{(1R,2R,4R)-4-methyl-1,2-cyclohexanediamine}oxalatoplatinum(II): a novel enantiomerically pure oxaliplatin derivative showing improved anticancer activity in vivo

Sergey A Abramkin, Ute Jungwirth, Seied M Valiahdi, Claudia Dworak, Ladislav Habala, Kristof Meelich, Walter Berger, Michael A Jakupec, Christian G Hartinger, Alexey A Nazarov, Markus Galanski, Bernhard K Keppler

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

Novel derivatives of the clinically established anticancer drug oxaliplatin were synthesized. Cytotoxicity of the compounds was studied in six human cancer cell lines by means of the MTT assay. Additionally, most promising complexes were also investigated in cisplatin- and oxaliplatin-resistant human cancer cell models. The therapeutic efficacy in vivo was studied in the murine L1210 leukemia model. Most remarkably, {(1R,2R,4R)-4-methyl-1,2-cyclohexanediamine}oxalatoplatinum(II), comprising an equatorial methyl substituent at position 4 of the cyclohexane ring, was as potent as oxaliplatin in vitro but distinctly more effective in the L1210 model in vivo at the optimal dose. The advantage observed in the in vivo situation was mainly based on a more favorable therapeutic index. The maximum tolerated dose of the novel analogue was higher than that of oxaliplatin and caused a greater increase in life span (>200% versus 152%), with more animals experiencing long-term survival (5/6 versus 2/6). These data support further (pre)clinical development of the methyl-substituted oxaliplatin analogue with improved anticancer activity.

Original languageEnglish
Pages (from-to)7356-64
Number of pages9
JournalJournal of Medicinal Chemistry
Volume53
Issue number20
DOIs
Publication statusPublished - 28 Oct 2010

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oxaliplatin
Leukemia L1210
Maximum Tolerated Dose
Cisplatin
Neoplasms
(4-methyl-1,2-cyclohexanediamine)oxalatoplatinum(II)
Cell Line

Keywords

  • Animals
  • Antineoplastic Agents/chemical synthesis
  • Cell Line, Tumor
  • Coordination Complexes/chemical synthesis
  • Drug Resistance, Neoplasm
  • Drug Screening Assays, Antitumor
  • Humans
  • Leukemia L1210/drug therapy
  • Mice
  • Mice, Inbred DBA
  • Neoplasm Transplantation
  • Organoplatinum Compounds/chemical synthesis
  • Stereoisomerism
  • Structure-Activity Relationship

Cite this

{(1R,2R,4R)-4-methyl-1,2-cyclohexanediamine}oxalatoplatinum(II) : a novel enantiomerically pure oxaliplatin derivative showing improved anticancer activity in vivo. / Abramkin, Sergey A; Jungwirth, Ute; Valiahdi, Seied M; Dworak, Claudia; Habala, Ladislav; Meelich, Kristof; Berger, Walter; Jakupec, Michael A; Hartinger, Christian G; Nazarov, Alexey A; Galanski, Markus; Keppler, Bernhard K.

In: Journal of Medicinal Chemistry, Vol. 53, No. 20, 28.10.2010, p. 7356-64.

Research output: Contribution to journalArticle

Abramkin, SA, Jungwirth, U, Valiahdi, SM, Dworak, C, Habala, L, Meelich, K, Berger, W, Jakupec, MA, Hartinger, CG, Nazarov, AA, Galanski, M & Keppler, BK 2010, '{(1R,2R,4R)-4-methyl-1,2-cyclohexanediamine}oxalatoplatinum(II): a novel enantiomerically pure oxaliplatin derivative showing improved anticancer activity in vivo', Journal of Medicinal Chemistry, vol. 53, no. 20, pp. 7356-64. https://doi.org/10.1021/jm100953c
Abramkin, Sergey A ; Jungwirth, Ute ; Valiahdi, Seied M ; Dworak, Claudia ; Habala, Ladislav ; Meelich, Kristof ; Berger, Walter ; Jakupec, Michael A ; Hartinger, Christian G ; Nazarov, Alexey A ; Galanski, Markus ; Keppler, Bernhard K. / {(1R,2R,4R)-4-methyl-1,2-cyclohexanediamine}oxalatoplatinum(II) : a novel enantiomerically pure oxaliplatin derivative showing improved anticancer activity in vivo. In: Journal of Medicinal Chemistry. 2010 ; Vol. 53, No. 20. pp. 7356-64.
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abstract = "Novel derivatives of the clinically established anticancer drug oxaliplatin were synthesized. Cytotoxicity of the compounds was studied in six human cancer cell lines by means of the MTT assay. Additionally, most promising complexes were also investigated in cisplatin- and oxaliplatin-resistant human cancer cell models. The therapeutic efficacy in vivo was studied in the murine L1210 leukemia model. Most remarkably, {(1R,2R,4R)-4-methyl-1,2-cyclohexanediamine}oxalatoplatinum(II), comprising an equatorial methyl substituent at position 4 of the cyclohexane ring, was as potent as oxaliplatin in vitro but distinctly more effective in the L1210 model in vivo at the optimal dose. The advantage observed in the in vivo situation was mainly based on a more favorable therapeutic index. The maximum tolerated dose of the novel analogue was higher than that of oxaliplatin and caused a greater increase in life span (>200{\%} versus 152{\%}), with more animals experiencing long-term survival (5/6 versus 2/6). These data support further (pre)clinical development of the methyl-substituted oxaliplatin analogue with improved anticancer activity.",
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AU - Abramkin, Sergey A

AU - Jungwirth, Ute

AU - Valiahdi, Seied M

AU - Dworak, Claudia

AU - Habala, Ladislav

AU - Meelich, Kristof

AU - Berger, Walter

AU - Jakupec, Michael A

AU - Hartinger, Christian G

AU - Nazarov, Alexey A

AU - Galanski, Markus

AU - Keppler, Bernhard K

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N2 - Novel derivatives of the clinically established anticancer drug oxaliplatin were synthesized. Cytotoxicity of the compounds was studied in six human cancer cell lines by means of the MTT assay. Additionally, most promising complexes were also investigated in cisplatin- and oxaliplatin-resistant human cancer cell models. The therapeutic efficacy in vivo was studied in the murine L1210 leukemia model. Most remarkably, {(1R,2R,4R)-4-methyl-1,2-cyclohexanediamine}oxalatoplatinum(II), comprising an equatorial methyl substituent at position 4 of the cyclohexane ring, was as potent as oxaliplatin in vitro but distinctly more effective in the L1210 model in vivo at the optimal dose. The advantage observed in the in vivo situation was mainly based on a more favorable therapeutic index. The maximum tolerated dose of the novel analogue was higher than that of oxaliplatin and caused a greater increase in life span (>200% versus 152%), with more animals experiencing long-term survival (5/6 versus 2/6). These data support further (pre)clinical development of the methyl-substituted oxaliplatin analogue with improved anticancer activity.

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KW - Coordination Complexes/chemical synthesis

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KW - Drug Screening Assays, Antitumor

KW - Humans

KW - Leukemia L1210/drug therapy

KW - Mice

KW - Mice, Inbred DBA

KW - Neoplasm Transplantation

KW - Organoplatinum Compounds/chemical synthesis

KW - Stereoisomerism

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