{(1 R,2 R,4 R)-4-Methyl-1,2-cyclohexanediamine}oxalatoplatinum(II): A Novel Enantiomerically Pure Oxaliplatin Derivative Showing Improved Anticancer Activity in Vivo
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.
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.
supporting information; experimental part
p. 7356 - 7364
(2011/01/12)
Methyl-substituted trans-1,2-cyclohexanediamines as new ligands for oxaliplatin-type complexes
Three different pathways for the synthesis of substituted trans-(±)-1,2-cyclohexanediamines as new ligands for oxaliplatin-type compounds are presented. The different synthetic routes lead (i) by the synthesis of the compound via ortho-bromination of a su
Habala, Ladislav,Dworak, Claudia,Nazarov, Alexey A.,Hartinger, Christian G.,Abramkin, Sergey A.,Arion, Vladimir B.,Lindner, Wolfgang,Galanski, Markus,Keppler, Bernhard K.
p. 137 - 146
(2008/09/17)
METHOD FOR PRODUCING 1,2-DIAMINO-3-METHYLCYCLOHEXANE AND/OR 1,2-DIAMINO-4-METHYLCYCLOHEXANE
The invention relates to a method for producing 1,2-diamino-3-methylcyclohexane and/or 1,2-diamino-4-methylcyclohexane by reacting 2,3- and/or 3,4-diaminotoluol with hydrogen under high pressure and high temperature in the presence of a heterogene catalys
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Page/Page column 5-7
(2008/06/13)
Synthesis, crystal structure and cytotoxicity of new oxaliplatin analogues indicating that improvement of anticancer activity is still possible
Oxaliplatin, (trans-R,R-cyclohexane-1,2-diamine)oxalatoplatinum(II), has recently been approved for combination chemotherapy of metastatic colorectal cancer. Oxaliplatin is significantly more active than its trans-S,S isomer and the mixture of both enanti
Galanski, Markus,Yasemi, Afshin,Slaby, Susanna,Jakupec, Michael A.,Arion, Vladimir B.,Rausch, Monika,Nazarov, Alexey A.,Keppler, Bernhard K.
p. 707 - 714
(2007/10/03)
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