKey="Zhang, Shumiao" sort="Zhang, Shumiao" uniqKey="Zhang S" first="Shumiao" last="Zhang">Shumiao Zhang</name><affiliation><nlm:aff id="aff1">Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, Department of Chemistry and Chemical Engineering,<institution>Qufu Normal University</institution>, Qufu 273165,<country>China</country></nlm:aff></affiliation></author><author><name sortKey="He, Xiangdong" sort="He, Xiangdong" uniqKey="He X" first="Xiangdong" last="He">Xiangdong He</name><affiliation><nlm:aff id="aff1">Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, Department of Chemistry and Chemical Engineering,<institution>Qufu Normal University</institution>, Qufu 273165,<country>China</country></nlm:aff></affiliation></author><author><name sortKey="Li, Juanjuan" sort="Li, Juanjuan" uniqKey="Li J" first="Juanjuan" last="Li">Juanjuan Li</name><affiliation><nlm:aff id="aff1">Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, Department of Chemistry and Chemical Engineering,<institution>Qufu Normal University</institution>, Qufu 273165,<country>China</country></nlm:aff></affiliation></author><author><name sortKey="Xia, Xiaorong" sort="Xia, Xiaorong" uniqKey="Xia X" first="Xiaorong" last="Xia">Xiaorong Xia</name><affiliation><nlm:aff id="aff1">Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, Department of Chemistry and Chemical Engineering,<institution>Qufu Normal University</institution>, Qufu 273165,<country>China</country></nlm:aff></affiliation></author><author><name sortKey="Chen, Xiaobing" sort="Chen, Xiaobing" uniqKey="Chen X" first="Xiaobing" last="Chen">Xiaobing Chen</name><affiliation><nlm:aff id="aff1">Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, Department of Chemistry and Chemical Engineering,<institution>Qufu Normal University</institution>, Qufu 273165,<country>China</country></nlm:aff></affiliation></author><author><name sortKey="Liu, Zhe" sort="Liu, Zhe" uniqKey="Liu Z" first="Zhe" last="Liu">Zhe Liu</name><affiliation><nlm:aff id="aff1">Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, Department of Chemistry and Chemical Engineering,<institution>Qufu Normal University</institution>, Qufu 273165,<country>China</country></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31552370</idno><idno type="pmc">6751730</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6751730</idno><idno type="RBID">PMC:6751730</idno><idno type="doi">10.1021/acsomega.9b01863</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000000</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000000</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Theranostic Lysosomal Targeting Anticancer and Antimetastatic
Agents: Half-Sandwich Iridium(III) Rhodamine Complexes</title><author><name sortKey="Ma, Wenli" sort="Ma, Wenli" uniqKey="Ma W" first="Wenli" last="Ma">Wenli Ma</name><affiliation><nlm:aff id="aff1">Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, Department of Chemistry and Chemical Engineering,<institution>Qufu Normal University</institution>, Qufu 273165,<country>China</country></nlm:aff></affiliation></author><author><name sortKey="Ge, Xingxing" sort="Ge, Xingxing" uniqKey="Ge X" first="Xingxing" last="Ge">Xingxing Ge</name><affiliation><nlm:aff id="aff1">Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, Department of Chemistry and Chemical Engineering,<institution>Qufu Normal University</institution>, Qufu 273165,<country>China</country></nlm:aff></affiliation></author><author><name sortKey="Xu, Zhishan" sort="Xu, Zhishan" uniqKey="Xu Z" first="Zhishan" last="Xu">Zhishan Xu</name><affiliation><nlm:aff id="aff1">Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, Department of Chemistry and Chemical Engineering,<institution>Qufu Normal University</institution>, Qufu 273165,<country>China</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Department of Chemistry and Chemical Engineering,<institution>Shandong Normal University</institution>, Jinan 250014,<country>China</country></nlm:aff></affiliation></author><author><name sortKey="Zhang, Shumiao" sort="Zhang, Shumiao" uniqKey="Zhang S" first="Shumiao" last="Zhang">Shumiao Zhang</name><affiliation><nlm:aff id="aff1">Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, Department of Chemistry and Chemical Engineering,<institution>Qufu Normal University</institution>, Qufu 273165,<country>China</country></nlm:aff></affiliation></author><author><name sortKey="He, Xiangdong" sort="He, Xiangdong" uniqKey="He X" first="Xiangdong" last="He">Xiangdong He</name><affiliation><nlm:aff id="aff1">Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, Department of Chemistry and Chemical Engineering,<institution>Qufu Normal University</institution>, Qufu 273165,<country>China</country></nlm:aff></affiliation></author><author><name sortKey="Li, Juanjuan" sort="Li, Juanjuan" uniqKey="Li J" first="Juanjuan" last="Li">Juanjuan Li</name><affiliation><nlm:aff id="aff1">Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, Department of Chemistry and Chemical Engineering,<institution>Qufu Normal University</institution>, Qufu 273165,<country>China</country></nlm:aff></affiliation></author><author><name sortKey="Xia, Xiaorong" sort="Xia, Xiaorong" uniqKey="Xia X" first="Xiaorong" last="Xia">Xiaorong Xia</name><affiliation><nlm:aff id="aff1">Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, Department of Chemistry and Chemical Engineering,<institution>Qufu Normal University</institution>, Qufu 273165,<country>China</country></nlm:aff></affiliation></author><author><name sortKey="Chen, Xiaobing" sort="Chen, Xiaobing" uniqKey="Chen X" first="Xiaobing" last="Chen">Xiaobing Chen</name><affiliation><nlm:aff id="aff1">Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, Department of Chemistry and Chemical Engineering,<institution>Qufu Normal University</institution>, Qufu 273165,<country>China</country></nlm:aff></affiliation></author><author><name sortKey="Liu, Zhe" sort="Liu, Zhe" uniqKey="Liu Z" first="Zhe" last="Liu">Zhe Liu</name><affiliation><nlm:aff id="aff1">Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, Department of Chemistry and Chemical Engineering,<institution>Qufu Normal University</institution>, Qufu 273165,<country>China</country></nlm:aff></affiliation></author></analytic><series><title level="j">ACS Omega</title><idno type="eISSN">2470-1343</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p content-type="toc-graphic"><graphic xlink:href="ao9b01863_0013" id="ab-tgr1"></graphic></p><p>Two rhodamine-modified half-sandwich
Ir(III) complexes with the
general formula [(Cp<sup>x</sup>)Ir(ĈN) Cl] were synthesized
and characterized, where Cp<sup>x</sup> is 1-biphenyl-2,3,4,5-tetramethylcyclopentadienyl
(Cp<sup>xbiph</sup>). Both complexes showed potent anticancer activity
against A549, HeLa, and HepG2 cancer cells and normal cells, and altered
ligands had an effect on proliferation resistance. The complex enters
cells through energy dependence, and because of the different ligands,
not only could it affect the anticancer ability of the complex but
also could affect the degree of complex lysosome targeting, lysosomal
damage, and further prove the antiproliferative mechanism of the complex.
Excitingly, antimetastatic experiments demonstrated that complex <bold>1</bold> has the ability to block the migration of cancer cells.
Furthermore, although the complex did not show a stronger ability
to interfere with the coenzyme NAD<sup>+</sup>/NADH pair by transfer
hydrogenation, the intracellular reactive oxygen species (ROS) content
has shown a marked increase. NF-κB activity is increased by
ROS regulation, and the role of ROS-NF-κB signaling pathway
further induces apoptosis. Moreover, cell flow experiments also demonstrated
that complex <bold>1</bold> blocked the cell cycle in S phase, but
the complex did not cause significant changes in the mitochondrial
membrane potential.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Rosenberg, B" uniqKey="Rosenberg B">B. Rosenberg</name></author><author><name sortKey="Vancamp, L" uniqKey="Vancamp L">L. Vancamp</name></author><author><name sortKey="Trosko, J E" uniqKey="Trosko J">J. E. Trosko</name></author><author><name sortKey="Mansour, V H" uniqKey="Mansour V">V. H. Mansour</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Trosko, N P" uniqKey="Trosko N">N. P. Trosko</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Johnstone, T C" uniqKey="Johnstone T">T. C. Johnstone</name></author><author><name sortKey="Suntharalingam, K" uniqKey="Suntharalingam K">K. Suntharalingam</name></author><author><name sortKey="Lippard, S J" uniqKey="Lippard S">S. J. Lippard</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wang, X" uniqKey="Wang X">X. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">ACS Omega</journal-id><journal-id journal-id-type="iso-abbrev">ACS Omega</journal-id><journal-id journal-id-type="publisher-id">ao</journal-id><journal-id journal-id-type="coden">acsodf</journal-id><journal-title-group><journal-title>ACS Omega</journal-title></journal-title-group><issn pub-type="epub">2470-1343</issn><publisher><publisher-name>American Chemical Society</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31552370</article-id><article-id pub-id-type="pmc">6751730</article-id><article-id pub-id-type="doi">10.1021/acsomega.9b01863</article-id><article-categories><subj-group><subject>Article</subject></subj-group></article-categories><title-group><article-title>Theranostic Lysosomal Targeting Anticancer and Antimetastatic
Agents: Half-Sandwich Iridium(III) Rhodamine Complexes</article-title></title-group><contrib-group><contrib contrib-type="author" id="ath1"><name><surname>Ma</surname><given-names>Wenli</given-names></name><xref rid="aff1" ref-type="aff">†</xref></contrib><contrib contrib-type="author" id="ath2"><name><surname>Ge</surname><given-names>Xingxing</given-names></name><xref rid="aff1" ref-type="aff">†</xref></contrib><contrib contrib-type="author" id="ath3"><name><surname>Xu</surname><given-names>Zhishan</given-names></name><xref rid="aff1" ref-type="aff">†</xref><xref rid="aff2" ref-type="aff">‡</xref></contrib><contrib contrib-type="author" id="ath4"><name><surname>Zhang</surname><given-names>Shumiao</given-names></name><xref rid="aff1" ref-type="aff">†</xref></contrib><contrib contrib-type="author" id="ath5"><name><surname>He</surname><given-names>Xiangdong</given-names></name><xref rid="aff1" ref-type="aff">†</xref></contrib><contrib contrib-type="author" id="ath6"><name><surname>Li</surname><given-names>JuanJuan</given-names></name><xref rid="aff1" ref-type="aff">†</xref></contrib><contrib contrib-type="author" id="ath7"><name><surname>Xia</surname><given-names>Xiaorong</given-names></name><xref rid="aff1" ref-type="aff">†</xref></contrib><contrib contrib-type="author" id="ath8"><name><surname>Chen</surname><given-names>Xiaobing</given-names></name><xref rid="aff1" ref-type="aff">†</xref></contrib><contrib contrib-type="author" corresp="yes" id="ath9"><name><surname>Liu</surname><given-names>Zhe</given-names></name><xref rid="cor1" ref-type="other">*</xref><xref rid="aff1" ref-type="aff">†</xref></contrib><aff id="aff1"><label>†</label>Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, Department of Chemistry and Chemical Engineering,<institution>Qufu Normal University</institution>, Qufu 273165,<country>China</country></aff><aff id="aff2"><label>‡</label>Department of Chemistry and Chemical Engineering,<institution>Shandong Normal University</institution>, Jinan 250014,<country>China</country></aff></contrib-group><author-notes><corresp id="cor1"><label>*</label>E-mail: <email>liuzheqd@163.com</email>.</corresp></author-notes><pub-date pub-type="epub"><day>03</day><month>09</month><year>2019</year></pub-date><pub-date pub-type="collection"><day>17</day><month>09</month><year>2019</year></pub-date><volume>4</volume><issue>12</issue><fpage>15240</fpage><lpage>15248</lpage><history><date date-type="received"><day>15</day><month>07</month><year>2019</year></date><date date-type="accepted"><day>30</day><month>07</month><year>2019</year></date></history><permissions><copyright-statement>Copyright © 2019 American Chemical
Society</copyright-statement><copyright-year>2019</copyright-year><copyright-holder>American Chemical
Society</copyright-holder><license><license-p>This is an open access article published under an ACS AuthorChoice <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/page/policy/authorchoice_termsofuse.html">License</ext-link>, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.</license-p></license></permissions><abstract><p content-type="toc-graphic"><graphic xlink:href="ao9b01863_0013" id="ab-tgr1"></graphic></p><p>Two rhodamine-modified half-sandwich
Ir(III) complexes with the
general formula [(Cp<sup>x</sup>)Ir(ĈN) Cl] were synthesized
and characterized, where Cp<sup>x</sup> is 1-biphenyl-2,3,4,5-tetramethylcyclopentadienyl
(Cp<sup>xbiph</sup>). Both complexes showed potent anticancer activity
against A549, HeLa, and HepG2 cancer cells and normal cells, and altered
ligands had an effect on proliferation resistance. The complex enters
cells through energy dependence, and because of the different ligands,
not only could it affect the anticancer ability of the complex but
also could affect the degree of complex lysosome targeting, lysosomal
damage, and further prove the antiproliferative mechanism of the complex.
Excitingly, antimetastatic experiments demonstrated that complex <bold>1</bold> has the ability to block the migration of cancer cells.
Furthermore, although the complex did not show a stronger ability
to interfere with the coenzyme NAD<sup>+</sup>/NADH pair by transfer
hydrogenation, the intracellular reactive oxygen species (ROS) content
has shown a marked increase. NF-κB activity is increased by
ROS regulation, and the role of ROS-NF-κB signaling pathway
further induces apoptosis. Moreover, cell flow experiments also demonstrated
that complex <bold>1</bold> blocked the cell cycle in S phase, but
the complex did not cause significant changes in the mitochondrial
membrane potential.</p></abstract><custom-meta-group><custom-meta><meta-name>document-id-old-9</meta-name><meta-value>ao9b01863</meta-value></custom-meta><custom-meta><meta-name>document-id-new-14</meta-name><meta-value>ao-2019-01863x</meta-value></custom-meta><custom-meta><meta-name>ccc-price</meta-name><meta-value></meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec id="sec1"><label>1</label><title>Introduction</title><p>Cancer
has become one of the main fatal diseases worldwide, which
has surpassed cardiovascular diseases as the leading cause of death.<sup><xref ref-type="bibr" rid="ref1">1</xref>−<xref ref-type="bibr" rid="ref3">3</xref></sup> Therefore, research on anticancer drugs cannot be delayed. Metal-based
anticancer drug therapy is a valuable class of drugs in oncology research,
including imaging applications, examples of novel chemotherapeutic
agents, and important research values in diagnostics and clinical
trials.<sup><xref ref-type="bibr" rid="ref4">4</xref></sup> A platinum-based drug is one of
the most commonly used drugs for the treatment of various human cancers,
but they still have shortcomings such as poor drug resistance and serious side effects and so
on.<sup><xref ref-type="bibr" rid="ref5">5</xref></sup> For these reasons, more and more researchers
are turning their attention to other alternative transition-metal
complexes. As new iridium complexes have been reported to have selective
biological activity and to overcome the resistance of platinum-based
therapies, the development of antitumor iridium complexes therapeutics
has been of great interest to researchers.<sup><xref ref-type="bibr" rid="ref6">6</xref>−<xref ref-type="bibr" rid="ref19">19</xref></sup></p><p>On the other hand, it has been reported that the fluorescent
ring
metallated Ir(III) complex exerts powerful anticancer effects through
different mechanisms, such as targeting subcellular organelles and
inhibiting proteins activities.<sup><xref ref-type="bibr" rid="ref20">20</xref>,<xref ref-type="bibr" rid="ref21">21</xref></sup> However, there is not
much research on the anticancer mechanism of half-sandwich iridium
complexes without fluorescence.<sup><xref ref-type="bibr" rid="ref22">22</xref>,<xref ref-type="bibr" rid="ref23">23</xref></sup> The study of lysosomal
targeted half-sandwich complexes has attracted a lot of interest from
researchers. It is well known that lysosomes are important acidic
cell organelles for decomposing biological macromolecules such as
proteins, nucleic acids, and polysaccharides; when the cell ages,
its lysosome ruptures, releasing hydrolase, digesting the entire cell,
and causing it to die.<sup><xref ref-type="bibr" rid="ref24">24</xref>,<xref ref-type="bibr" rid="ref25">25</xref></sup> In cancer cells, the lysosomes
will be larger, more unstable, more numerous, and exhibit more hydrolytic
enzymes (such as cathepsins) than normal cells.<sup><xref ref-type="bibr" rid="ref26">26</xref>,<xref ref-type="bibr" rid="ref27">27</xref></sup> Additionally, when lysosomal targeted drugs enter cells, they accumulate
specifically in lysosomes, leading to changes in the osmotic pressure
in lysosomes and in turn causing lysosomal swelling, rupture, and
lysosomal membrane permeabilization (LMP).<sup><xref ref-type="bibr" rid="ref26">26</xref>,<xref ref-type="bibr" rid="ref28">28</xref></sup> The escape of a hydrolase leads to autolysis of the cell, which
in turn induces cell death.<sup><xref ref-type="bibr" rid="ref29">29</xref>−<xref ref-type="bibr" rid="ref31">31</xref></sup></p><p>It is well known that derivatives
of rhodamine usually have excellent
fluorescent properties.<sup><xref ref-type="bibr" rid="ref32">32</xref>,<xref ref-type="bibr" rid="ref33">33</xref></sup></p><p>Inspired by the
pioneering work of Czarnik and colleagues, rhodamine derivatives are often used as fluorescent
chemicals.<sup><xref ref-type="bibr" rid="ref34">34</xref>,<xref ref-type="bibr" rid="ref35">35</xref></sup> Thus, various rhodamine-based
fluorescent probe metal cations have been reported over the past few
years.<sup><xref ref-type="bibr" rid="ref36">36</xref>−<xref ref-type="bibr" rid="ref38">38</xref></sup> Besides, rhodamine-modified complexes generally have
excellent anticancer activity.<sup><xref ref-type="bibr" rid="ref39">39</xref>−<xref ref-type="bibr" rid="ref41">41</xref></sup> In addition, the ĈN-chelating
ligands lead to an increase in the hydrophobicity of the complexes,
resulting in better accumulation of the complexes in the cells,<sup><xref ref-type="bibr" rid="ref42">42</xref>,<xref ref-type="bibr" rid="ref43">43</xref></sup> which is more conducive to studying the anticancer mechanism of
fluorescent complexes. Besides, we have studied the rhodamine-modified
N̂N-chelating ligands for half-sandwich iridium(III) complexes
before, with the increase of the phenyl group in the tetramethylcyclopentadienyl
ring, the complexes would show better anticancer ability.<sup><xref ref-type="bibr" rid="ref12">12</xref>,<xref ref-type="bibr" rid="ref39">39</xref>,<xref ref-type="bibr" rid="ref41">41</xref>,<xref ref-type="bibr" rid="ref44">44</xref></sup> Herein, we designed and synthesized a new type of half-sandwich
iridium complex (<xref rid="sch1" ref-type="scheme">Scheme <xref rid="sch1" ref-type="scheme">1</xref></xref>). It is well known that both rhodamine B and rhodamine 6G are good
dyes. By introducing these two fluorophores, a new ĈN ligand
is constructed to make the complexes exhibit fluorescent characteristics,
and the difference in antiproliferative ability and localization in
the cell of the two complexes are compared, which facilitates the
study of the specific anticancer mechanism of the complex in the cell.
Our results showed that these newly synthesized iridium complexes
have good two-photon performance, strong color development, and high
targeting and have potential application values in the synthesis of
cancer-targeting drugs, probe designs, and fluorescent biomarkers.</p><fig id="sch1" position="float"><label>Scheme 1</label><caption><title>Structure of Relevant Iridium(III) Complexes and Our Current Work</title></caption><graphic xlink:href="ao9b01863_0011" id="gr11" position="float"></graphic></fig></sec><sec id="sec2"><label>2</label><title>Results and Discussion</title><sec id="sec2.1"><label>2.1</label><title>Synthesis, Stability, and Fluorescence Characteristics
of Complexes</title><p>In this paper, a total of two new ĈN
coordination iridium complexes have been synthesized. Detailed synthesis
routes for ligands and complexes are shown in <xref rid="sch2" ref-type="scheme">Scheme <xref rid="sch2" ref-type="scheme">2</xref></xref>. Ligands L<sub>1</sub>–L<sub>2</sub> were synthesized by the condensation of rhodamine B hydrazide (or
rhodamine 6G hydrazide) with 1 equiv of 4-(2-pyridyl)-benzaldehyde
in dichloromethane at a reflux temperature. These iridium complexes <bold>1–2</bold> were synthesized from the corresponding ligands
in high yield (60–75%) by stirring at heating temperature with
[(η<sup>5</sup>-Cp<sup>xbiph</sup>)IrCl<sub>2</sub>]<sub>2</sub> (dimer). The two complexes in this article were characterized by
mass spectrometry and NMR spectroscopy (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acsomega.9b01863/suppl_file/ao9b01863_si_001.pdf">Figures S10–S14</ext-link>), and we also studied the stability and fluorescence
properties of the complexes, indicating that the complex has good
stability. In addition, because of the different ligands, it also
has an effect on the emission of the complex. The rhodamine B-modified
half-sandwich iridium complex has a larger Stokes shift (<xref rid="fig1" ref-type="fig">Figures <xref rid="fig1" ref-type="fig">1</xref></xref> and <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acsomega.9b01863/suppl_file/ao9b01863_si_001.pdf">S1</ext-link>).</p><fig id="fig1" position="float"><label>Figure 1</label><caption><p>(A) Emission spectra of complexes <bold>1–2</bold> (10 μM)
measured in CH<sub>3</sub>CN at 298 K (excitation at 488 nm and 520/540
nm). (B) Excitation spectra of complexes <bold>1–2</bold> (10
μM) measured in CH<sub>3</sub>CN at 298 K (emission at 588/572
nm).</p></caption><graphic xlink:href="ao9b01863_0001" id="gr1" position="float"></graphic></fig><fig id="sch2" position="float"><label>Scheme 2</label><caption><title>Synthesis of L<sub>1</sub>–L<sub>2</sub> and Complexes <bold>1–2</bold></title></caption><graphic xlink:href="ao9b01863_0012" id="gr12" position="float"></graphic></fig></sec><sec id="sec2.2"><label>2.2</label><title>Antiproliferative Studies</title><p>We evaluated
the in vitro antiproliferative activity of complexes <bold>1–2</bold> using the MTT method of A549, HeLa, and HepG2 cancer cells and normal
cells.<sup><xref ref-type="bibr" rid="ref45">45</xref></sup> The IC<sub>50</sub> values (half
maximal inhibitory concentration) of the complexes <bold>1–2</bold> were tested (<xref rid="tbl1" ref-type="other">Table <xref rid="tbl1" ref-type="other">1</xref></xref>). The IC<sub>50</sub> value of complex <bold>2</bold> is greater
than complex <bold>1</bold> because of the difference in the ligand.
This is similar to the anticancer activity of complexes A and B we
reported, indicating that the introduction of rhodamine 6G can increase
the anticancer activity of the complex. It has been previously reported
that the complex of ĈN ligand has better anticancer activity
than N̂N,<sup><xref ref-type="bibr" rid="ref42">42</xref>,<xref ref-type="bibr" rid="ref46">46</xref></sup> but interestingly, the activity
of complexes <bold>1</bold> and <bold>2</bold>, which is designed
to synthesize a ĈN ligand, is not as good as complexes A and
B.<sup><xref ref-type="bibr" rid="ref39">39</xref>,<xref ref-type="bibr" rid="ref41">41</xref></sup> The reason for this result may be due to
the enhanced lipophilicity of the neutral complex containing the ĈN
ligand, while the cationic complex with the N̂N ligand is more
hydrophobic, resulting that the anticancer activity of complexes <bold>1</bold> and <bold>2</bold> is rather lowered. In addition, we have
compared the anticancer activity of complexes <bold>1</bold> and <bold>2</bold> and dimer; the experimental results show that by introducing
a fluorophore, the anticancer activity of the complex can be increased.
Therefore, the ligand could not only affect the fluorescence characteristics
of the complexes but also affect the antiproliferation ability of
the complexes.</p><table-wrap id="tbl1" position="float"><label>Table 1</label><caption><title>IC<sub>50</sub> Values of Complexes <bold>1–2</bold>, Complexes A–B, and Cisplatin toward A549,
HeLa, and HepG2 Cancer Cells and Normal Cells</title></caption><table frame="hsides" rules="groups" border="0"><colgroup><col align="left"></col><col align="left"></col><col align="left"></col><col align="left"></col><col align="left"></col></colgroup><thead><tr><th style="border:none;" align="center"> </th><th colspan="4" align="center">IC<sub>50</sub> (μM)<hr></hr></th></tr><tr><th style="border:none;" align="center">complex</th><th style="border:none;" align="center">A549</th><th style="border:none;" align="center">HeLa</th><th style="border:none;" align="center">HepG2</th><th style="border:none;" align="center">BEAS-2B</th></tr></thead><tbody><tr><td style="border:none;" align="left">[(η<sup>5</sup>-C<sub>5</sub>Me<sub>4</sub>C<sub>6</sub>H<sub>4</sub>C<sub>6</sub>H<sub>5</sub>)Ir(L<sub>1</sub>)Cl]PF<sub>6</sub> (<bold>1</bold>)</td><td style="border:none;" align="left">23.2 ± 3.6</td><td style="border:none;" align="left">18.7 ± 2.7</td><td style="border:none;" align="left">19.4 ± 7.5</td><td style="border:none;" align="left">19.96 ± 0.7</td></tr><tr><td style="border:none;" align="left">[(η<sup>5</sup>-C<sub>5</sub>Me<sub>4</sub>C<sub>6</sub>H<sub>4</sub>C<sub>6</sub>H<sub>5</sub>)Ir(L<sub>2</sub>)Cl]PF<sub>6</sub> (<bold>2</bold>)</td><td style="border:none;" align="left">36.8 ± 1.6</td><td style="border:none;" align="left">28.2 ± 3.8</td><td style="border:none;" align="left">28.7 ± 6.9</td><td style="border:none;" align="left">30.12 ± 0.3</td></tr><tr><td style="border:none;" align="left">dimer ([(η<sup>5</sup>-Cp<sup>xbiph</sup>)IrCl<sub>2</sub>]<sub>2</sub>)</td><td style="border:none;" align="left">>50</td><td style="border:none;" align="left">>50</td><td style="border:none;" align="left">>50</td><td style="border:none;" align="left">>50</td></tr><tr><td style="border:none;" align="left">complex A</td><td style="border:none;" align="left">2.6 ± 0.3</td><td style="border:none;" align="left">3.6 ± 0.8</td><td style="border:none;" align="left">5.5 ± 0.7</td><td style="border:none;" align="left">3.0 ± 0.2</td></tr><tr><td style="border:none;" align="left">complex B</td><td style="border:none;" align="left">4.3 ± 0.2</td><td style="border:none;" align="left">4.2 ± 0.2</td><td style="border:none;" align="left">5.1 ± 0.1</td><td style="border:none;" align="left">7.2 ± 0.6</td></tr><tr><td style="border:none;" align="left">cisplatin</td><td style="border:none;" align="left">21.3 ± 1.7</td><td style="border:none;" align="left">7.5 ± 0.2</td><td style="border:none;" align="left">22.7 ± 1.1</td><td style="border:none;" align="left">42.0 ± 2.3</td></tr></tbody></table></table-wrap></sec><sec id="sec2.3"><label>2.3</label><title>BSA Binding
Studies</title><p>Serum albumin
is abundant in plasma and has significant binding properties, playing
a vital role in drug delivery systems. The reaction of metal-based
anticancer agents with proteins may have significance in cytotoxicity,
biodistribution, and even the mechanism of action of anticancer agents
and thus has attracted widespread attention.<sup><xref ref-type="bibr" rid="ref47">47</xref>,<xref ref-type="bibr" rid="ref48">48</xref></sup> In order to study the transport
of complexes into the human body.<sup><xref ref-type="bibr" rid="ref49">49</xref>−<xref ref-type="bibr" rid="ref51">51</xref></sup> The interaction between
complex <bold>1</bold> and bovine serum albumin (BSA) is taken as
an example (<xref rid="fig2" ref-type="fig">Figure <xref rid="fig2" ref-type="fig">2</xref></xref>).<sup><xref ref-type="bibr" rid="ref52">52</xref>,<xref ref-type="bibr" rid="ref53">53</xref></sup> The specific experimental steps are supplemented
in the <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acsomega.9b01863/suppl_file/ao9b01863_si_001.pdf">Supporting Information</ext-link> The experimental
results show that complexes <bold>1</bold> and <bold>2</bold> have
stronger degree of binding to BSA than previously reported complex
A (<italic>K</italic><sub>b</sub> = 4.00 × 10<sup>4</sup> M<sup>–1</sup>).</p><fig id="fig2" position="float"><label>Figure 2</label><caption><p>(A) UV–vis spectra of BSA (10 μM, 50 mM Tris-HCl,
50 mM NaCl, pH = 7.2) and complex <bold>1</bold> (0–4.0 μM)
reaction. Arrows indicate the direction of change in absorbance. Inset:
UV absorption spectra from 240 to 300 nm. (B) Fluorescence spectra
of BSA (10 μM, 50 mM Tris-HCl, 50 mM NaCl, pH = 7.2) reacted
with complex <bold>1</bold> (0–4.0 μM) (BSA: 10 μM;
λ<sub>ex</sub> = 280 nm; λ<sub>em</sub> = 343 nm).</p></caption><graphic xlink:href="ao9b01863_0003" id="gr2" position="float"></graphic></fig><p>Moreover, the study of BSA by synchronous fluorescence
spectroscopy
studied the molecular environment near the fluorophore.<sup><xref ref-type="bibr" rid="ref54">54</xref></sup> The characteristic information of the tyrosine
residue of BSA is Δλ = 15 nm in the wavelength interval
and the characteristic information of tryptophan residues is in the
wavelength interval Δλ = 60 nm. The fluorescence spectrum
is shown in <xref rid="fig3" ref-type="fig">Figure <xref rid="fig3" ref-type="fig">3</xref></xref>. The specific experimental steps are supplemented in the <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acsomega.9b01863/suppl_file/ao9b01863_si_001.pdf">Supporting Information</ext-link>, and we also studied the
interaction of complex <bold>2</bold> with BSA (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acsomega.9b01863/suppl_file/ao9b01863_si_001.pdf">Figures S2–S4</ext-link>). By studying the interaction between
the complex and BSA, it was shown that the synthesized drug can be
carried to the needed place by binding to BSA (<xref rid="tbl2" ref-type="other">Table <xref rid="tbl2" ref-type="other">2</xref></xref>).</p><fig id="fig3" position="float"><label>Figure 3</label><caption><p>(A) Synchronous fluorescence spectrum of the
reaction of BSA (10
μM, 50 mM Tris-HCl, 50 mM NaCl, pH = 7.2) with complex <bold>1</bold> (0–4.0 μM) when Δλ = 60 nm, and
(B) synchronous fluorescence spectrum of the reaction of BSA (10 μM,
50 mM Tris-HCl, 50 mM NaCl, pH = 7.2) with complex <bold>1</bold> (0–4.0
μM) at Δλ = 15 nm. Arrows indicate the changes in
wavelength as the compound increases.</p></caption><graphic xlink:href="ao9b01863_0004" id="gr3" position="float"></graphic></fig><table-wrap id="tbl2" position="float"><label>Table 2</label><caption><title>Values of <italic>K</italic><sub>b</sub>, <italic>K</italic><sub>SV</sub>, and <italic>K</italic><sub>q</sub> for Complexes <bold>1</bold> and <bold>2</bold> at 298 K</title></caption><table frame="hsides" rules="groups" border="0"><colgroup><col align="left"></col><col align="left"></col><col align="char" char="±"></col><col align="char" char="."></col><col align="char" char="×"></col><col align="char" char="."></col></colgroup><thead><tr><th style="border:none;" align="center">complex</th><th style="border:none;" align="center"><italic>T</italic> (K)</th><th style="border:none;" align="center" char="±"><italic>K</italic><sub>SV</sub> (10<sup>5</sup> M<sup>–1</sup>)</th><th style="border:none;" align="center" char="."><italic>K</italic><sub>q</sub> (10<sup>13</sup> M<sup>–1</sup> s<sup>–1</sup>)</th><th style="border:none;" align="center" char="×"><italic>K</italic><sub>b</sub> (M<sup>–1</sup>)</th><th style="border:none;" align="center" char="."><italic>n</italic></th></tr></thead><tbody><tr><td style="border:none;" align="left"><bold>1</bold></td><td style="border:none;" align="left">298</td><td style="border:none;" align="char" char="±">3.42 ± 0.4</td><td style="border:none;" align="char" char=".">3.42</td><td style="border:none;" align="char" char="×">3.71 × 10<sup>5</sup></td><td style="border:none;" align="char" char=".">0.885</td></tr><tr><td style="border:none;" align="left"><bold>2</bold></td><td style="border:none;" align="left">298</td><td style="border:none;" align="char" char="±">3.22 ± 0.2</td><td style="border:none;" align="char" char=".">3.22</td><td style="border:none;" align="char" char="×">3.31 × 10<sup>5</sup></td><td style="border:none;" align="char" char=".">0.944</td></tr></tbody></table></table-wrap></sec><sec id="sec2.4"><label>2.4</label><title>Cell Cycle Arrest</title><p>To investigate
the anticancer mechanism of complex entry into cells, analysis of
whether complex <bold>1</bold> with good antiproliferative capacity
can disrupt or prevent cell cycle to affect apoptosis by using flow
cytometry.<sup><xref ref-type="bibr" rid="ref55">55</xref></sup> A549 cells were treated with
complex <bold>1</bold> at the IC<sub>50</sub> concentrations of 0.25,
0.5, 1.0, and 2.0 for 24 h (<xref rid="fig4" ref-type="fig">Figure <xref rid="fig4" ref-type="fig">4</xref></xref>, <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acsomega.9b01863/suppl_file/ao9b01863_si_001.pdf">Table S1</ext-link>). By flow cytometry
analysis, the cells in the S phase increased by 8.58% compared to
the control treatment at a complex’s concentration of 2 ×
IC<sub>50</sub>. This has similar properties to complex A with the
same fluorophore. For complex A, the cells in the S phase increased
by 5.90% compared to the control treatment at a complex’s concentration
of 2 × IC<sub>50</sub>. Complex <bold>1</bold> is able to arrest
the S phase of the cell cycle more than complex A.</p><fig id="fig4" position="float"><label>Figure 4</label><caption><p>(A) Cell cycle analysis
of A549 cancer cells after 24 h of exposure
to complex <bold>1</bold> at 310 K. Cell staining for flow cytometry
was carried out using PI/RNase. (B) A histogram of the cell cycle
distribution. The data are quoted as mean ± SD of two replicates
of experimental data.</p></caption><graphic xlink:href="ao9b01863_0005" id="gr4" position="float"></graphic></fig></sec><sec id="sec2.5"><label>2.5</label><title>Apoptosis
Assay</title><p>Apoptosis plays an
important role in the evolution of organisms, the development of multiple
systems, and the stability of internal environment. Many metal anticancer
complexes can inhibit cell growth through the apoptotic pathway.<sup><xref ref-type="bibr" rid="ref43">43</xref></sup> We tried to use the annexin V/PI method to study
whether complex <bold>1</bold> causes apoptosis. Annexin V was used
as one of the sensitive indicators to detect early apoptosis of cells.
Propidium iodide (PI) is a nucleic acid dye that does not penetrate
intact cell membranes because of the increase in cell membrane permeability,
metaphase, and late apoptotic cells. Therefore, annexin V/PI are used
to distinguish cells at different stages of apoptosis. Flow cytometry
was used to analyze the apoptosis of the complex. A549 cells were
treated with 0.5, 1.0, 2.0, and 3.0 equiv of IC<sub>50</sub> complex <bold>1</bold> for 24 h. In the A549 control experiment, only 6.34% cells
(late apoptosis of early apoptosis) have undergone apoptosis. When
the concentration of the complex was 3 × IC<sub>50</sub>, a total
of 96.71% cells (early apoptosis, late apoptosis) developed apoptosis
(<xref rid="fig5" ref-type="fig">Figure <xref rid="fig5" ref-type="fig">5</xref></xref>, <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acsomega.9b01863/suppl_file/ao9b01863_si_001.pdf">Table S2</ext-link>). The experimental results show that
complex <bold>1</bold> could induce cell apoptosis and increase in
a dose-dependent manner.</p><fig id="fig5" position="float"><label>Figure 5</label><caption><p>(A) Apoptosis analysis of A549 cancer cells
after 24 h of exposure
to complex <bold>1</bold> at 310 K determined by flow cytometry with
annexin V-FITC vs PI staining. (B) Histogram showing populations for
A549 cells in four stages treated by complex <bold>1</bold>. Data
are quoted as mean ± SD of three replicates.</p></caption><graphic xlink:href="ao9b01863_0006" id="gr5" position="float"></graphic></fig></sec><sec id="sec2.6"><label>2.6</label><title>Cellular Localization Assay</title><p>First,
using the luminescent properties of the complex, we used confocal
microscopy to study the way these complexes enter the cell.<sup><xref ref-type="bibr" rid="ref37">37</xref></sup> We selected complex <bold>1</bold> to study
how the complexes entered the cells, pretreating A549 cells at 37
or 4 °C. Furthermore, pretreatment of A549 cells with carbonylcyanide <italic>m</italic>-chlorophenylhydrazone (CCCP, metabolic inhibitor 50 μM)
and chloroquine (endocytosis modulator 50 μM) and laser confocal
contrast experiments were performed on the samples under the same
parameters. The experimental results show that at room temperature
(37 °C), complex <bold>1</bold> (1 × IC<sub>50</sub>) mainly
enter the cell cytoplasm, but A549 cells treated at 4 °C and
CCCP did not enter the complex (<xref rid="fig6" ref-type="fig">Figure <xref rid="fig6" ref-type="fig">6</xref></xref>). As a result, the efficiency of cell entry was significantly
reduced, but treatment of A549 cells with chloroquine was almost the
same as at room temperature. This shows that the iridium complexes
in this system mainly enter into the cells in an energy-dependent
manner.</p><fig id="fig6" position="float"><label>Figure 6</label><caption><p>Effect of incubation temperature, metabolic inhibitor (CCCP, 50
μM), and chloroquine (50 μM) of complex <bold>1</bold> (1 × IC<sub>50</sub>, 1 h) measured by a two-photon laser scanning
microscope (complex: λ<sub>ex</sub> = 488 nm and λ<sub>em</sub> = 500–600 nm; scale bar: 20 μm).</p></caption><graphic xlink:href="ao9b01863_0007" id="gr6" position="float"></graphic></fig><p>Next, because of the difference in fluorophores in the ligands,
the colocalization of complexes <bold>1</bold> and <bold>2</bold> (1
× IC<sub>50</sub>) and Lyso Tracker Deep Red (LTDR, 500 nM) in
A549 cells was different, and the homologous localization coefficients
between Pearson correlation coefficients (PCC) were 0.64 and 0.87,
respectively (<xref rid="fig7" ref-type="fig">Figure <xref rid="fig7" ref-type="fig">7</xref></xref>).<sup><xref ref-type="bibr" rid="ref16">16</xref>,<xref ref-type="bibr" rid="ref56">56</xref></sup> Laser confocal experiments show that complex <bold>2</bold> modified with rhodamine B better targets lysosome than complex <bold>1</bold>, and complex <bold>1</bold> has a stronger targeting than
complex A (PCC = 0.53) with the same fluorophore. The colocalization
coefficients of rhodamine B hydrazide and rhodamine 6G hydrazide and
lysosome were 0.62 and 0.58, respectively.<sup><xref ref-type="bibr" rid="ref41">41</xref></sup> This indicates that the metal-containing drug will concentrate better
in lysosomes. In addition, complex and Mito Tracker Deep Red (500
nM) have not been colocated, and PCC can be ignored (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acsomega.9b01863/suppl_file/ao9b01863_si_001.pdf">Figure S5</ext-link>). The results indicate that the complex is distributed
in the cytoplasm and can specifically target lysosomes rather than
other organelles.</p><fig id="fig7" position="float"><label>Figure 7</label><caption><p>Intercellular colocalization of complexes <bold>1</bold> and <bold>2</bold> with LTDR. A549 cells were incubated with 1 ×
IC<sub>50</sub> of complexes <bold>1</bold> and <bold>2</bold> and
at 1
h, then stained with LTDR (500 nM, 1 h) at 310 K (complexes <bold>1</bold> and <bold>2</bold>: λ<sub>ex</sub> = 488 nm and λ<sub>em</sub> = 500–600 nm; LTDR, λ<sub>ex</sub> = 594 nm
and λ<sub>em</sub> = 600–660 nm). Scale bar: 20 μm.</p></caption><graphic xlink:href="ao9b01863_0008" id="gr7" position="float"></graphic></fig></sec><sec id="sec2.7"><label>2.7</label><title>Lysosomal Membrane Permeabilization</title><p>The lysosomal damage of complex <bold>1</bold> using the fluorescent
dye acridine orange (AO) was also investigated. The fluorescent dye
AO is a metachromatic dye. The single-stranded nucleic acid is an
orange-red fluorescent, and the double-stranded nucleic acid is a
green fluorescent. AO is weakly alkaline, and the pH inside the lysosome
is low. AO can enter the lysosome through the cell membrane structure
and combine with its internal hydrolase to produce orange-red fluorescence.<sup><xref ref-type="bibr" rid="ref16">16</xref>,<xref ref-type="bibr" rid="ref57">57</xref></sup> Studies have shown that apoptosis is accompanied by acidification
of the entire cell, including the nucleus. The lysosomes may play
an important role in the induction of apoptosis. When the lysosome
remains substantially intact, the AO dye can accumulate in the lysosome,
so more orange-red fluorescent fragments are visible in the cells.
The necrotic cells that have undergone apoptosis will destroy the
complete structure of the lysosome and destroy the accumulation ability
of AO, so the orange-red fluorescence will be less. After treatment
of A549 cells with complex <bold>1</bold> at 1 × IC<sub>50</sub> and 2 × IC<sub>50</sub>, the red fluorescence significantly
decreased with increasing drug toxicity (<xref rid="fig8" ref-type="fig">Figure <xref rid="fig8" ref-type="fig">8</xref></xref>). Furthermore, complex <bold>1</bold> can
cause permeabilization of the lysosomal membrane. We designed the
synthesis of synthetic iridium complexes in lysosomes, which would
lead to changes in the osmotic pressure of lysosomes and would cause
lysosomes to swell and rupture, leading to LMP. In addition, disruption
of lysosomal membrane integrity results in the release of proteases
from lysosomes into the cytosol, such as cathepsin B, which induces
cell death through a variety of mechanisms.<sup><xref ref-type="bibr" rid="ref7">7</xref></sup></p><fig id="fig8" position="float"><label>Figure 8</label><caption><p>LMP
in A549 cancer cells. (I) A549 cells without added complex <bold>1</bold>. A549 cells were incubated with complex <bold>1</bold> of
1 × IC<sub>50</sub> (II) and 2 × IC<sub>50</sub> (III) for
6 h and then stained with AO (5 μM, 15 min) at 310 K. The cells
were measured using a two-photon laser scanning microscope (AO green
fluorescence, λ<sub>ex</sub> = 488 nm and λ<sub>em</sub> = 510 ± 20 nm; AO red fluorescence, λ<sub>ex</sub> =
488 nm and λ<sub>em</sub> = 625 ± 20 nm). Scale bar: 20
μm.</p></caption><graphic xlink:href="ao9b01863_0009" id="gr8" position="float"></graphic></fig></sec><sec id="sec2.8"><label>2.8</label><title>Analysis
of Mitochondrial Membrane Potential</title><p>Loss of mitochondrial
membrane potential (MMP) may be one of the
important causes of apoptosis.<sup><xref ref-type="bibr" rid="ref10">10</xref></sup> Fluorescence
probe JC-1(5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethyl-imidacarbocyanine)
is used for detecting MMP in cells by flow cytometry.<sup><xref ref-type="bibr" rid="ref58">58</xref></sup> As the incubation concentration increased to 2 × IC<sub>50</sub> of complex <bold>1</bold>, the percentage of cells with
green fluorescence increased from 1.32 to 3.86% (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acsomega.9b01863/suppl_file/ao9b01863_si_001.pdf">Figure S6</ext-link> and <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acsomega.9b01863/suppl_file/ao9b01863_si_001.pdf">Table S3</ext-link>), indicating
that complex <bold>1</bold> had no significant effect on MMP. It may
be that the complex does not directly act on the mitochondria, so
the damage to the mitochondria is low.</p></sec><sec id="sec2.9"><label>2.9</label><title>Induction
of Reactive Oxygen Species in A549
Cancer Cells</title><p>The normal metabolism in the body can produce
reactive oxygen species (ROS), but under the pathological conditions,
excessive ROS usually cause damage to cells. According to reports,
transition-metal-based anticancer drugs can often induce cell death
by inducing cell damage.<sup><xref ref-type="bibr" rid="ref59">59</xref></sup> Using flow cytometry,
we studied changes in intracellular ROS content at various concentrations
of complex <bold>1</bold>. The results showed that when A549 cancer
cells were exposed to complex <bold>1</bold> for 24 h, it was observed
that the level of ROS induced by complex <bold>1</bold> in cancer
cells increased significantly in a dose-dependent manner. When the
concentration of complex was 0.5 × IC<sub>50</sub>, the content
of ROS was increased by 2.5 times compared with the control group
(<xref rid="fig9" ref-type="fig">Figure <xref rid="fig9" ref-type="fig">9</xref></xref>). This indicates
that the complex can induce an increase in intracellular ROS content,
which may be caused by mitochondrial stimulation caused by lysosomal
damage, thereby inducing apoptosis.<sup><xref ref-type="bibr" rid="ref60">60</xref></sup> However,
there was no significant change in ROS in cells exposed to N̂N
ligand complexes A and B. This is an exciting finding that our newly
designed synthetic complexes have new advantages in anticancer research.
In addition, intracellular ROS, which acts as a second messenger,
regulate many key signaling pathways, such as NF-κB. NF-κB
is a mammalian transcription factor that controls the expression of
cell survival genes and the induction of proinflammatory enzymes and
cytokines. Flow cytometry analysis showed that complex <bold>1</bold> significantly increased ROS levels. Excessive ROS can activate the
NF-κB channel. Therefore, we used flow cytometry to detect the
amount of NF-κBp65 protein in the cells exposed to the complex.
Compared with the control group, the content of NF-κBp65 protein
in the cells with complexes was significantly increased. However,
when <italic>N</italic>-acetylcysteine (a known antioxidant) was added
to the cells with complexes, the content of NF-κBp65 protein
was not significantly changed compared with the control group (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acsomega.9b01863/suppl_file/ao9b01863_si_001.pdf">Figure S7</ext-link>). The experimental results indicate
that NF-κB activity is increased by ROS regulation, and role
of ROS-NF-κB signaling pathway further induces apoptosis.</p><fig id="fig9" position="float"><label>Figure 9</label><caption><p>(A) Effect
of complex <bold>1</bold> on intracellular ROS levels
in A549 lung cancer cells treated at the indicated concentrations
for 24 h. (B) Histogram shows the level of ROS induction in A549 cancer
cells treated with complex <bold>1</bold>. Data were quoted as the
mean ± SD of three replicates.</p></caption><graphic xlink:href="ao9b01863_0010" id="gr9" position="float"></graphic></fig></sec><sec id="sec2.10"><label>2.10</label><title>Reaction with NADH Studies</title><p>Nicotinamide
adenine dinucleotide (NADH) is a reduced form of NADH. As NADH and
NAD<sup>+</sup> play a crucial role in biocatalysis, an increase in
NADH levels indicates the occurrence of metabolic imbalance.<sup><xref ref-type="bibr" rid="ref61">61</xref></sup> Previously, we have reported that NADH can provide
hydride to the half-sandwich Ir(III) complex and could produce ROS
and H<sub>2</sub>O<sub>2</sub>. Therefore, monitoring the redox state
of NADH is one of the important parameters that characterize the production
of ROS.<sup><xref ref-type="bibr" rid="ref59">59</xref></sup> We investigated the reaction
of complexes <bold>1</bold> and <bold>2</bold> (1 μM) with NADH
(100 μM) in 20% MeOH/80% H<sub>2</sub>O (v/v) by UV–Vis
at 298 K for 8 h. As the complex reacts with NADH, the turnover number
(TONs) of revolutions of complex <bold>1</bold> and complex <bold>2</bold> are calculated using a UV spectrophotometer by calculating
the difference in UV absorption at 339 nm (UV absorption peak of NADH)
(<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acsomega.9b01863/suppl_file/ao9b01863_si_001.pdf">Figure S8</ext-link>). The TONs of complex <bold>1</bold> (6.10%) and complex <bold>2</bold> (3.21%) were calculated.
It is indicated that there is no obvious complex reaction with NADH
in this system, which is not the main cause of the increase of intracellular
ROS.</p></sec><sec id="sec2.11"><label>2.11</label><title>Antimetastatic Properties</title><p>Tumor
metastasis is an important manifestation of malignant tumors. If tumor
cells are repeatedly transferred, the consequences are quite serious.
This is a major cause of refractory tumors. Therefore, it is very
important to study the mechanism of antitumor drugs against tumor
metastasis, so as to screen and develop new drugs that can promote
the body’s antitumor metastasis.<sup><xref ref-type="bibr" rid="ref45">45</xref></sup> Therefore, we examined the effect of complex <bold>1</bold> on A549
cells using a wound healing assay. During wound healing, the wound
healing of A549 cancer cells showed significant antimigration ability
after 24 h of treatment compared with the untreated control group
(<xref rid="fig10" ref-type="fig">Figure <xref rid="fig10" ref-type="fig">10</xref></xref>). MMPs
are a large family that can degrade various protein components in
the extracellular matrix, destroy the histological barrier of tumor
cell invasion, and play a key role in tumor invasion and metastasis.
Among the many MMPs, MMP-9 (matrix metalloproteinase 9) is involved
in angiogenesis, directly related to the degradation of the basement
membrane, and closely related to tumor metastasis and prognosis.<sup><xref ref-type="bibr" rid="ref62">62</xref>−<xref ref-type="bibr" rid="ref66">66</xref></sup> In order to further prove that the complex has the antimetastatic
ability of cancer cells, we used flow cytometry to detect the content
of MMP-9 in the cells exposed to the complex (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acsomega.9b01863/suppl_file/ao9b01863_si_001.pdf">Figure S9</ext-link>). The experimental results showed that intracellular
MMP-9 was compared with the blank control group. The content is significantly
reduced, thereby inhibiting the migration of cancer cells.</p><fig id="fig10" position="float"><label>Figure 10</label><caption><p>Wound healing
assay of A549 cells treated with or without complex <bold>1</bold> for 24 h. (A) Typical images were taken at 0 and 24 h. The
widths of wounds are indicated with the lines (μm). Scale bar:
20 μm. (B) Quantification of microscope images. Data are quoted
as mean ± SD of three replicates.</p></caption><graphic xlink:href="ao9b01863_0002" id="gr10" position="float"></graphic></fig></sec></sec><sec id="sec3"><label>3</label><title>Conclusions</title><p>Two kinds of rhodamine-modified
half-sandwich (III) complexes with
ĈN coordination were designed and synthesized. These complexes
have good antiproliferative ability while having good stability and
fluorescent properties. Both complexes could be combined with BSA.
Subsequently, we also performed a series of bioactivity tests on complex <bold>1</bold> using a cell flow cytometer. Cell cycle, apoptosis, MMP,
and ROS were examined. This complex <bold>1</bold> could block the
S phase of the cell cycle, promote early and late atrophy, and a significant
increase in intracellular ROS, but the interaction with NADH is not
obvious, which is also an interesting phenomenon. The experimental
results indicate that NF-κB activity is increased by ROS regulation,
and the role of ROS-NF-κB signaling pathway further induces
apoptosis. Next, confocal microscopy imaging experiments provide a
better way to observe the specific anticancer mechanisms of these
complexes. The way this complex enters A549 cells is an energy-dependent
pathway and preferentially accumulates in lysosomes rather than mitochondria.
Because of the difference in fluorophores, the degree of targeting
of the complex to lysosomes is also different. These iridium complexes
cause cell autolysis and cell death by destroying the lysosomal membrane.
Excitingly, the antimigration experiments prove that the iridium complex <bold>1</bold> we designed has good antimigration ability. These rhodamine-modified
complexes that target lysosomes may play an important role in the
research of anticancer mechanisms and intracellular imaging, and they
are promising candidates for future potential anticancer agents for
the treatment of cancer.</p></sec><sec id="sec4"><label>4</label><title>Materials and Methods</title><p>Detailed synthesis steps for ligands and complexes are provided
in the <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acsomega.9b01863/suppl_file/ao9b01863_si_001.pdf">Supporting Information (Figures S10–S14)</ext-link>.</p><p>L<sub>1</sub>: 1.063 g, yield: 89%.<sup>1</sup>H NMR (500
MHz,
CDCl<sub>3</sub>): δ 8.67 (d, <italic>J</italic> = 4.6 Hz, 1H),
8.44 (s, 1H), 8.06–8.02 (m, 1H), 7.90 (d, <italic>J</italic> = 8.3 Hz, 2H), 7.75 (t, <italic>J</italic> = 7.7 Hz, 1H), 7.69 (d, <italic>J</italic> = 7.9 Hz, 1H), 7.63 (d, <italic>J</italic> = 8.3 Hz, 2H),
7.51–7.46 (m, 2H), 7.25–7.22 (m, 1H), 7.07 (dd, <italic>J</italic> = 5.5, 2.8 Hz, 1H), 6.42 (s, 2H), 6.35 (s, 2H), 3.22 (q, <italic>J</italic> = 7.1 Hz, 4H), 1.87 (s, 6H), 1.31 (t, <italic>J</italic> = 7.1 Hz, 6H). Anal. Calcd for L<sub>1</sub>: C, 76.87; H, 5.94;
N, 11.80. Found: C, 76.78; H, 5.92; N, 11.76.</p><p>L<sub>2</sub>:
0.852 g, yield: 69%.<sup>1</sup>H NMR (500 MHz,
CDCl<sub>3</sub>): δ 8.74–8.59 (m, 2H), 8.00 (d, <italic>J</italic> = 7.7 Hz, 1H), 7.91 (d, <italic>J</italic> = 8.4 Hz, 2H),
7.74–7.64 (m, 4H), 7.52–7.46 (m, 2H), 7.20 (ddd, <italic>J</italic> = 6.5, 4.8, 1.4 Hz, 1H), 7.14 (d, <italic>J</italic> =
6.9 Hz, 1H), 6.57–6.42 (m, 4H), 6.25 (d, <italic>J</italic> = 8.0 Hz, 2H), 3.32 (q, <italic>J</italic> = 7.0 Hz, 8H), 1.15 (t, <italic>J</italic> = 7.0 Hz, 12H). Anal. Calcd for L<sub>2</sub>: C, 77.27;
H, 6.32; N, 11.26. Found: C, 77.31; H, 6.25; N, 11.20.</p><p>[(η<sup>5</sup>-C<sub>5</sub>Me<sub>4</sub>C<sub>6</sub>H<sub>4</sub>C<sub>6</sub>H<sub>5</sub>)Ir(L<sub>1</sub>)Cl]PF<sub>6</sub> (<bold>1</bold>): 0.110 g, yield: 60.25%. <sup>1</sup>H NMR (500
MHz, DMSO): δ 8.72 (s, 1H), 8.49 (d, <italic>J</italic> = 5.7
Hz, 1H), 8.13 (d, <italic>J</italic> = 8.2 Hz, 1H), 7.91 (d, <italic>J</italic> = 6.5 Hz, 1H), 7.87–7.81 (m, 2H), 7.74 (d, <italic>J</italic> = 7.4 Hz, 2H), 7.68–7.56 (m, 6H), 7.48 (t, <italic>J</italic> = 7.7 Hz, 2H), 7.39 (d, <italic>J</italic> = 7.3 Hz, 1H),
7.32 (d, <italic>J</italic> = 8.3 Hz, 2H), 7.19 (t, <italic>J</italic> = 7.7 Hz, 2H), 7.05 (d, <italic>J</italic> = 7.0 Hz, 1H), 6.23 (s,
1H), 6.20 (s, 1H), 6.17 (s, 1H), 6.11 (s, 1H), 3.14–3.05 (m,
4H), 1.82 (d, <italic>J</italic> = 19.8 Hz, 6H), 1.73–1.62
(m, 9H), 1.47 (s, 3H), 1.22–1.14 (m, 6H). Anal. Calcd for [(η<sup>5</sup>-C<sub>5</sub>Me<sub>4</sub>C<sub>6</sub>H<sub>4</sub>C<sub>6</sub>H<sub>5</sub>)Ir(L<sub>1</sub>)Cl] (1093.37): C, 64.79; H,
5.07; N, 6.40. Found: C, 64.66; H, 5.01; N, 6.20. MS <italic>m</italic>/<italic>z</italic>: 1058.92 [(η<sup>5</sup>-C<sub>5</sub>Me<sub>4</sub>C<sub>6</sub>H<sub>4</sub>C<sub>6</sub>H<sub>5</sub>)Ir(L<sub>1</sub>)]<sup>+</sup>.</p><p>[(η<sup>5</sup>-C<sub>5</sub>Me<sub>4</sub>C<sub>6</sub>H<sub>4</sub>C<sub>6</sub>H<sub>5</sub>)Ir(L<sub>2</sub>)Cl]PF<sub>6</sub> (<bold>2</bold>): 0.080 g, yield: 71.71%. <sup>1</sup>H NMR (500
MHz, DMSO): δ 8.94 (s, 1H), 8.46 (d, <italic>J</italic> = 5.4
Hz, 1H), 8.13 (d, <italic>J</italic> = 8.1 Hz, 1H), 7.91 (d, <italic>J</italic> = 7.7 Hz, 1H), 7.84 (dd, <italic>J</italic> = 18.9, 7.7
Hz, 2H), 7.73 (d, <italic>J</italic> = 9.5 Hz, 3H), 7.61 (ddd, <italic>J</italic> = 18.8, 17.3, 8.4 Hz, 5H), 7.48 (t, <italic>J</italic> = 7.7 Hz, 2H), 7.38 (s, 1H), 7.32 (d, <italic>J</italic> = 8.3 Hz,
2H), 7.19 (dd, <italic>J</italic> = 8.3, 4.7 Hz, 2H), 7.11 (d, <italic>J</italic> = 5.8 Hz, 1H), 6.42 (d, <italic>J</italic> = 9.0 Hz, 1H),
6.38 (d, <italic>J</italic> = 8.8 Hz, 1H), 6.36–6.30 (m, 4H),
3.31–3.22 (m, 8H), 1.70 (d, <italic>J</italic> = 12.5 Hz, 6H),
1.61 (s, 3H), 1.46 (s, 3H), 1.05 (dt, <italic>J</italic> = 29.8, 7.0
Hz, 12H). Anal. Calcd for [(η<sup>5</sup>-C<sub>5</sub>Me<sub>4</sub>C<sub>6</sub>H<sub>4</sub>C<sub>6</sub>H<sub>5</sub>)Ir(L<sub>2</sub>)Cl] (1121.40): C, 65.31; H, 5.30; N, 6.24. Found: C, 65.36;
H, 5.22; N, 6.18. MS <italic>m</italic>/<italic>z</italic>: 1086.05
[(η<sup>5</sup>-C<sub>5</sub>Me<sub>4</sub>C<sub>6</sub>H<sub>4</sub>C<sub>6</sub>H<sub>5</sub>)Ir(L<sub>2</sub>)]<sup>+</sup>.</p></sec></body><back><notes id="notes1" notes-type="si"><title>Supporting Information Available</title><p>The Supporting
Information is
available free of charge on the <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org">ACS Publications website</ext-link> at DOI: <ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/abs/10.1021/acsomega.9b01863">10.1021/acsomega.9b01863</ext-link>.<list id="silist" list-type="simple"><list-item><p>Detailed experimental
procedures, experimental pictures,
and related references for the following experiments: UV–vis
spectroscopy; stability and fluorescence characteristics of complexes
(picture of the stability of complex <bold>2</bold>); BSA binding
studies (experimental picture of complex <bold>2</bold>) combined
with BSA; cell culture; viability assay (MTT assay); cell cycle analysis
(experimental data of the cell cycle); induction of apoptosis (experimental
data of apoptosis); cellular localization assay (complexes and mitochondria
colocalization picture); mitochondrial membrane assay (picture of
the effect of complex <bold>1</bold> on MMP); ROS determination (effect
of complex <bold>1</bold> on intracellular NF-κBp65 protein
content); reaction with NADH (picture of the complexes reacting with
NADH); transwell migration assay (effect of complex <bold>1</bold> on intracellular MMP-9 content); AO assay; and materials and syntheses
(mass spectrometry and NMR spectroscopy of complexes) (<ext-link ext-link-type="uri" xlink:href="http://pubs.acs.org/doi/suppl/10.1021/acsomega.9b01863/suppl_file/ao9b01863_si_001.pdf">PDF</ext-link>)</p></list-item></list></p></notes><sec sec-type="supplementary-material"><title>Supplementary Material</title><supplementary-material content-type="local-data" id="sifile1"><media xlink:href="ao9b01863_si_001.pdf"><caption><p>ao9b01863_si_001.pdf</p></caption></media></supplementary-material></sec><notes notes-type="COI-statement" id="NOTES-d7e1770-autogenerated"><p>The authors declare no
competing financial interest.</p></notes><ack><title>Acknowledgments</title><p>The authors thank the National
Natural Science Foundation
of China (grant no. 21671118) and the Taishan Scholars Program for
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