{(1R,2R,4R)-4-Methyl-1,2-cyclohexanediamine}oxalatoplatinum(II): A Novel Enantiomerically Pure Oxaliplatin Derivative Showing Improved Anticancer Activity in Vivo
- Author(s)
- Sergey Abramkin, Ute Jungwirth, Seied Mojtaba Valiahdi, Claudia Dworak, Ladislav Habala, Kristof Meelich, Walter Berger, Michael Jakupec, Christian Hartinger, Alexey A. Nazarov, Mathea Sophia Galanski, Bernhard Keppler
- 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.
- Organisation(s)
- Department of Inorganic Chemistry, Department of Organic Chemistry
- External organisation(s)
- Medizinische Universität Wien, École polytechnique fédérale de Lausanne
- Journal
- Journal of Medicinal Chemistry
- Volume
- 53
- Pages
- 7356-7364
- No. of pages
- 9
- ISSN
- 0022-2623
- DOI
- https://doi.org/10.1021/jm100953c
- Publication date
- 2010
- Peer reviewed
- Yes
- Austrian Fields of Science 2012
- 104003 Inorganic chemistry, 301305 Medical chemistry
- Sustainable Development Goals
- SDG 3 - Good Health and Well-being
- Portal url
- https://ucrisportal.univie.ac.at/en/publications/c6aa944f-5e98-4a32-b962-62f9341c8a04