Synthesis, antiproliferative activity in cancer cells and DNA interaction studies of [Pt(cis-1,3-diaminocycloalkane)Cl2] analogs
The search for more effective platinum anticancer drugs has led to the design, synthesis, and preclinical testing of hundreds of new platinum complexes. This search resulted in the recognition and subsequent FDA approval of the third-generation Pt(II) anticancer drug, [Pt(1,2-diaminocyclohexane)(oxa...
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| Veröffentlicht in: | Journal of biological inorganic chemistry 2020-09, Vol.25 (6), p.913-924 |
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| creator | Hoeschele, James D. Kasparkova, Jana Kostrhunova, Hana Novakova, Olga Pracharova, Jitka Pineau, Paul Brabec, Viktor |
| description | The search for more effective platinum anticancer drugs has led to the design, synthesis, and preclinical testing of hundreds of new platinum complexes. This search resulted in the recognition and subsequent FDA approval of the third-generation Pt(II) anticancer drug, [Pt(1,2-diaminocyclohexane)(oxalate)], oxaliplatin, as an effective agent in treating colorectal and gastrointestinal cancers. Another promising example of the class of anticancer platinum(II) complexes incorporating the Pt(1,n-diaminocycloalkane) moiety is kiteplatin ([Pt(
cis
-1,4-DACH)Cl
2
], DACH = diaminocyclohexane). We report here our progress in evaluating the role of the cycloalkyl moiety in these complexes focusing on the synthesis, characterization, evaluation of the antiproliferative activity in tumor cells and studies of the mechanism of action of new [Pt(
cis
-1,3-diaminocycloalkane)Cl
2
] complexes wherein the
cis
-1,3-diaminocycloalkane group contains the cyclobutyl, cyclopentyl, and cyclohexyl moieties. We demonstrate that [Pt(
cis
-1,3-DACH)Cl
2
] destroys cancer cells with greater efficacy than the other two investigated 1,3-diamminocycloalkane derivatives, or cisplatin. Moreover, the investigated [Pt(
cis
-1,3-diaminocycloalkane)Cl
2
] complexes show selectivity toward tumor cells relative to non-tumorigenic normal cells. We also performed several mechanistic studies in cell-free media focused on understanding some early steps in the mechanism of antitumor activity of bifunctional platinum(II) complexes. Our data indicate that reactivities of the investigated [Pt(
cis
-1,3-diaminocycloalkane)Cl
2
] complexes and cisplatin with glutathione and DNA binding do not correlate with antiproliferative activity of these platinum(II) complexes in cancer cells. In contrast, we show that the higher antiproliferative activity in cancer cells of [Pt(
cis
-1,3-DACH)Cl
2
] originates from its highest hydrophobicity and most efficient cellular uptake.
Graphic abstract |
| doi_str_mv | 10.1007/s00775-020-01809-9 |
| format | Article |
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cis
-1,4-DACH)Cl
2
], DACH = diaminocyclohexane). We report here our progress in evaluating the role of the cycloalkyl moiety in these complexes focusing on the synthesis, characterization, evaluation of the antiproliferative activity in tumor cells and studies of the mechanism of action of new [Pt(
cis
-1,3-diaminocycloalkane)Cl
2
] complexes wherein the
cis
-1,3-diaminocycloalkane group contains the cyclobutyl, cyclopentyl, and cyclohexyl moieties. We demonstrate that [Pt(
cis
-1,3-DACH)Cl
2
] destroys cancer cells with greater efficacy than the other two investigated 1,3-diamminocycloalkane derivatives, or cisplatin. Moreover, the investigated [Pt(
cis
-1,3-diaminocycloalkane)Cl
2
] complexes show selectivity toward tumor cells relative to non-tumorigenic normal cells. We also performed several mechanistic studies in cell-free media focused on understanding some early steps in the mechanism of antitumor activity of bifunctional platinum(II) complexes. Our data indicate that reactivities of the investigated [Pt(
cis
-1,3-diaminocycloalkane)Cl
2
] complexes and cisplatin with glutathione and DNA binding do not correlate with antiproliferative activity of these platinum(II) complexes in cancer cells. In contrast, we show that the higher antiproliferative activity in cancer cells of [Pt(
cis
-1,3-DACH)Cl
2
] originates from its highest hydrophobicity and most efficient cellular uptake.
Graphic abstract</description><identifier>ISSN: 0949-8257</identifier><identifier>EISSN: 1432-1327</identifier><identifier>DOI: 10.1007/s00775-020-01809-9</identifier><identifier>PMID: 32851480</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Antineoplastic drugs ; Antitumor activity ; Antitumor agents ; Biochemistry ; Biomedical and Life Sciences ; Cancer ; Cisplatin ; Deoxyribonucleic acid ; DNA ; Drug development ; FDA approval ; Glutathione ; Hydrophobicity ; Life Sciences ; Microbiology ; Original Paper ; Oxalic acid ; Oxaliplatin ; Platinum ; Tumor cells</subject><ispartof>Journal of biological inorganic chemistry, 2020-09, Vol.25 (6), p.913-924</ispartof><rights>Society for Biological Inorganic Chemistry (SBIC) 2020</rights><rights>Society for Biological Inorganic Chemistry (SBIC) 2020.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c375t-d8012a2444c4eb4504f832f1ea66a6c4b2b7ae3bf7ae02097a8c40a7d183b4f93</citedby><cites>FETCH-LOGICAL-c375t-d8012a2444c4eb4504f832f1ea66a6c4b2b7ae3bf7ae02097a8c40a7d183b4f93</cites><orcidid>0000-0003-2706-6491 ; 0000-0001-7324-8347 ; 0000-0003-2700-1284 ; 0000-0002-5279-5381 ; 0000-0002-8233-1393</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s00775-020-01809-9$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00775-020-01809-9$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,780,784,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32851480$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hoeschele, James D.</creatorcontrib><creatorcontrib>Kasparkova, Jana</creatorcontrib><creatorcontrib>Kostrhunova, Hana</creatorcontrib><creatorcontrib>Novakova, Olga</creatorcontrib><creatorcontrib>Pracharova, Jitka</creatorcontrib><creatorcontrib>Pineau, Paul</creatorcontrib><creatorcontrib>Brabec, Viktor</creatorcontrib><title>Synthesis, antiproliferative activity in cancer cells and DNA interaction studies of [Pt(cis-1,3-diaminocycloalkane)Cl2] analogs</title><title>Journal of biological inorganic chemistry</title><addtitle>J Biol Inorg Chem</addtitle><addtitle>J Biol Inorg Chem</addtitle><description>The search for more effective platinum anticancer drugs has led to the design, synthesis, and preclinical testing of hundreds of new platinum complexes. This search resulted in the recognition and subsequent FDA approval of the third-generation Pt(II) anticancer drug, [Pt(1,2-diaminocyclohexane)(oxalate)], oxaliplatin, as an effective agent in treating colorectal and gastrointestinal cancers. Another promising example of the class of anticancer platinum(II) complexes incorporating the Pt(1,n-diaminocycloalkane) moiety is kiteplatin ([Pt(
cis
-1,4-DACH)Cl
2
], DACH = diaminocyclohexane). We report here our progress in evaluating the role of the cycloalkyl moiety in these complexes focusing on the synthesis, characterization, evaluation of the antiproliferative activity in tumor cells and studies of the mechanism of action of new [Pt(
cis
-1,3-diaminocycloalkane)Cl
2
] complexes wherein the
cis
-1,3-diaminocycloalkane group contains the cyclobutyl, cyclopentyl, and cyclohexyl moieties. We demonstrate that [Pt(
cis
-1,3-DACH)Cl
2
] destroys cancer cells with greater efficacy than the other two investigated 1,3-diamminocycloalkane derivatives, or cisplatin. Moreover, the investigated [Pt(
cis
-1,3-diaminocycloalkane)Cl
2
] complexes show selectivity toward tumor cells relative to non-tumorigenic normal cells. We also performed several mechanistic studies in cell-free media focused on understanding some early steps in the mechanism of antitumor activity of bifunctional platinum(II) complexes. Our data indicate that reactivities of the investigated [Pt(
cis
-1,3-diaminocycloalkane)Cl
2
] complexes and cisplatin with glutathione and DNA binding do not correlate with antiproliferative activity of these platinum(II) complexes in cancer cells. In contrast, we show that the higher antiproliferative activity in cancer cells of [Pt(
cis
-1,3-DACH)Cl
2
] originates from its highest hydrophobicity and most efficient cellular uptake.
Graphic abstract</description><subject>Antineoplastic drugs</subject><subject>Antitumor activity</subject><subject>Antitumor agents</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Cancer</subject><subject>Cisplatin</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>Drug development</subject><subject>FDA approval</subject><subject>Glutathione</subject><subject>Hydrophobicity</subject><subject>Life Sciences</subject><subject>Microbiology</subject><subject>Original Paper</subject><subject>Oxalic acid</subject><subject>Oxaliplatin</subject><subject>Platinum</subject><subject>Tumor cells</subject><issn>0949-8257</issn><issn>1432-1327</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNp9kU1rFTEUhoMo9lr9Ay4k4KZCU08-5iazLLf1A4oKrSuRkMlkatq5kzbJCHfXn-653mrBhZtzIHnynvfkJeQlhyMOoN8WLLphIIABN9Cy9hFZcCUF41Lox2QBrWqZEY3eI89KuQIA2fDmKdmTwjRcGViQu_PNVH-EEsshdVONNzmNcQjZ1fgzUOexxbqhcaLeTT5k6sM4FkR7evLpGM8rskiliZY69zEUmgb67Us98LEwfihZH906Tslv_JjceO2m8GY1iu8o4cZ0WZ6TJ4MbS3hx3_fJ13enF6sP7Ozz-4-r4zPmpW4q6w1w4YRSyqvQqQbUYKQYeHDLpVt61YlOuyC7ASt-SKud8Qqc7rmRnRpauU8Odrq44e0cSrXrWLbLoKE0FyuU1Ea1AhSir_9Br9Kc0e6WakCC4mqJlNhRPqdSchjsTY5rlzeWg93mY3f5WLRjf-djty5e3UvP3Tr0f5_8CQQBuQMKXk2XIT_M_o_sL-ttm3A</recordid><startdate>20200901</startdate><enddate>20200901</enddate><creator>Hoeschele, James D.</creator><creator>Kasparkova, Jana</creator><creator>Kostrhunova, Hana</creator><creator>Novakova, Olga</creator><creator>Pracharova, Jitka</creator><creator>Pineau, Paul</creator><creator>Brabec, Viktor</creator><general>Springer Berlin Heidelberg</general><general>Springer Nature B.V</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-2706-6491</orcidid><orcidid>https://orcid.org/0000-0001-7324-8347</orcidid><orcidid>https://orcid.org/0000-0003-2700-1284</orcidid><orcidid>https://orcid.org/0000-0002-5279-5381</orcidid><orcidid>https://orcid.org/0000-0002-8233-1393</orcidid></search><sort><creationdate>20200901</creationdate><title>Synthesis, antiproliferative activity in cancer cells and DNA interaction studies of [Pt(cis-1,3-diaminocycloalkane)Cl2] analogs</title><author>Hoeschele, James D. ; Kasparkova, Jana ; Kostrhunova, Hana ; Novakova, Olga ; Pracharova, Jitka ; Pineau, Paul ; Brabec, Viktor</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c375t-d8012a2444c4eb4504f832f1ea66a6c4b2b7ae3bf7ae02097a8c40a7d183b4f93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Antineoplastic drugs</topic><topic>Antitumor activity</topic><topic>Antitumor agents</topic><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Cancer</topic><topic>Cisplatin</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>Drug development</topic><topic>FDA approval</topic><topic>Glutathione</topic><topic>Hydrophobicity</topic><topic>Life Sciences</topic><topic>Microbiology</topic><topic>Original Paper</topic><topic>Oxalic acid</topic><topic>Oxaliplatin</topic><topic>Platinum</topic><topic>Tumor cells</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hoeschele, James D.</creatorcontrib><creatorcontrib>Kasparkova, Jana</creatorcontrib><creatorcontrib>Kostrhunova, Hana</creatorcontrib><creatorcontrib>Novakova, Olga</creatorcontrib><creatorcontrib>Pracharova, Jitka</creatorcontrib><creatorcontrib>Pineau, Paul</creatorcontrib><creatorcontrib>Brabec, Viktor</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of biological inorganic chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hoeschele, James D.</au><au>Kasparkova, Jana</au><au>Kostrhunova, Hana</au><au>Novakova, Olga</au><au>Pracharova, Jitka</au><au>Pineau, Paul</au><au>Brabec, Viktor</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis, antiproliferative activity in cancer cells and DNA interaction studies of [Pt(cis-1,3-diaminocycloalkane)Cl2] analogs</atitle><jtitle>Journal of biological inorganic chemistry</jtitle><stitle>J Biol Inorg Chem</stitle><addtitle>J Biol Inorg Chem</addtitle><date>2020-09-01</date><risdate>2020</risdate><volume>25</volume><issue>6</issue><spage>913</spage><epage>924</epage><pages>913-924</pages><issn>0949-8257</issn><eissn>1432-1327</eissn><abstract>The search for more effective platinum anticancer drugs has led to the design, synthesis, and preclinical testing of hundreds of new platinum complexes. This search resulted in the recognition and subsequent FDA approval of the third-generation Pt(II) anticancer drug, [Pt(1,2-diaminocyclohexane)(oxalate)], oxaliplatin, as an effective agent in treating colorectal and gastrointestinal cancers. Another promising example of the class of anticancer platinum(II) complexes incorporating the Pt(1,n-diaminocycloalkane) moiety is kiteplatin ([Pt(
cis
-1,4-DACH)Cl
2
], DACH = diaminocyclohexane). We report here our progress in evaluating the role of the cycloalkyl moiety in these complexes focusing on the synthesis, characterization, evaluation of the antiproliferative activity in tumor cells and studies of the mechanism of action of new [Pt(
cis
-1,3-diaminocycloalkane)Cl
2
] complexes wherein the
cis
-1,3-diaminocycloalkane group contains the cyclobutyl, cyclopentyl, and cyclohexyl moieties. We demonstrate that [Pt(
cis
-1,3-DACH)Cl
2
] destroys cancer cells with greater efficacy than the other two investigated 1,3-diamminocycloalkane derivatives, or cisplatin. Moreover, the investigated [Pt(
cis
-1,3-diaminocycloalkane)Cl
2
] complexes show selectivity toward tumor cells relative to non-tumorigenic normal cells. We also performed several mechanistic studies in cell-free media focused on understanding some early steps in the mechanism of antitumor activity of bifunctional platinum(II) complexes. Our data indicate that reactivities of the investigated [Pt(
cis
-1,3-diaminocycloalkane)Cl
2
] complexes and cisplatin with glutathione and DNA binding do not correlate with antiproliferative activity of these platinum(II) complexes in cancer cells. In contrast, we show that the higher antiproliferative activity in cancer cells of [Pt(
cis
-1,3-DACH)Cl
2
] originates from its highest hydrophobicity and most efficient cellular uptake.
Graphic abstract</abstract><cop>Berlin/Heidelberg</cop><pub>Springer Berlin Heidelberg</pub><pmid>32851480</pmid><doi>10.1007/s00775-020-01809-9</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0003-2706-6491</orcidid><orcidid>https://orcid.org/0000-0001-7324-8347</orcidid><orcidid>https://orcid.org/0000-0003-2700-1284</orcidid><orcidid>https://orcid.org/0000-0002-5279-5381</orcidid><orcidid>https://orcid.org/0000-0002-8233-1393</orcidid></addata></record> |
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| ispartof | Journal of biological inorganic chemistry, 2020-09, Vol.25 (6), p.913-924 |
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| source | SpringerLink Journals - AutoHoldings |
| subjects | Antineoplastic drugs Antitumor activity Antitumor agents Biochemistry Biomedical and Life Sciences Cancer Cisplatin Deoxyribonucleic acid DNA Drug development FDA approval Glutathione Hydrophobicity Life Sciences Microbiology Original Paper Oxalic acid Oxaliplatin Platinum Tumor cells |
| title | Synthesis, antiproliferative activity in cancer cells and DNA interaction studies of [Pt(cis-1,3-diaminocycloalkane)Cl2] analogs |
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