Chemical Stability of the Peroxide Bond Enables Diversified Synthesis of Potent Tetraoxane Antimalarials
Identifieur interne : 002317 ( Istex/Corpus ); précédent : 002316; suivant : 002318Chemical Stability of the Peroxide Bond Enables Diversified Synthesis of Potent Tetraoxane Antimalarials
Auteurs : Igor Opsenica ; Dejan Opsenica ; Kirsten S. Smith ; Wilbur K. Milhous ; Bogdan A. ŠolajaSource :
- Journal of Medicinal Chemistry [ 0022-2623 ] ; 2008.
Abstract
Of 17 prepared 1,2,4,5-tetraoxacyclohexanes stable to reductive and acidic conditions, 3 of them were more active than artemisinin against CQ and MFQ resistant strain TM91C235 and all compounds were more active in vitro against W2 than against D6 strain. In vivo, amines 10 and 11a cured all mice at higher doses with MCD ≤ 37.5 (mg/kg)/day. Triol 13 was exceptionally active against melanoma (LOX IMVI) and ovarian cancer (IGROV1), both with LC50 = 60 nM.
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DOI: 10.1021/jm701417a
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of Potent Tetraoxane Antimalarials</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>American Chemical Society</publisher><availability><licence>Copyright © 2008 American Chemical Society</licence><p>American Chemical Society</p></availability><date type="e-published" when="2008-03-11">2008</date><date when="2008-04-10">2008</date><date type="Copyright" when="2008">2008</date></publicationStmt><notesStmt><note type="content-type" source="article" scheme="https://content-type.data.istex.fr/ark:/67375/XTP-6N5SZHKN-D">article</note><note type="publication-type" scheme="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</note></notesStmt><sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">Chemical Stability of the Peroxide Bond Enables Diversified Synthesis of Potent Tetraoxane Antimalarials<ref type="bibr" target="#ref1"></ref></title><title level="a" type="short">Synthesis of Tetraoxane Antimalarials</title><author xml:id="author-0000"><persName><surname>Opsenica</surname><forename type="first">Igor</forename></persName><affiliation>Institute of Chemistry, Technology and Metallurgy, Belgrade, Serbia, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Washington, D.C. 20307-5100, and Faculty of Chemistry, University of Belgrade, Belgrade, Serbia</affiliation><note place="foot"><ref>†</ref><p>Institute of Chemistry, Technology and Metallurgy.</p></note></author><author xml:id="author-0001"><persName><surname>Opsenica</surname><forename type="first">Dejan</forename></persName><affiliation>Institute of Chemistry, Technology and Metallurgy, Belgrade, Serbia, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Washington, D.C. 20307-5100, and Faculty of Chemistry, University of Belgrade, Belgrade, Serbia</affiliation><note place="foot"><ref>†</ref><p>Institute of Chemistry, Technology and Metallurgy.</p></note></author><author xml:id="author-0002"><persName><surname>Smith</surname><forename type="first">Kirsten S.</forename></persName><affiliation>Institute of Chemistry, Technology and Metallurgy, Belgrade, Serbia, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Washington, D.C. 20307-5100, and Faculty of Chemistry, University of Belgrade, Belgrade, Serbia</affiliation><note place="foot"><ref>¶</ref><p>Walter Reed Army Institute of Research.</p></note></author><author xml:id="author-0003"><persName><surname>Milhous</surname><forename type="first">Wilbur K.</forename></persName><affiliation>Institute of Chemistry, Technology and Metallurgy, Belgrade, Serbia, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Washington, D.C. 20307-5100, and Faculty of Chemistry, University of Belgrade, Belgrade, Serbia</affiliation><note place="foot"><ref>¶</ref><p>Walter Reed Army Institute of Research.</p></note></author><author xml:id="author-0004" role="corresp"><persName><surname>Šolaja</surname><forename type="first">Bogdan A.</forename></persName><affiliation>Institute of Chemistry, Technology and Metallurgy, Belgrade, Serbia, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Washington, D.C. 20307-5100, and Faculty of Chemistry, University of Belgrade, Belgrade, Serbia</affiliation><note place="foot"><ref>§</ref><p>University of Belgrade.</p></note><email>bsolaja@chem.bg.ac.yu</email></author><idno type="istex">9C9966A54E410585DB7A11697BE935A4BDDC9BB3</idno><idno type="ark">ark:/67375/TPS-5KX3Q15W-K</idno><idno type="DOI">10.1021/jm701417a</idno></analytic><monogr><title level="j" type="main">Journal of Medicinal Chemistry</title><title level="j" type="abbrev">J. Med. Chem.</title><idno type="acspubs">jm</idno><idno type="coden">jmcmar</idno><idno type="pISSN">0022-2623</idno><idno type="eISSN">1520-4804</idno><imprint><publisher>American Chemical Society</publisher><date type="e-published" when="2008-03-11">2008</date><date when="2008-04-10">2008</date><biblScope unit="vol">51</biblScope><biblScope unit="issue">7</biblScope><biblScope unit="page" from="2261">2261</biblScope><biblScope unit="page" to="2266">2266</biblScope></imprint></monogr></biblStruct></sourceDesc></fileDesc><profileDesc><abstract><p><graphic url="jm-2007-01417a_0003.tif"></graphic></p><p>Of 17 prepared 1,2,4,5-tetraoxacyclohexanes stable to reductive and acidic conditions, 3 of them were more active than artemisinin against CQ and MFQ resistant strain TM91C235 and all compounds were more active in vitro against W2 than against D6 strain. In vivo, amines <hi rend="bold">10</hi> and <hi rend="bold">11a</hi> cured all mice at higher doses with MCD ≤ 37.5 (mg/kg)/day. Triol <hi rend="bold">13</hi> was exceptionally active against melanoma (LOX IMVI) and ovarian cancer (IGROV1), both with LC<hi rend="subscript">50</hi> = 60 nM.</p></abstract><textClass ana="subject"><keywords scheme="document-type-name"><term>Article</term></keywords></textClass><langUsage><language ident="zxx"></language></langUsage></profileDesc></teiHeader></istex:fulltextTEI></fulltext><metadata><istex:metadataXml wicri:clean="corpus acs not found" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="UTF-8"</istex:xmlDeclaration><istex:document><article dtd-version="1.1d1"><front><journal-meta><journal-id journal-id-type="acspubs">jm</journal-id><journal-id journal-id-type="coden">jmcmar</journal-id><journal-title-group><journal-title>Journal of Medicinal Chemistry</journal-title><abbrev-journal-title>J. Med. Chem.</abbrev-journal-title></journal-title-group><issn pub-type="ppub">0022-2623</issn><issn pub-type="epub">1520-4804</issn><publisher><publisher-name>American Chemical Society</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.1021/jm701417a</article-id><article-categories><subj-group subj-group-type="document-type-name"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Chemical Stability of the Peroxide Bond Enables Diversified Synthesis of Potent Tetraoxane Antimalarials<xref rid="ref1" ref-type="bibr"></xref></article-title><alt-title alt-title-type="short">Synthesis of Tetraoxane Antimalarials</alt-title></title-group><contrib-group><contrib contrib-type="author" id="ath1"><name name-style="western"><surname>Opsenica</surname><given-names>Igor</given-names></name><xref rid="afn1"></xref></contrib><contrib contrib-type="author" id="ath2"><name name-style="western"><surname>Opsenica</surname><given-names>Dejan</given-names></name><xref rid="afn1"></xref></contrib><contrib contrib-type="author" id="ath3"><name name-style="western"><surname>Smith</surname><given-names>Kirsten S.</given-names></name><xref rid="afn2"></xref></contrib><contrib contrib-type="author" id="ath4"><name name-style="western"><surname>Milhous</surname><given-names>Wilbur K.</given-names></name><xref rid="afn2"></xref></contrib><contrib contrib-type="author" corresp="yes" id="ath5"><name name-style="western"><surname>Šolaja</surname><given-names>Bogdan A.</given-names></name><xref rid="cor1"></xref><xref rid="afn3"></xref></contrib><aff>Institute of Chemistry, Technology and Metallurgy, Belgrade, Serbia, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Washington, D.C. 20307-5100, and Faculty of Chemistry, University of Belgrade, Belgrade, Serbia</aff></contrib-group><author-notes><corresp id="cor1"><label>*</label>
To whom correspondence should be addressed. Phone:
<phone>+381-11-263-86-06</phone>
. Fax: <fax>+381-11-263-60-61</fax>. E-mail: <email>bsolaja@chem.bg.ac.yu</email>.</corresp><fn id="afn1"><label>†</label><p>Institute of Chemistry, Technology and Metallurgy.</p></fn><fn id="afn2"><label>¶</label><p>Walter Reed Army Institute of Research.</p></fn><fn id="afn3"><label>§</label><p>University of Belgrade.</p></fn></author-notes><pub-date pub-type="epub"><day>11</day><month>03</month><year>2008</year></pub-date><pub-date pub-type="ppub"><day>10</day><month>04</month><year>2008</year></pub-date><volume>51</volume><issue>7</issue><fpage>2261</fpage><lpage>2266</lpage><supplementary-material content-type="pdf" xlink:href="jm701417a-File003.pdf" orientation="portrait" position="float"></supplementary-material><history><date date-type="issue-pub"><day>10</day><month>04</month><year>2008</year></date><date date-type="asap"><day>11</day><month>03</month><year>2008</year></date><date date-type="received"><day>10</day><month>11</month><year>2007</year></date></history><permissions><copyright-statement>Copyright © 2008 American Chemical Society</copyright-statement><copyright-year>2008</copyright-year><copyright-holder>American Chemical Society</copyright-holder></permissions><abstract><p content-type="toc-graphic"><graphic xlink:href="jm-2007-01417a_0003.tif" id="tgr1" orientation="portrait" position="float"></graphic></p><p>Of 17 prepared 1,2,4,5-tetraoxacyclohexanes stable to reductive and acidic conditions, 3 of them were more active than artemisinin against CQ and MFQ resistant strain TM91C235 and all compounds were more active in vitro against W2 than against D6 strain. In vivo, amines <bold>10</bold> and <bold>11a</bold> cured all mice at higher doses with MCD ≤ 37.5 (mg/kg)/day. Triol <bold>13</bold> was exceptionally active against melanoma (LOX IMVI) and ovarian cancer (IGROV1), both with LC<sub>50</sub> = 60 nM.</p></abstract><custom-meta-group><custom-meta><meta-name>document-id-old-9</meta-name><meta-value>jm701417a</meta-value></custom-meta><custom-meta><meta-name>document-id-new-14</meta-name><meta-value>jm-2007-01417a</meta-value></custom-meta><custom-meta><meta-name>ccc-price</meta-name><meta-value>40.75</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec id="sec1"><title>Introduction</title><p>The development of widespread drug resistance to chloroquine (CQ<xref rid="fn1"></xref>)
<fn id="fn1"><label>a</label><p>Abbreviations: CQ, chloroquine; MFQ, mefloquine; ART, artemisinin; CA, cholic acid; DCA, deoxycholic acid; MCD, mimimal curative dose; MAD, minimal active dose; MG_MID, mean graph midpoint.</p></fn>
has resulted in severe health issues for countries in malaria endemic regions. The antimalarial properties of artemisinin<xref rid="ref2" ref-type="bibr"></xref> and of other peroxides, such as 1,2,4,5-tetraoxacycloalkanes (tetraoxanes),<named-content content-type="bibref-group"><xref rid="ref3" ref-type="bibr"></xref>,<xref rid="ref4" ref-type="bibr"></xref></named-content> have recently begun to be exploited in the development of new approaches to fighting CQ-resistant strains of malaria. New tetraoxanes employing a steroidal backbone have now been prepared that are highly active, are inexpensive, and demonstrate low toxicity.<named-content content-type="bibref-group"><xref rid="ref5" ref-type="bibr"></xref>,<xref rid="ref6" ref-type="bibr"></xref></named-content></p><p>A part of our research in this field is focused on the development of a new type of tetraoxane with nonidentical substituents<xref rid="ref6" ref-type="bibr"></xref> that utilize a steroid and small cyclohexylidene carriers possessing secondary amide bonds. Also, during our work in this field we discovered that tetraoxanes are unusually stable, even at pH 1.6,<xref rid="cit6c" ref-type="bibr"></xref> a characteristic that subsequently allowed the synthesis of many interesting derivatives.</p><p>This communication encompasses the synthesis of various amino-functionalized antimalarials based on the appreciable stability of the tetraoxane moiety to reaction conditions such as reductive amination and LiAlH<sub>4</sub> reduction. Their respective antimalarial activities and the pronounced antiproliferative activity of certain products are reported along with in vitro metabolism studies.</p></sec><sec id="sec1.1"><title>Results and Discussion</title><p>The discovery of the appreciable stability of tetraoxanes to basic (pH 12, NaOH/<italic toggle="yes">i</italic>-PrOH/H<sub>2</sub>O, room temp → 80 °C)<xref rid="cit5a" ref-type="bibr"></xref> and acidic (pH 1.6, CH<sub>3</sub>OH/HCl, 37 °C)<xref rid="cit6c" ref-type="bibr"></xref> conditions initiated our research into the application of classical reagents for reductive amination conditions (NaBH<sub>3</sub>CN, NaBH(OAc)<sub>3</sub>), reduction (NaBH<sub>4</sub>, LiAlH<sub>4</sub>), and acetylation (cat. TMSOTf/Ac<sub>2</sub>O).<xref rid="ref7" ref-type="bibr"></xref></p><p>As noted previously,<named-content content-type="bibref-group"><xref rid="ref5" ref-type="bibr"></xref>,<xref rid="ref6" ref-type="bibr"></xref></named-content> our approach to functionalized tetraoxanes consists of an ester → acid → amide sequence. Thus, we prepared 1,1-dihydroperoxycyclohexane (<bold>1</bold>) in 50% yield,<named-content content-type="bibref-group"><xref rid="ref8" ref-type="bibr"></xref>,<xref rid="ref9" ref-type="bibr"></xref></named-content> which was subsequently coupled to methyl 4-oxocyclohexanecarboxylate, affording <bold>2</bold> in 28–35% yield and the side product hexaoxonane <bold>4</bold> (Scheme <xref rid="sch1"></xref>).<xref rid="ref10" ref-type="bibr"></xref> Upon transformations furnishing tetraoxane amides (<bold>2</bold> → <bold>3</bold> → <bold>5</bold>−<bold>7</bold>) in 65–79% yield, we explored the stability of the tetraoxane moiety under reducing conditions. We discovered that ester <bold>2</bold> was reduced in very high yield to alcohol <bold>8</bold> (Scheme <xref rid="sch1"></xref>) with no appreciable cleavage of the tetraoxane moiety observed with use of LiAlH<sub>4</sub>.<xref rid="ref11" ref-type="bibr"></xref> Stability of this moiety to LAH was confirmed by azide-to-amine reduction (Scheme <xref rid="sch1"></xref>) and the reduction of steroidal tetraoxane <bold>12</bold> to triol <bold>13</bold> (Scheme <xref rid="sch2"></xref>). Established stability<xref rid="cit6c" ref-type="bibr"></xref> of a tetraoxacyclohexane at pH 1.6 enabled us to use an acidic workup procedure (see <xref rid="sec3">Experimental Section</xref>). Additionally, we successfully applied a TMSOTf/Ac<sub>2</sub>O esterification method en route to mononalcohol <bold>15</bold>, which was further oxidized in 83% yield under aprotic conditions. Finally, NaBH(OAc)<sub>3</sub> and NaBH<sub>4</sub> were applied for reductive ammination and the reduction of mixed anhydride to alcohol, respectively. Thus, we have shown that the tetraoxane moiety is stable to reducing conditions (LiAlH<sub>4</sub>, NaBH(OAc)<sub>3</sub>, and NaBH<sub>4</sub>) and mild acidic conditions (protic and aprotic).</p><fig id="sch1" position="float" fig-type="scheme" orientation="portrait"><label>1</label><caption><title><xref rid="sch1-fn1"></xref></title></caption><graphic xlink:href="jm-2007-01417a_0001.tif" id="gs1" position="float" orientation="portrait"></graphic><p><fn id="sch1-fn1"><label>a</label><p>(a) 30% H<sub>2</sub>O<sub>2</sub>/HCl, CH<sub>3</sub>CN/CH<sub>2</sub>Cl<sub>2</sub>; (b) methyl 4-oxocyclohexanecarboxylate, CH<sub>2</sub>Cl<sub>2</sub>, H<sub>2</sub>SO<sub>4</sub>/CH<sub>3</sub>CN; (c) NaOH, <italic toggle="yes">i</italic>-PrOH/H<sub>2</sub>O/Δ; (d) ClCO<sub>2</sub>Et/Et<sub>3</sub>N, R<sub>1</sub>NH<sub>2</sub>, (e) LiAlH<sub>4</sub>, Et<sub>2</sub>O; (f) (1) MsCl, Py, (2) NaN<sub>3</sub>, DMF; (g) LiAlH<sub>4</sub>, Et<sub>2</sub>O; (h) carbonyl, NaBH(OAc)<sub>3</sub>, CH<sub>2</sub>Cl<sub>2</sub>.</p></fn></p></fig><fig id="sch2" position="float" fig-type="scheme" orientation="portrait"><label>2</label><caption><title><xref rid="sch2-fn1"></xref></title></caption><graphic xlink:href="jm-2007-01417a_0002.tif" id="gs2" position="float" orientation="portrait"></graphic><p><fn id="sch2-fn1"><label>a</label><p>(a) LiAlH<sub>4</sub>, Et<sub>2</sub>O; (b) Ac<sub>2</sub>O, TMSOTf, CH<sub>2</sub>Cl<sub>2</sub>; (c) K<sub>2</sub>CO<sub>3</sub>, MeOH; (d) PCC, CH<sub>2</sub>Cl<sub>2</sub>; (e) RNH<sub>2</sub>, NaBH(OAc)<sub>3</sub>, CH<sub>2</sub>Cl<sub>2</sub>; (f) (i) ClCO<sub>2</sub>Et/Et<sub>3</sub>N/THF; (ii) NaBH<sub>4</sub>; (g) (i) MsCl/Py; (ii) NaN<sub>3</sub>/DMF.</p></fn></p></fig><sec id="sec1.2"><title>Biological Screening</title><sec id="sec1.2.1"><title>Antimalarial Activity</title><p>All synthesized compounds were screened in vitro against CQ-susceptible, CQ-resistant, and multidrug resistant strains, D6, W2, and TM91C235 (Thailand), respectively.<xref rid="ref12" ref-type="bibr"></xref> The least active compounds were hexaoxonane <bold>4</bold>, a type of peroxide much less active than tetraoxanes, trioxanes, or trioxolanes,<xref rid="cit4c" ref-type="bibr"></xref> and the most polar compounds <bold>3</bold> and <bold>13</bold>. The significantly lower in vitro activity of acid <bold>3</bold>, in comparison to corresponding methyl ester <bold>2</bold>, was expected on the basis of previous results.<named-content content-type="bibref-group"><xref rid="cit4a" ref-type="bibr"></xref>,<xref rid="cit6c" ref-type="bibr"></xref></named-content> However, one can observe that the differences in activities of the tetraoxane acids and corresponding esters diminish with a decrease of polarity of the molecule. An example is in Table <xref rid="tbl1"></xref>, <bold>12</bold> and <bold>19</bold>, with further examples in refs <xref specific-use="ref-style=base-text" rid="cit6a" ref-type="bibr"></xref> and <xref specific-use="ref-style=base-text" rid="cit6b" ref-type="bibr"></xref>. Steroidal triol <bold>13</bold> is much less active than its diacetoxy derivative <bold>15</bold>, and this information clearly indicates that the protected hydroxy groups at C(7) and C(12) of cholic acid are needed for good activity. In addition, no effect on activity is excerted by the C(24)-O functionality; triacetate <bold>14</bold>, monoalcohol <bold>15</bold>, and starting ester <bold>12</bold> have very similar activities, and this trend is similar to that seen with trioxolanes.<xref rid="ref13" ref-type="bibr"></xref> The analysis given above possibly points to the high importance of the substitution pattern at C(7) and C(12) of the steroidal tetraoxanes.</p><table-wrap id="tbl1" position="float" orientation="portrait"><label>1</label><caption><title>In Vitro Antimalarial Activities of Tetraoxanes <bold>2</bold>–<bold>19</bold> against <italic toggle="yes">P. falciparum</italic> D6,<xref rid="tbl1-fn1"></xref> W2,<xref rid="tbl1-fn2"></xref> and TM91C235<xref rid="tbl1-fn3"></xref> Strains</title></caption><oasis:table><oasis:tgroup cols="9"><oasis:colspec align="left" colname="col1"></oasis:colspec><oasis:colspec align="char" char="." colname="col2"></oasis:colspec><oasis:colspec align="char" char="." colname="col3"></oasis:colspec><oasis:colspec align="char" char="." colname="col4"></oasis:colspec><oasis:colspec align="char" char="." colname="col5"></oasis:colspec><oasis:colspec align="char" char="." colname="col6"></oasis:colspec><oasis:colspec align="char" char="." colname="col7"></oasis:colspec><oasis:colspec align="char" char="." colname="col8"></oasis:colspec><oasis:colspec align="char" char="." colname="col9"></oasis:colspec><oasis:thead valign="middle"><oasis:row><oasis:entry align="center"></oasis:entry><oasis:entry align="center" nameend="col4" namest="col2">IC<sub>50</sub> (nM)</oasis:entry><oasis:entry align="center" nameend="col7" namest="col5">IC<sub>90</sub> (nM)</oasis:entry><oasis:entry align="center" nameend="col9" namest="col8">met. stab. <italic toggle="yes">t</italic><sub>1/2</sub> (min)</oasis:entry></oasis:row><oasis:row rowsep="1"><oasis:entry align="center">compd</oasis:entry><oasis:entry align="center">D6</oasis:entry><oasis:entry align="center">W2</oasis:entry><oasis:entry align="center">TM91C235</oasis:entry><oasis:entry align="center">D6</oasis:entry><oasis:entry align="center">W2</oasis:entry><oasis:entry align="center">TM91C235</oasis:entry><oasis:entry align="center">human</oasis:entry><oasis:entry align="center">mouse</oasis:entry></oasis:row></oasis:thead><oasis:tbody><oasis:row><oasis:entry><bold>2</bold></oasis:entry><oasis:entry>29.20<xref rid="tbl1-fn4"></xref></oasis:entry><oasis:entry>40.41<xref rid="tbl1-fn4"></xref></oasis:entry><oasis:entry>26.96</oasis:entry><oasis:entry>83.92</oasis:entry><oasis:entry>62.48</oasis:entry><oasis:entry>110.22</oasis:entry><oasis:entry></oasis:entry><oasis:entry></oasis:entry></oasis:row><oasis:row><oasis:entry><bold>3</bold></oasis:entry><oasis:entry>429.27<xref rid="tbl1-fn4"></xref></oasis:entry><oasis:entry>413.18<xref rid="tbl1-fn4"></xref></oasis:entry><oasis:entry>410.58</oasis:entry><oasis:entry>467.17</oasis:entry><oasis:entry>519.94</oasis:entry><oasis:entry>522.55</oasis:entry><oasis:entry></oasis:entry><oasis:entry></oasis:entry></oasis:row><oasis:row><oasis:entry><bold>4</bold></oasis:entry><oasis:entry>>499.41</oasis:entry><oasis:entry>>499.41</oasis:entry><oasis:entry>>499.41</oasis:entry><oasis:entry></oasis:entry><oasis:entry></oasis:entry><oasis:entry></oasis:entry><oasis:entry></oasis:entry><oasis:entry></oasis:entry></oasis:row><oasis:row><oasis:entry><bold>5</bold></oasis:entry><oasis:entry>23.96</oasis:entry><oasis:entry>20.16</oasis:entry><oasis:entry>27.24</oasis:entry><oasis:entry>42.75</oasis:entry><oasis:entry>40.36</oasis:entry><oasis:entry>55.62</oasis:entry><oasis:entry></oasis:entry><oasis:entry></oasis:entry></oasis:row><oasis:row><oasis:entry><bold>6</bold></oasis:entry><oasis:entry>19.27</oasis:entry><oasis:entry>21.98</oasis:entry><oasis:entry>25.34</oasis:entry><oasis:entry>49.17</oasis:entry><oasis:entry>44.54</oasis:entry><oasis:entry>53.89</oasis:entry><oasis:entry></oasis:entry><oasis:entry></oasis:entry></oasis:row><oasis:row><oasis:entry><bold>7</bold></oasis:entry><oasis:entry>11.24</oasis:entry><oasis:entry>9.72</oasis:entry><oasis:entry>7.24</oasis:entry><oasis:entry>15.10</oasis:entry><oasis:entry>17.87</oasis:entry><oasis:entry>12.79</oasis:entry><oasis:entry>>60</oasis:entry><oasis:entry>>60</oasis:entry></oasis:row><oasis:row><oasis:entry><bold>8</bold></oasis:entry><oasis:entry>15.18</oasis:entry><oasis:entry>6.54</oasis:entry><oasis:entry>12.62</oasis:entry><oasis:entry>22.52</oasis:entry><oasis:entry>11.57</oasis:entry><oasis:entry>23.66</oasis:entry><oasis:entry></oasis:entry><oasis:entry></oasis:entry></oasis:row><oasis:row><oasis:entry><bold>9</bold></oasis:entry><oasis:entry>9.87</oasis:entry><oasis:entry>6.07</oasis:entry><oasis:entry>11.29</oasis:entry><oasis:entry>20.34</oasis:entry><oasis:entry>11.04</oasis:entry><oasis:entry>22.24</oasis:entry><oasis:entry></oasis:entry><oasis:entry></oasis:entry></oasis:row><oasis:row><oasis:entry><bold>10</bold></oasis:entry><oasis:entry>12.84</oasis:entry><oasis:entry>7.79</oasis:entry><oasis:entry>19.75</oasis:entry><oasis:entry>24.14</oasis:entry><oasis:entry>16.00</oasis:entry><oasis:entry>28.98</oasis:entry><oasis:entry></oasis:entry><oasis:entry></oasis:entry></oasis:row><oasis:row><oasis:entry><bold>11a</bold></oasis:entry><oasis:entry>11.18</oasis:entry><oasis:entry>6.17</oasis:entry><oasis:entry>10.78</oasis:entry><oasis:entry>14.02</oasis:entry><oasis:entry>17.68</oasis:entry><oasis:entry>13.93</oasis:entry><oasis:entry>15.9</oasis:entry><oasis:entry>43.9</oasis:entry></oasis:row><oasis:row><oasis:entry><bold>11b</bold></oasis:entry><oasis:entry>9.40</oasis:entry><oasis:entry>7.54</oasis:entry><oasis:entry>9.27</oasis:entry><oasis:entry>14.54</oasis:entry><oasis:entry>22.91</oasis:entry><oasis:entry>16.73</oasis:entry><oasis:entry>38.7</oasis:entry><oasis:entry>9.9</oasis:entry></oasis:row><oasis:row><oasis:entry><bold>11c</bold></oasis:entry><oasis:entry>13.82</oasis:entry><oasis:entry>8.19</oasis:entry><oasis:entry>13.89</oasis:entry><oasis:entry>34.52</oasis:entry><oasis:entry>20.60</oasis:entry><oasis:entry>39.51</oasis:entry><oasis:entry>42.0</oasis:entry><oasis:entry>3.5</oasis:entry></oasis:row><oasis:row><oasis:entry><bold>12</bold></oasis:entry><oasis:entry>21.47<xref rid="tbl1-fn5"></xref></oasis:entry><oasis:entry>16.96<xref rid="tbl1-fn5"></xref></oasis:entry><oasis:entry></oasis:entry><oasis:entry></oasis:entry><oasis:entry></oasis:entry><oasis:entry></oasis:entry><oasis:entry></oasis:entry><oasis:entry></oasis:entry></oasis:row><oasis:row><oasis:entry><bold>13</bold></oasis:entry><oasis:entry>129.72</oasis:entry><oasis:entry>108.88</oasis:entry><oasis:entry>165.77</oasis:entry><oasis:entry>623.30</oasis:entry><oasis:entry>297.96</oasis:entry><oasis:entry>339.88</oasis:entry><oasis:entry></oasis:entry><oasis:entry></oasis:entry></oasis:row><oasis:row><oasis:entry><bold>14</bold></oasis:entry><oasis:entry>15.92</oasis:entry><oasis:entry>11.61</oasis:entry><oasis:entry>19.24</oasis:entry><oasis:entry>28.40</oasis:entry><oasis:entry>26.34</oasis:entry><oasis:entry>29.31</oasis:entry><oasis:entry></oasis:entry><oasis:entry></oasis:entry></oasis:row><oasis:row><oasis:entry><bold>15</bold></oasis:entry><oasis:entry>15.64</oasis:entry><oasis:entry>9.77</oasis:entry><oasis:entry>18.15</oasis:entry><oasis:entry>28.67</oasis:entry><oasis:entry>24.21</oasis:entry><oasis:entry>27.19</oasis:entry><oasis:entry></oasis:entry><oasis:entry></oasis:entry></oasis:row><oasis:row><oasis:entry><bold>17a</bold></oasis:entry><oasis:entry>24.12</oasis:entry><oasis:entry>11.10</oasis:entry><oasis:entry>20.77</oasis:entry><oasis:entry>49.29</oasis:entry><oasis:entry>26.85</oasis:entry><oasis:entry>73.88</oasis:entry><oasis:entry>>60</oasis:entry><oasis:entry>>60</oasis:entry></oasis:row><oasis:row><oasis:entry><bold>17b</bold></oasis:entry><oasis:entry>46.77</oasis:entry><oasis:entry>18.51</oasis:entry><oasis:entry>49.67</oasis:entry><oasis:entry>109.81</oasis:entry><oasis:entry>65.44</oasis:entry><oasis:entry>88.09</oasis:entry><oasis:entry>>60</oasis:entry><oasis:entry>>60</oasis:entry></oasis:row><oasis:row><oasis:entry><bold>18</bold></oasis:entry><oasis:entry>8.60</oasis:entry><oasis:entry>6.30</oasis:entry><oasis:entry>13.93</oasis:entry><oasis:entry>13.31</oasis:entry><oasis:entry>21.60</oasis:entry><oasis:entry>20.56</oasis:entry><oasis:entry></oasis:entry><oasis:entry></oasis:entry></oasis:row><oasis:row><oasis:entry><bold>19</bold></oasis:entry><oasis:entry>30.57<xref rid="tbl1-fn5"></xref></oasis:entry><oasis:entry>19.22<xref rid="tbl1-fn5"></xref></oasis:entry><oasis:entry></oasis:entry><oasis:entry></oasis:entry><oasis:entry></oasis:entry><oasis:entry></oasis:entry><oasis:entry></oasis:entry><oasis:entry></oasis:entry></oasis:row><oasis:row><oasis:entry>MFQ<xref rid="tbl1-fn6"></xref></oasis:entry><oasis:entry>7.34</oasis:entry><oasis:entry>4.89</oasis:entry><oasis:entry>22.45</oasis:entry><oasis:entry>19.49</oasis:entry><oasis:entry>9.45</oasis:entry><oasis:entry>50.14</oasis:entry><oasis:entry></oasis:entry><oasis:entry></oasis:entry></oasis:row><oasis:row><oasis:entry>CQ<xref rid="tbl1-fn6"></xref></oasis:entry><oasis:entry>13.17</oasis:entry><oasis:entry>616.94</oasis:entry><oasis:entry>244.76</oasis:entry><oasis:entry>17.58</oasis:entry><oasis:entry>1019.71</oasis:entry><oasis:entry>345.08</oasis:entry><oasis:entry></oasis:entry><oasis:entry></oasis:entry></oasis:row><oasis:row><oasis:entry>ART<xref rid="tbl1-fn7"></xref></oasis:entry><oasis:entry>9.0</oasis:entry><oasis:entry>6.7</oasis:entry><oasis:entry>13.04</oasis:entry><oasis:entry>12.8</oasis:entry><oasis:entry>11.5</oasis:entry><oasis:entry>17.40</oasis:entry><oasis:entry></oasis:entry><oasis:entry></oasis:entry></oasis:row></oasis:tbody></oasis:tgroup></oasis:table><table-wrap-foot><fn id="tbl1-fn1"><label>a</label><p><italic toggle="yes">P. falciparum</italic> African D6 clone.</p></fn><fn id="tbl1-fn2"><label>b</label><p><italic toggle="yes">P. falciparum</italic> Indochina W2 clone.</p></fn><fn id="tbl1-fn3"><label>c</label><p><italic toggle="yes">P. falciparum</italic> multidrug resistant TM91C23 strain (Thailand).</p></fn><fn id="tbl1-fn4"><label>d</label><p>Taken from ref <xref specific-use="ref-style=base-text" rid="cit3b" ref-type="bibr"></xref> for comparison.</p></fn><fn id="tbl1-fn5"><label>e</label><p>Taken from ref <xref specific-use="ref-style=base-text" rid="cit6a" ref-type="bibr"></xref> for comparison.</p></fn><fn id="tbl1-fn6"><label>f</label><p>Control drugs.</p></fn><fn id="tbl1-fn7"><label>g</label><p>Average of greater than eight replicates.</p></fn></table-wrap-foot></table-wrap><p>The in vitro antimalarial potency of dicyclohexylidene carboxylic amides <bold>5</bold>–<bold>7</bold>, prepared via mixed anhydrides, is higher than that of the ester <bold>3</bold>; however, they are less active than most amino derivatives. Thus, when directly compared (on the same plate), the activity of primary amide <bold>5</bold> appears to be one-half that of the corresponding amine <bold>10</bold>. Of the amides, the most active was the <italic toggle="yes">N</italic>,<italic toggle="yes">N</italic>-dimethylethan-1,2-diamino derivative <bold>7</bold>, projected to possess a weak base structural subunit. Resitance of the tetraoxane moiety to LAH and applied reductive amination conditions enabled easy approach to amines (<bold>8</bold> → <bold>9</bold> → <bold>10</bold> → <bold>11</bold>). For the first time we tested tetraoxane azides as possible antimalarial candidates. Interestingly, dicyclohexylidene azide <bold>9</bold> and its steroidal analogue <bold>18</bold> (<bold>19</bold> → <bold>15</bold> → <bold>18</bold>) are equipotent antimalarials with activities very similar to that of artemisinin.</p><p>In vitro metabolism studies were performed on compounds <bold>7</bold>, <bold>11a</bold>−<bold>c</bold>, <bold>17a</bold>,<bold>b</bold> to assess the bioavailability of possible drug candidates after oral administration. Metabolic stability assays were done using human and mouse liver microsomes.<xref rid="cit6c" ref-type="bibr"></xref> Stable compounds were defined as having half-lives of >60 min, and the relevant data are given in Table <xref rid="tbl1"></xref>. The data showed that <bold>7</bold>, <bold>17a</bold>, and <bold>17b</bold> were metabolically stable. However, <bold>11a</bold>, <bold>11b</bold>, and <bold>11c</bold> were metabolically less stable, with half-lives of 43.9, 9.9, and 3.5 min in mouse, and the lesser in vivo activity of <bold>11b</bold> compared to <bold>11a</bold> might be ascribed to the shorter half-life.</p><p>Five achiral dicyclohexylidene tetraoxanes were chosen for further evaluation in vivo against <italic toggle="yes">P. berghei</italic> infected mice using a modified Thompson test.<xref rid="cit6c" ref-type="bibr"></xref> The amide <bold>7</bold> was tested orally, while tetraoxane azide <bold>9</bold> and amines <bold>10</bold>, <bold>11a</bold>, and <bold>11b</bold> were administered subcutaneously. In both tests the mice were infected on day 0, and the tested compounds were administered accordingly on days 3−5 postinfection. To our surprise, tetraoxane <bold>7</bold>, despite being a metabolically stable compound (<italic toggle="yes">t</italic><sub>1/2</sub> > 60 min, no metabolite produced upon incubation with human, mouse, rat, and rhesus monkey microsomes), was inactive in the in vivo test even at a dose of 320 (mg/kg)/day (MTD > 960 mg/kg, Table <xref rid="tbl2"></xref>). However, peroxide azide <bold>9</bold> cured 4 of 5 mice at a dose of 300 (mg/kg)/day, with a mean survival time of 30.6 days versus 7–9 days in the control mice. Cure of 2 of 5 mice and increased survival were also seen in mice dosed with 150 (mg/kg)/day, with a group mean survival time of >26 days. In the present set of compounds, the most active were tetraoxane amines <bold>10</bold>, <bold>11a</bold>, and <bold>11b</bold>, with a minimum curative dose (MCD) of ≤37.5 (mg/kg)/day. Primary amine <bold>10</bold> cured all test animals at doses of 300 and 150 (mg/kg)/day and 2 of 5 at 37.5 (mg/kg)/day, with a minimum active dose (MAD) of 9.3 (mg/kg)/day. Secondary amines <bold>11a</bold> and <bold>11b</bold> were less active than <bold>10</bold>, both with minimal curative dose of 37.5 (mg/kg)/day. Toxicity was not observed at any dose; all animals not cured in the above tests died of malaria.</p><table-wrap id="tbl2" position="float" orientation="portrait"><label>2</label><caption><title>In Vivo Antimalarial Activities of Tested Tetraoxanes against <italic toggle="yes">P. berghei</italic><xref rid="tbl2-fn1"></xref></title></caption><oasis:table><oasis:tgroup cols="4"><oasis:colspec align="left" colname="col1"></oasis:colspec><oasis:colspec align="left" colname="col2"></oasis:colspec><oasis:colspec align="left" colname="col3"></oasis:colspec><oasis:colspec align="char" char="." colname="col4"></oasis:colspec><oasis:thead valign="middle"><oasis:row rowsep="1"><oasis:entry align="center">mg·kg<sup>−1</sup>·day<sup>−1</sup></oasis:entry><oasis:entry align="center" valign="bottom">mice dead/day died</oasis:entry><oasis:entry align="center">mice alive day 31/total</oasis:entry><oasis:entry align="center">survival time (day)<xref rid="tbl2-fn2"></xref></oasis:entry></oasis:row></oasis:thead><oasis:tbody><oasis:row><oasis:entry align="center" nameend="col4" namest="col1">Compound <bold>7</bold><xref rid="tbl2-fn3"></xref></oasis:entry></oasis:row><oasis:row><oasis:entry>320</oasis:entry><oasis:entry>1/14, 1/16, 1/17, 1/19, 1/21</oasis:entry><oasis:entry>0/5</oasis:entry><oasis:entry>17.4</oasis:entry></oasis:row><oasis:row><oasis:entry>80</oasis:entry><oasis:entry>3/7, 1/8, 1/9</oasis:entry><oasis:entry>0/5</oasis:entry><oasis:entry>7.6</oasis:entry></oasis:row><oasis:row><oasis:entry>20</oasis:entry><oasis:entry>1/6, 3/7, 1/9</oasis:entry><oasis:entry>0/5</oasis:entry><oasis:entry>7.2</oasis:entry></oasis:row><oasis:row><oasis:entry align="center" nameend="col4" namest="col1">Compound <bold>9</bold><xref rid="tbl2-fn4"></xref></oasis:entry></oasis:row><oasis:row><oasis:entry>300</oasis:entry><oasis:entry>1/29</oasis:entry><oasis:entry>4/5</oasis:entry><oasis:entry>30.6</oasis:entry></oasis:row><oasis:row><oasis:entry>150</oasis:entry><oasis:entry>1/15, 1/27, 1/28</oasis:entry><oasis:entry>2/5</oasis:entry><oasis:entry>26.4</oasis:entry></oasis:row><oasis:row><oasis:entry>37.5</oasis:entry><oasis:entry>1/10, 1/17, 1/20, 1/24, 1/25</oasis:entry><oasis:entry>0/5</oasis:entry><oasis:entry>19.2</oasis:entry></oasis:row><oasis:row><oasis:entry>9.3</oasis:entry><oasis:entry>1/8, 3/10, 1/12</oasis:entry><oasis:entry>0/5</oasis:entry><oasis:entry>10</oasis:entry></oasis:row><oasis:row><oasis:entry align="center" nameend="col4" namest="col1">Compound <bold>10</bold><xref rid="tbl2-fn4"></xref></oasis:entry></oasis:row><oasis:row><oasis:entry>300</oasis:entry><oasis:entry></oasis:entry><oasis:entry>5/5</oasis:entry><oasis:entry>>31</oasis:entry></oasis:row><oasis:row><oasis:entry>150</oasis:entry><oasis:entry></oasis:entry><oasis:entry>5/5</oasis:entry><oasis:entry>>31</oasis:entry></oasis:row><oasis:row><oasis:entry>37.5</oasis:entry><oasis:entry>1/17, 1/20, 1/24</oasis:entry><oasis:entry>2/5</oasis:entry><oasis:entry>24.6</oasis:entry></oasis:row><oasis:row><oasis:entry>9.3</oasis:entry><oasis:entry>1/8, 1/10, 1/14, 1/20, 1/31</oasis:entry><oasis:entry>0/5</oasis:entry><oasis:entry>16.6</oasis:entry></oasis:row><oasis:row><oasis:entry align="center" nameend="col4" namest="col1">Compound <bold>11a</bold><xref rid="tbl2-fn4"></xref></oasis:entry></oasis:row><oasis:row><oasis:entry>300</oasis:entry><oasis:entry></oasis:entry><oasis:entry>5/5</oasis:entry><oasis:entry>>31</oasis:entry></oasis:row><oasis:row><oasis:entry>150</oasis:entry><oasis:entry>1/21</oasis:entry><oasis:entry>4/5</oasis:entry><oasis:entry>29</oasis:entry></oasis:row><oasis:row><oasis:entry>37.5</oasis:entry><oasis:entry>2/17, 2/24</oasis:entry><oasis:entry>1/5</oasis:entry><oasis:entry>22.6</oasis:entry></oasis:row><oasis:row><oasis:entry>9.3</oasis:entry><oasis:entry>1/8, 2/11, 1/17, 1/20</oasis:entry><oasis:entry>0/5</oasis:entry><oasis:entry>13.4</oasis:entry></oasis:row><oasis:row><oasis:entry align="center" nameend="col4" namest="col1">Compound <bold>11b</bold><xref rid="tbl2-fn4"></xref></oasis:entry></oasis:row><oasis:row><oasis:entry>300</oasis:entry><oasis:entry>1/6, 1/19, 1/29</oasis:entry><oasis:entry>2/5</oasis:entry><oasis:entry>23.2</oasis:entry></oasis:row><oasis:row><oasis:entry>150</oasis:entry><oasis:entry>1/17, 1/18, 1/25, 1/27</oasis:entry><oasis:entry>1/5</oasis:entry><oasis:entry>23.6</oasis:entry></oasis:row><oasis:row><oasis:entry>37.5</oasis:entry><oasis:entry>1/8, 1/10, 1/16, 1/26</oasis:entry><oasis:entry>1/5</oasis:entry><oasis:entry>18.2</oasis:entry></oasis:row><oasis:row><oasis:entry>9.3</oasis:entry><oasis:entry>2/8, 2/9, 1/25</oasis:entry><oasis:entry>0/5</oasis:entry><oasis:entry>11.8</oasis:entry></oasis:row><oasis:row><oasis:entry align="center" nameend="col4" namest="col1">Infected Controls<xref rid="tbl2-fn5"></xref></oasis:entry></oasis:row><oasis:row><oasis:entry>0</oasis:entry><oasis:entry>7–9</oasis:entry><oasis:entry>0/5</oasis:entry><oasis:entry></oasis:entry></oasis:row></oasis:tbody></oasis:tgroup></oasis:table><table-wrap-foot><fn id="tbl2-fn1"><label>a</label><p>Groups of five <italic toggle="yes">P. berghei</italic> (KBG 173 strain) infected CD-1 mice were treated on days 3−5 postinfection with tetraoxanes suspended in 0.5% hydroxyethylcellulose/0.1% Tween-80 (po) or sesame oil (sc). Mice alive on day 31 with no parasites in a blood film are considered cured.</p></fn><fn id="tbl2-fn2"><label>b</label><p>Including cured mice.</p></fn><fn id="tbl2-fn3"><label>c</label><p>Compound administered orally.</p></fn><fn id="tbl2-fn4"><label>d</label><p>Compounds administered subcutaneously.</p></fn><fn id="tbl2-fn5"><label>e</label><p>All noninfected age controls survived (5/5).</p></fn></table-wrap-foot></table-wrap></sec><sec id="sec1.2.2"><title>Antiproliferative Activity</title><p>The antiproliferative activity of five compounds in Table <xref rid="tbl3"></xref> was tested against a diverse panel of 60 human cancer cell lines at NIH-NCI, starting at 10<sup>−4</sup> M.<xref rid="ref14" ref-type="bibr"></xref> Compounds <bold>2</bold>, <bold>5</bold>, <bold>7</bold>, and <bold>17b</bold> showed low to moderate activity as exemplified by low MG_MID values (Table <xref rid="tbl3"></xref>). However, the most polar, and one of the least active compounds in antimalarial screen, tetraoxane <bold>13</bold>, was found to be a very effective antiproliferative agent against a broad spectrum of cancer cells. The results of the activity against 19 cancer cell lines, shown in Table <xref rid="tbl4"></xref>, indicate that triol <bold>13</bold> totally inhibits the cancer growth (TGI) at submicromolar levels, with an average concentration of 0.40 µM. This pronounced antitumor activity is further accented by very high and selective toxicity of <bold>13</bold> against melanoma (LOX IMVI, LC<sub>50</sub> = 60 nM) and ovarian cancer (IGROV1, LC<sub>50</sub> = 60 nM).</p><table-wrap id="tbl3" position="float" orientation="portrait"><label>3</label><caption><title>MG_MID (TGI) Values for Compounds <bold>2</bold>, <bold>5</bold>, <bold>7</bold>, <bold>13</bold>, and <bold>17b</bold></title></caption><oasis:table><oasis:tgroup cols="5"><oasis:colspec align="left" colname="col1"></oasis:colspec><oasis:colspec align="char" char="." colname="col2"></oasis:colspec><oasis:colspec align="char" char="." colname="col3"></oasis:colspec><oasis:colspec align="char" char="." colname="col4"></oasis:colspec><oasis:colspec align="char" char="." colname="col5"></oasis:colspec><oasis:thead valign="middle"><oasis:row rowsep="1"><oasis:entry align="center"><bold>2</bold></oasis:entry><oasis:entry align="center"><bold>5</bold></oasis:entry><oasis:entry align="center"><bold>7</bold></oasis:entry><oasis:entry align="center"><bold>13</bold></oasis:entry><oasis:entry align="center"><bold>17b</bold></oasis:entry></oasis:row></oasis:thead><oasis:tbody><oasis:row><oasis:entry>−4.34</oasis:entry><oasis:entry>−4.13</oasis:entry><oasis:entry>−4.00</oasis:entry><oasis:entry>−5.92</oasis:entry><oasis:entry>−4.64</oasis:entry></oasis:row></oasis:tbody></oasis:tgroup></oasis:table></table-wrap><table-wrap id="tbl4" position="float" orientation="portrait"><label>4</label><caption><title>In Vitro Antiproliferative Activities of Tetraoxane <bold>13</bold> (µM, after 48 h, Selected Data)</title></caption><oasis:table><oasis:tgroup cols="5"><oasis:colspec align="left" colname="col1"></oasis:colspec><oasis:colspec align="left" colname="col2"></oasis:colspec><oasis:colspec align="char" char="." colname="col3"></oasis:colspec><oasis:colspec align="char" char="." colname="col4"></oasis:colspec><oasis:colspec align="char" char="." colname="col5"></oasis:colspec><oasis:thead valign="middle"><oasis:row rowsep="1"><oasis:entry align="center" nameend="col2" namest="col1">cell line</oasis:entry><oasis:entry align="center">GI<sub>50</sub><xref rid="tbl4-fn1"></xref></oasis:entry><oasis:entry align="center">TGI<xref rid="tbl4-fn2"></xref></oasis:entry><oasis:entry align="center">LC<sub>50</sub><xref rid="tbl4-fn3"></xref></oasis:entry></oasis:row></oasis:thead><oasis:tbody><oasis:row><oasis:entry>leukemia</oasis:entry><oasis:entry>CCRF-CEM</oasis:entry><oasis:entry>0.10</oasis:entry><oasis:entry>0.24</oasis:entry><oasis:entry>0.56</oasis:entry></oasis:row><oasis:row><oasis:entry></oasis:entry><oasis:entry>HL-60(TB)</oasis:entry><oasis:entry>0.15</oasis:entry><oasis:entry>0.31</oasis:entry><oasis:entry>0.62</oasis:entry></oasis:row><oasis:row><oasis:entry></oasis:entry><oasis:entry>MOLT-4</oasis:entry><oasis:entry>0.18</oasis:entry><oasis:entry>0.41</oasis:entry><oasis:entry>0.96</oasis:entry></oasis:row><oasis:row><oasis:entry></oasis:entry><oasis:entry>SR</oasis:entry><oasis:entry>0.16</oasis:entry><oasis:entry>0.34</oasis:entry><oasis:entry>0.72</oasis:entry></oasis:row><oasis:row><oasis:entry>non-small-cell lung cancer</oasis:entry><oasis:entry>EKVX</oasis:entry><oasis:entry>0.14</oasis:entry><oasis:entry>0.31</oasis:entry><oasis:entry>0.65</oasis:entry></oasis:row><oasis:row><oasis:entry></oasis:entry><oasis:entry>HOP-92</oasis:entry><oasis:entry>0.14</oasis:entry><oasis:entry>0.32</oasis:entry><oasis:entry>0.73</oasis:entry></oasis:row><oasis:row><oasis:entry></oasis:entry><oasis:entry>NCI-H460</oasis:entry><oasis:entry>0.24</oasis:entry><oasis:entry>0.62</oasis:entry><oasis:entry>2.68</oasis:entry></oasis:row><oasis:row><oasis:entry>CNS cancer</oasis:entry><oasis:entry>SF-295</oasis:entry><oasis:entry>0.17</oasis:entry><oasis:entry>0.33</oasis:entry><oasis:entry>0.66</oasis:entry></oasis:row><oasis:row><oasis:entry></oasis:entry><oasis:entry>SF-539</oasis:entry><oasis:entry>0.17</oasis:entry><oasis:entry>0.32</oasis:entry><oasis:entry>0.59</oasis:entry></oasis:row><oasis:row><oasis:entry></oasis:entry><oasis:entry>U251</oasis:entry><oasis:entry>0.21</oasis:entry><oasis:entry>0.46</oasis:entry><oasis:entry>0.98</oasis:entry></oasis:row><oasis:row><oasis:entry>melanoma</oasis:entry><oasis:entry>LOX IMVI</oasis:entry><oasis:entry>0.02</oasis:entry><oasis:entry>0.03</oasis:entry><oasis:entry>0.06</oasis:entry></oasis:row><oasis:row><oasis:entry></oasis:entry><oasis:entry>SK-MEL-2</oasis:entry><oasis:entry>0.20</oasis:entry><oasis:entry>0.39</oasis:entry><oasis:entry>0.73</oasis:entry></oasis:row><oasis:row><oasis:entry>ovarian cancer</oasis:entry><oasis:entry>IGROV1</oasis:entry><oasis:entry><0.01</oasis:entry><oasis:entry>0.01</oasis:entry><oasis:entry>0.06</oasis:entry></oasis:row><oasis:row><oasis:entry morerows="1">renal cancer</oasis:entry><oasis:entry>786-0</oasis:entry><oasis:entry>0.23</oasis:entry><oasis:entry>0.54</oasis:entry><oasis:entry>2.01</oasis:entry></oasis:row><oasis:row><oasis:entry>UO-31</oasis:entry><oasis:entry>0.04</oasis:entry><oasis:entry>0.17</oasis:entry><oasis:entry>0.61</oasis:entry></oasis:row><oasis:row><oasis:entry>prostate cancer</oasis:entry><oasis:entry>PC-3</oasis:entry><oasis:entry>0.29</oasis:entry><oasis:entry>0.99</oasis:entry><oasis:entry>3.41</oasis:entry></oasis:row><oasis:row><oasis:entry></oasis:entry><oasis:entry>DU-145</oasis:entry><oasis:entry>0.11</oasis:entry><oasis:entry>0.23</oasis:entry><oasis:entry>0.48</oasis:entry></oasis:row><oasis:row><oasis:entry>breast cancer</oasis:entry><oasis:entry>NCI/ADR-RES</oasis:entry><oasis:entry>0.25</oasis:entry><oasis:entry>0.59</oasis:entry><oasis:entry>4.27</oasis:entry></oasis:row><oasis:row><oasis:entry></oasis:entry><oasis:entry>T-47D</oasis:entry><oasis:entry>0.33</oasis:entry><oasis:entry>0.93</oasis:entry><oasis:entry>5.30</oasis:entry></oasis:row></oasis:tbody></oasis:tgroup></oasis:table><table-wrap-foot><fn id="tbl4-fn1"><label>a</label><p>50% growth inhibitory activity.</p></fn><fn id="tbl4-fn2"><label>b</label><p>Total growth inhibition.</p></fn><fn id="tbl4-fn3"><label>c</label><p>Concentration of the compound at which 50% of the cells are killed.</p></fn></table-wrap-foot></table-wrap></sec></sec></sec><sec id="sec2"><title>Conclusion</title><p>The stability of the tetraoxane moiety to hydride reduction and to acidic conditions (up to pH 1.6) enabled the synthesis of a series of mixed dicyclohexylidene tetraoxanes and a new type of steroidal mixed tetraoxane. In contrast to the steroidal tetraoxanes, the amines of the dicyclohexylidene series were more active in vitro and in vivo than the corresponding carboxylic amides. In vitro, all compounds were more active against the CQ-resistant W2 strain than against the CQ-susceptible D6. Compounds <bold>7</bold>, <bold>11a</bold>, <bold>11b</bold> were more active than ART against the CQ and MFQ-resistant strain TM91C235 (Thailand). In vivo, amines <bold>10</bold> and <bold>11a</bold> cured all mice at higher doses and exhibited MCD ≤ 37.5 (mg/kg)/day. As in our earlier studies, no peroxide bond scission was observed in any in vitro ADME studies. Of the tested compounds, triol <bold>13</bold> is exceptionally active in an in vitro antiproliferative screen against a panel of 60 cell lines.</p></sec><sec id="sec3"><title>Experimental Section</title><p>For general remarks see ref <xref specific-use="ref-style=base-text" rid="cit6c" ref-type="bibr"></xref>.</p><sec id="sec3.1"><title>1,1-Dihydroperoxycyclohexane (<bold>1</bold>)</title><p>Cyclohexanone (1 mL, 10 mmol) was dissolved at room temperature in a CH<sub>2</sub>Cl<sub>2</sub>/CH<sub>3</sub>CN mixture (20 mL, 1:3 v/v) followed by 30% H<sub>2</sub>O<sub>2</sub> (10.4 mL, 0.1 mol) and 6 drops of concentrated HCl. The reaction mixture was stirred for 2 h at room temperature and quenched with saturated NaHCO<sub>3</sub> and CH<sub>2</sub>Cl<sub>2</sub>. The organic layer was separated, and the water layer was additionally extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over anhydrous MgSO<sub>4</sub> and evaporated to dryness. The obtained crude product (740 mg, 50%) was used in the following step.</p></sec><sec id="sec3.2"><title>Methyl 7,8,15,16-Tetraoxadispiro[5.2.5.2]hexadecane-3-carboxylate and Methyl 7,8,15,16,23,24-Hexaoxatrispiro[5.2.5.2.5.2]tetracosane-3-carboxylate (<bold>2</bold> and <bold>4</bold>)</title><p>To a cooled solution (ice bath) of dihydroperoxide <bold>1</bold> (0.34 g, 2.3 mmol) in CH<sub>2</sub>Cl<sub>2</sub> (20 mL) was added ketone <bold>3</bold> (0.36 g, 2.3 mmol). After the mixture was stirred for 30 min at the same temperature, a cooled H<sub>2</sub>SO<sub>4</sub>/CH<sub>3</sub>CN mixture (1.66 mL, 1:10, v/v) was added dropwise. After an additional 50 min of stirring, the mixture was worked up in the usual manner and was purified by SiO<sub>2</sub> column chromatography (Lobar B, LichroPrep Si 60, eluent heptane/EtOAc = 95/5) affording 185 mg (28%) <bold>2</bold> and 37 mg (8%) <bold>4</bold>. <bold>2</bold>: colorless foam, softness 75–80 °C. Anal. (C<sub>14</sub>H<sub>22</sub>O<sub>6</sub>·<sup>1</sup>/<sub>4</sub>H<sub>2</sub>O) C, H. <bold>4</bold>: solid oil. Anal. (C<sub>20</sub>H<sub>32</sub>O<sub>8</sub>·H<sub>2</sub>O) C, H.</p></sec><sec id="sec3.3"><title>7,8,15,16-Tetraoxadispiro[5.2.5.2]hexadecane-3-carboxylic Acid (<bold>3</bold>)</title><p>Methyl ester <bold>2</bold> (142 mg, 0.5mmol) was hydrolyzed at 80 °C with NaOH (29.5 mg, 0.7mmol) in an <italic toggle="yes">i</italic>-PrOH/H<sub>2</sub>O mixture (12 mL, 3:1 v/v). After 15 min, the mixture was cooled and diluted with H<sub>2</sub>O (20 mL) and CH<sub>2</sub>Cl<sub>2</sub> (50 mL). The water layer was acidified to pH 2 with diluted HCl, and the layers were separated. The water layer was further extracted with CH<sub>2</sub>Cl<sub>2</sub> (3 × 20 mL). Then the combined organic layers were washed with water and brine, dried over anhydrous MgSO<sub>4</sub>, and evaporated to dryness. Trituration with Et<sub>2</sub>O afforded 120 mg (88%) of the product. With heating at 144–156 °C, the amorphous powder transforms into rhombic crystals, which melt at 168 °C. Anal. (C<sub>13</sub>H<sub>20</sub>O<sub>6</sub>·<sup>1</sup>/<sub>3</sub>H<sub>2</sub>O) C, H.</p></sec><sec id="sec3.4"><title>General Procedure for Preparation of Amides <bold>5</bold>–<bold>7</bold></title><p>A solution of <bold>4</bold> (250 mg, 0.92 mmol) in dry CH<sub>2</sub>Cl<sub>2</sub> (25 mL) with added Et<sub>3</sub>N (130µL, 0.92mmol) and ClCO<sub>2</sub>Et (90 µL, 0.92mmol) was stirred for 90 min at 0 °C. Amine was added, and after 30 min of stirring the mixture was warmed to room temperature. After 90 min it was diluted with H<sub>2</sub>O, the layers were separated, and the organic layer was washed with brine, dried over anhydrous MgSO<sub>4</sub>, and evaporated to dryness.</p></sec><sec id="sec3.5"><title>7,8,15,16-Tetraoxadispiro[5.2.5.2]hexadecane-3-carboxamide (<bold>5</bold>)</title><p>By use of the above procedure, <bold>3</bold> was reacted with 10 equiv of NH<sub>4</sub>Cl and 10 equiv of Et<sub>3</sub>N in dry CH<sub>2</sub>Cl<sub>2</sub> (20 mL) to afford the primary amide <bold>5</bold> (200 mg, 80%), which was then triturated with Et<sub>2</sub>O. <bold>5</bold>: mp 168–172 °C. Anal. (C<sub>13</sub>H<sub>21</sub>NO<sub>5</sub>·H<sub>2</sub>O) C, H.</p></sec><sec id="sec3.6"><title><italic toggle="yes">N</italic>-Propyl-7,8,15,16-tetraoxadispiro[5.2.5.2]hexadecane-3-carboxamide (<bold>6</bold>)</title><p>Acid <bold>3</bold> (250 mg, 0.92 mmol) was transformed into amide <bold>6</bold> (220 mg, 77%) using 10 equiv of <italic toggle="yes">n</italic>-PrNH<sub>2</sub> in dry CH<sub>2</sub>Cl<sub>2</sub> (45 mL). Column chromatography: Lobar B, LichroPrep RP-18, eluent MeOH/H<sub>2</sub>O = 8/2. Colorless foam, softness at 200–203 °C. Anal. (C<sub>16</sub>H<sub>27</sub>NO<sub>5</sub>) C, H.</p></sec><sec id="sec3.7"><title><italic toggle="yes">N</italic>-[2-(Dimethylamino)ethyl]-7,8,15,16-tetraoxadispiro[5.2.5.2]hexadecane-3-carboxamide (<bold>7</bold>)</title><p>Acid <bold>4</bold> (250 mg, 0.92 mmol) was transformed into amide <bold>7</bold> (280 mg, 90%) using 10 equiv of Me<sub>2</sub>NCH<sub>2</sub>CH<sub>2</sub>NH<sub>2</sub> in dry CH<sub>2</sub>Cl<sub>2</sub> (45 mL). Column chromatography: Lobar B, LichroPrep RP-18, eluent MeOH. Colorless foam, softness at 179–182 °C. Anal. (C<sub>17</sub>H<sub>30</sub>N<sub>2</sub>O<sub>5</sub>·H<sub>2</sub>O) C, H, N.</p></sec><sec id="sec3.8"><title>7,8,15,16-Tetraoxadispiro[5.2.5.2]hexadec-3-ylmethanol (<bold>8</bold>)</title><p>A solution of methyl ester <bold>2</bold> (1 g, 3.5 mmol) in dry ether (5 mL) was added in portions to a suspension of LiAlH<sub>4</sub> (177 mg, 4.7 mmol) in dry ether (5 mL) at room temperature. After 50 min it was diluted with H<sub>2</sub>O and EtOAc. The water layer was acidified to pH 2 with diluted HCl, the layers were separated, and the water layer was further extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over anhydrous Na<sub>2</sub>SO<sub>4</sub> and evaporated to dryness. The crude product was purified using dry flash chromatography, with an eluent of heptane/EtOAc (8/2). Yield 813 mg (90%). Colorless foam, softness 116–118 °C. Anal. (C<sub>13</sub>H<sub>22</sub>O<sub>5</sub>) C, H.</p></sec><sec id="sec3.9"><title>3-(Azidomethyl)-7,8,15,16-tetraoxadispiro[5.2.5.2]hexadecane (<bold>9</bold>)</title><p>To a solution of alcohol <bold>8</bold> (650 mg, 2.5 mmol) in pyridine (5 mL) at room temperature was added methanesulfonyl chloride (250 µL, 3.0 mmol). The mixture was stirred at room temperature for 2 h, then diluted with H<sub>2</sub>O and EtOAc. The water layer was acidified with diluted HCl, and the layers were separated. The water layer was further extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over anhydrous Na<sub>2</sub>SO<sub>4</sub> and evaporated to dryness. The obtained crude product was used in the following step. To a solution of mesylate (1.4 g, 4.2 mmol) in DMF (15 mL) was added NaN<sub>3</sub> (2.7g, 42 mmol). The mixture was stirred at 50 °C for 16 h before being quenched with water and EtOAc, and the layers were separated. The water layer was further extracted with EtOAc (3 × 75 mL). The combined organic layers were washed with brine, dried over anhydrous Na<sub>2</sub>SO<sub>4</sub>, and evaporated to dryness. The crude product was purified using dry flash chromatography with a heptane/EtOAc eluent (8/2). Yield 1.57 g (>99%). Colorless foam, softness 86–87 °C. Anal. (C<sub>13</sub>H<sub>21</sub>N<sub>3</sub>O<sub>4</sub>) C, H, N.</p></sec><sec id="sec3.10"><title>1-(7,8,15,16-Tetraoxadispiro[5.2.5.2]hexadec-3-yl)methanamine (<bold>10</bold>)</title><p>A solution of azide <bold>9</bold> (900 mg, 3.18 mmol) in dry ether (5 mL) was added in one portion to a suspension of LiAlH<sub>4</sub> (165 mg, 4.35 mmol) in dry ether (5 mL) at room temperature. After 50 min it was diluted with H<sub>2</sub>O and NaOH (10%). The solution was filtered, and the residue was washed with a small portion of ether. The filtrate was extracted with ether (2 × 50 mL), and the combined organic layers were dried over anhydrous Na<sub>2</sub>SO<sub>4</sub> and evaporated to dryness. The crude product was purified using dry flash chromatography with an EtOAc/MeOH/NH<sub>3</sub> eluent (8/1/1). Yield 475 mg (60%). Colorless foam, softness 75–77 °C. Anal. (C<sub>13</sub>H<sub>23</sub>NO<sub>4</sub>·<sup>1</sup>/<sub>2</sub>H<sub>2</sub>O) C, H, N.</p></sec><sec id="sec3.11"><title>7,8,15,16-Tetraoxadispiro[5.2.5.2]hexadecane-3-methanamine, <italic toggle="yes">N</italic>-cyclohexyl- (<bold>11a</bold>)</title><p>To a mixture of amine <bold>10</bold> (145 mg, 0.56 mmol) and cyclohexanone (59 µL, 0.56 mmol) in CH<sub>2</sub>Cl<sub>2</sub> (10 mL) was added sodium triacetoxyborohydride (286 mg, 1.35 mmol). After the mixture was stirred at room temperature for 18 h, it was poured into water and extracted with CH<sub>2</sub>Cl<sub>2</sub> (2 × 50 mL). The combined organic layers were dried over anhydrous Na<sub>2</sub>SO<sub>4</sub> and evaporated to dryness. The crude product was purified by dry flash chromatography with an eluent of EtOAc/MeOH/NH<sub>3aq</sub> = 27/0.5/0.5. Yield 97 mg (48%). Colorless foam, softness 104–106 °C. Anal. (C<sub>19</sub>H<sub>33</sub>NO<sub>4</sub>·<sup>1</sup>/<sub>3</sub>H<sub>2</sub>O) C, H, N.</p></sec><sec id="sec3.12"><title><italic toggle="yes">N</italic>-(7,8,15,16-Tetraoxadispiro[5.2.5.2]hexadec-3-ylmethyl)propan-2-amine (<bold>11b</bold>)</title><p>Amine <bold>10</bold> (220 mg, 0.85 mmol) was transformed into amine <bold>11b</bold> (172 mg, 67%) using acetone (69 µL, 0.94 mmol) and NaBH(OAc)<sub>3</sub> (473 mg, 2.23 mmol). The crude product was purified using dry flash chromatography with an eluent of EtOAc/MeOH (8/2). Colorless foam, softness 87–89 °C. Anal. (C<sub>16</sub>H<sub>29</sub>NO<sub>4</sub>) C, H, N.</p></sec><sec id="sec3.13"><title><italic toggle="yes">N</italic>-(Phenylmethyl)-7,8,15,16-tetraoxadispiro[5.2.5.2]hexadecane-3-methanamine (<bold>11c</bold>)</title><p>Amine <bold>10</bold> (100 mg, 0.39 mmol) was transformed into amine <bold>11c</bold> (45 mg, 50%) using PhCHO (40 µL, 0.39 mmol) and NaBH(OAc)<sub>3</sub> (200 mg, 0.94 mmol). The crude product was purified using dry flash chromatography with an eluent of EtOAc/MeOH (8/2) and repeated dry flash chromatography using EtOAc. Colorless foam, softness 61–62 °C. Anal. (C<sub>20</sub>H<sub>29</sub>NO<sub>4</sub>·<sup>1</sup>/<sub>2</sub>H<sub>2</sub>O) C, H, N.</p></sec><sec id="sec3.14"><title>5β-Cholan-7α,12α,24-triol-3-spiro-6′-(1′,2′,4′,5′-tetraoxacyclohexane)-3′-spirocyclohexane (<bold>13</bold>)</title><p>A solution of methyl ester <bold>12</bold> (100 mg, 0.16 mmol) in dry ether (5 mL) was added in one portion to a suspension of LiAlH<sub>4</sub> (21 mg, 0.57 mmol) in dry ether (5 mL) at room temperature. After 50 min the reaction was quenched with H<sub>2</sub>O and EtOAc. The water layer was acidified to pH 2 with diluted HCl, and layers were separated. The water layer was further extracted with EtOAc (3 × 50 mL), and the combined organic layers were dried over anhydrous Na<sub>2</sub>SO<sub>4</sub> and evaporated to dryness. Crude triol <bold>13</bold> was purified using dry flash chromatography using a heptane/EtOAc eluent (2/8). Yield 81 mg (98%). Colorless foam, softness 119–121 °C. [α]<sup>20</sup><sub>D</sub> +24.0 (<italic toggle="yes">c</italic> 0.2, CHCl<sub>3</sub>). Anal. (C<sub>30</sub>H<sub>50</sub>O<sub>7</sub>·<sup>1</sup>/<sub>2</sub>H<sub>2</sub>O) C, H.</p></sec><sec id="sec3.15"><title>7α,12α,24-Triacetoxy-5β-cholan-3-spiro-6′-(1′,2′,4′,5′-tetraoxacyclohexane)-3′-spirocyclohexane (<bold>14</bold>)</title><p>Alcohol <bold>13</bold> (1.67 g, 3.19 mmol) was dissolved in a previously prepared solution of Ac<sub>2</sub>O (1.7 mL) and TMSOTf (35 µL, 0.19 mmol) in dry CH<sub>2</sub>Cl<sub>2</sub> (30 mL) at room temperature. After stirring for 15 min, the reaction was quenched with saturated NaHCO<sub>3</sub> and the layers were separated. The water layer was further extracted with CH<sub>2</sub>Cl<sub>2</sub> (3 × 15 mL), and the combined organic layers were washed with brine, dried over anhydrous Na<sub>2</sub>SO<sub>4</sub>, and evaporated to dryness. Crude triacetate <bold>14</bold> was purified using dry flash chromatography using a heptane/EtOAc eluent (7/3). Yield 1.92 g (93%). Colorless foam, softness 136–137 °C. [α]<sup>20</sup><sub>D</sub> +55.5 (<italic toggle="yes">c</italic> 0.2, CHCl<sub>3</sub>). Anal. (C<sub>36</sub>H<sub>56</sub>O<sub>10</sub>) C, H.</p></sec><sec id="sec3.16"><title>7α,12α-Diacetoxy-5β-cholan-24-ol-3-spiro-6′-(1′,2′,4′,5′-tetraoxacyclohexane)-3′-spirocyclohexane (<bold>15</bold>)</title><p><bold>Hydrolysis of Triacetate 14.</bold> Triacetate <bold>14</bold> (1.67 g, 2.57 mmol) was dissolved in dry methanol (50 mL), followed by addition of anhydrous K<sub>2</sub>CO<sub>3</sub> (640 mg, 4.63 mmol). The suspension was stirred at room temperature for 5 h. The mixture was evaporated to dryness, dissolved in CH<sub>2</sub>Cl<sub>2</sub> and H<sub>2</sub>O, and the layers were separated. The organic layer was washed with brine, dried over anhydrous Na<sub>2</sub>SO<sub>4</sub>, and evaporated to dryness. The crude monoalcohol <bold>15</bold> was purified using dry flash chromatography using a heptane/EtOAc eluent (4/6). Yield 1.50 g (96%). Colorless foam, softness 207–210 °C. [α]<sup>20</sup><sub>D</sub> +57.0 (<italic toggle="yes">c</italic> 0.2, CHCl<sub>3</sub>). Anal. (C<sub>34</sub>H<sub>54</sub>O<sub>9</sub>) C, H.</p><p><bold>Via Mixed Anhydride.</bold> Acid <bold>19</bold> (50 mg, 0.08 mmol) was dissolved in dry THF (5 mL) and treated with Et<sub>3</sub>N (23 µL, 0.16 mmol) and ClCO<sub>2</sub>Et (15.34 µL, 0.16 mmol). After 3 h of stirring at 0 °C, NaBH<sub>4</sub> (30.5 mg, 0.8 mmol) was added. After an additional 24 h of stirring at room temperature, the mixture was diluted with H<sub>2</sub>O and CH<sub>2</sub>Cl<sub>2</sub>, and the layers were separated. The water layer was further extracted with CH<sub>2</sub>Cl<sub>2</sub>(2 × 50 mL) and the combined organic layers were dried over anh. Na<sub>2</sub>SO<sub>4</sub> and evaporated to dryness. The crude alcohol <bold>15</bold> was purified using dry flash chromatography using a heptane/EtOAc eluent (1/1). Yield 37 mg (76%).</p></sec><sec id="sec3.17"><title>7α,12α-Diacetoxy-5β-cholan-24-al-3-spiro-6′-(1′,2′,4′,5′-tetraoxacyclohexane)-3′-spirocyclohexane (<bold>16</bold>)</title><p>Alcohol <bold>15</bold> (100 mg, 0.16 mmol) was dissolved in dichloromethane (20 mL) followed by the addition of pyridinium chlorochromate (53 mg, 0.25 mmol). After 2 h the mixture was transferred to a silica gel column and eluted with CH<sub>2</sub>Cl<sub>2</sub> to afford 83 mg (83%) of <bold>16</bold> as a colorless solid.</p></sec><sec id="sec3.18"><title><italic toggle="yes">N</italic>-(<italic toggle="yes">n</italic>-Propyl)-7α,12α-diacetoxy-5β-cholan-24-amine-3-spiro-6′-(1′,2′,4′,5′-tetraoxacyclohexane)-3′-spirocyclohexane (<bold>17a</bold>)</title><p>To a mixture of crude aldehyde <bold>16</bold> (83 mg, 0.14 mmol) and <italic toggle="yes">n</italic>-PrNH<sub>2</sub> (23 µL, 0.28 mmol) in dichloromethane (20 mL), sodium triacetoxyborohydride (58 mg, 0.28 mmol) was added. The mixture was stirred at room temperature for 18 h. The mixture was then poured onto water and extracted with CH<sub>2</sub>Cl<sub>2</sub> (2 × 50 mL). The combined organic layers were dried over anhydrous Na<sub>2</sub>SO<sub>4</sub> and evaporated to dryness. The crude amine <bold>17a</bold> was purified by dry flash chromatography using an eluent of EtOAc/MeOH/NH<sub>3aq</sub> = 8/1/1. Yield 64 mg (72%). Colorless foam, softness 76–78 °C. [α]<sup>20</sup><sub>D</sub> +43.0 (<italic toggle="yes">c</italic> 0.2, CHCl<sub>3</sub>). Anal. (C<sub>37</sub>H<sub>61</sub>NO<sub>8</sub>) C, H, N.</p></sec><sec id="sec3.19"><title><italic toggle="yes">N</italic>-(2-Dimethylamino)ethyl)-7α,12α-diacetoxy-5β-cholan-24-amine-3-spiro-6′-(1′,2′,4′,5′-tetraoxacyclohexane)-3′-spirocyclohexane (<bold>17b</bold>)</title><p>Aldehyde <bold>16</bold> (200 mg, 0.33 mmol) was transformed into amine <bold>17b</bold> (168 mg, 75%) using Me<sub>2</sub>NCH<sub>2</sub>CH<sub>2</sub>NH<sub>2</sub> (72.5 µL, 0.66 mmol) and NaBH(OAc)<sub>3</sub> (140 mg, 0.66 mmol). The crude product was purified using dry flash chromatography with an EtOAc/MeOH/NH<sub>3aq</sub> (8/1/1) eluent. Solid. [α]<sup>20</sup><sub>D</sub> +45.0 (<italic toggle="yes">c</italic> 0.2, CHCl<sub>3</sub>). Anal. (C<sub>38</sub>H<sub>64</sub>N<sub>2</sub>O<sub>8</sub>·5H<sub>2</sub>O) C, H, N.</p></sec><sec id="sec3.20"><title>7α,12α-Diacetoxy-5β-cholan-24-azido-3-spiro-6′-(1′,2′,4′,5′-tetraoxacyclohexane)-3′-spirocyclohexane (<bold>18</bold>)</title><p>To a solution of alcohol <bold>15</bold> (200 mg, 0.33 mmol) in pyridine (4 mL) at room temperature was added methanesulfonyl chloride (31 µL, 0.4 mmol). The mixture was stirred at room temperature for 2 h, then diluted with H<sub>2</sub>O and EtOAc. The water layer was acidified with diluted HCl, and layers were separated. The water layer was further extracted with EtOAc (3 × 50 mL), and the combined organic layers were dried over anhydrous Na<sub>2</sub>SO<sub>4</sub> and evaporated to dryness. The obtained crude product was used in the following step. To a solution of mesylate (226 mg, 0.33 mmol) in DMF (5 mL) was added NaN<sub>3</sub> (214 mg, 3.3 mmol). The mixture was stirred at 50 °C for 16 h before being quenched with water and EtOAc, and layers were separated. The water layer was further extracted with EtOAc (3 × 75 mL), and the combined organic layers were washed with brine, dried over anhydrous Na<sub>2</sub>SO<sub>4</sub>, and evaporated to dryness. The crude product was purified using dry flash chromatography using a heptane/EtOAc (7/3) eluent. Yield 198,5 mg (95%). Solid oil. [α]<sup>20</sup><sub>D</sub> +44.5 (<italic toggle="yes">c</italic> 0.2, CHCl<sub>3</sub>). Anal. (C<sub>34</sub>H<sub>53</sub>N<sub>3</sub>O<sub>8</sub>·2H<sub>2</sub>O) C, H, N.</p></sec><sec id="sec3.21"><title>In Vitro Antimalarial Activity</title><p>The in vitro antimalarial drug susceptibility screen is a modification of the procedures first published by Desjardins et al.,<xref rid="ref15" ref-type="bibr"></xref> with modifications developed by Milhous et al.,<xref rid="ref16" ref-type="bibr"></xref> and the details are given in ref <xref specific-use="ref-style=base-text" rid="cit5a" ref-type="bibr"></xref>.</p></sec><sec id="sec3.22"><title>In Vivo Antimalarial Activity</title><p>The <italic toggle="yes">P. berghei</italic> mouse efficacy tests were conducted using a modified version of the Thompson test. Groups of five mice were inoculated intraperitoneally with erythrocytes infected with a drugsensitive strain of <italic toggle="yes">P. berghei</italic> on day 0. Drugs were suspended in 0.5% hydroxyethylcellulose/0.1% Tween-80 (for po administration) or in sesame oil (for sc administration). Drugs were administered orally once a day beginning on day 3 postinfection. Dosings are given in Table <xref rid="tbl2"></xref>. Cure was defined as survival until day 31 posttreatment. Untreated control mice die on day 7–9 postinfection.</p></sec><sec id="sec3.23"><title>In Vitro Metabolism Studies</title><p>The metabolic stability assay sample preparation was performed in a 96-well plate on a TECAN Genesis robotic sample processor. All incubations were carried out in 0.1 M sodium phosphate buffer (pH 7.4) in the presence of an NADPH-regenerating system (NADP<sup>+</sup> sodium salt, MgCl<sub>2</sub>·6H<sub>2</sub>O, and glucose 6-phosphate). Test drug (10 µM), microsomes (1 mg/mL total protein), buffer, and NADPH-regenerating system were warmed to 37 °C, and the reaction was initiated by the addition of glucose 6-phosphate dehydrogenase (G6PD). Samples were quenched using an equal volume of cold methanol. Samples were centrifuged to pellet the proteins, and the supernatant was analyzed by LC−MS/MS using fast LC gradient or isocratic methods. Percentages of parent drug remaining at each time point were calculated using the ratio of the peak area at each time point to the area of the time zero point. To calculate the half-life, a first-order rate of decay was assumed. A plot of the natural log (ln) of the drug concentration versus time was generated, where the slope of that line was −<italic toggle="yes">k</italic>. The half-life was calculated as 0.693/<italic toggle="yes">k</italic>.</p></sec></sec></body><back><ack><title>Acknowledgments</title><p>This work was supported by the Ministry of Science of Serbia (Grant No. 142022) and the Serbian Academy of Sciences and Arts. Research was conducted in compliance with the Animal Welfare Act and other federal statutes and regulations relating to animals and experiments involving animals and adheres to principles stated in the Guide for the Care and Use of Laboratory Animals, NRC Publication, 1996 edition. Material has been reviewed by the Walter Reed Army Institute of Research. There is no objection to its presentation or publication. The opinions or assertions contained herein are the private views of the author and are not to be construed as official or as reflecting the true views of the Department of the Army or the Department of Defense.</p></ack><notes id="si1" notes-type="si"><p>Analytical data of synthesized/isolated compounds. 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In vivo, amines 10 and 11a cured all mice at higher doses with MCD ≤ 37.5 (mg/kg)/day. Triol 13 was exceptionally active against melanoma (LOX IMVI) and ovarian cancer (IGROV1), both with LC50 = 60 nM.</abstract><note type="si" ID="si1">Analytical data of synthesized/isolated compounds. This material is available free of charge via the Internet at http://pubs.acs.org.</note><relatedItem type="host"><titleInfo><title>Journal of Medicinal Chemistry</title></titleInfo><titleInfo type="abbreviated"><title>J. Med. 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