trans,cis,cis-bis(benzoato)dichlorido(cyclohexane-1R,2R-diamine)platinum(IV): a prodrug candidate for the treatment of oxaliplatin-refractory colorectal cancer.
The gold standard for the treatment of metastatic colorectal cancer consists of combination chemotherapy. Over time, however, the development of chemoresistant tumor clones leads to relapse. It may be possible to overcome oxaliplatin chemoresistance in colorectal cancer cells by exploiting a complex obtained from the insertion of the cyclohexane-1R,2R-diamine carrier ligand (the same diamine present in oxaliplatin) into an octahedral Pt(IV) scaffold with high lipophilicity conferred by two benzoate axial ligands. Herein we report the synthesis, characterization (including X-ray structure), biological activity, and cellular accumulation of trans,cis,cis-bis(benzoato)dichlorido(cyclohexane-1R,2R-diamine)platinum(IV) complex in a panel of several human cancer cell lines, including a colon carcinoma cell line resistant to oxaliplatin. The compound under investigation shows the best performance in terms of in vitro anti-proliferative activity and ability to overcome chemoresistance, with respect to oxaliplatin and some other Pt(II) reference complexes. This result is likely related to the high lipophilicity shown by the title compound that favors its cellular accumulation by passive diffusion.
Dipartimento di Scienze del Farmaco, Università di Padova, Via Marzolo 5, 35131 Padova (Italy).
Valentina
V
Gandin
Cristina
C
Marzano
Giorgio
G
Pelosi
Mauro
M
Ravera
Elisabetta
E
Gabano
Domenico
D
Osella
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D056831:Coordination Complexes / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D018360:Crystallography, X-Ray; D003510:Cyclohexanes / Q000737:chemistry; D003959:Diamines / Q000737:chemistry; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D007536:Isomerism; D008968:Molecular Conformation; D009944:Organoplatinum Compounds / Q000627:therapeutic use; D000077150:Oxaliplatin; D010984:Platinum / Q000737:chemistry*; D011355:Prodrugs / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity
D000970:Antineoplastic Agents; D056831:Coordination Complexes; D003510:Cyclohexanes; D003959:Diamines; D009944:Organoplatinum Compounds; D011355:Prodrugs; D000077150:Oxaliplatin; C506365:Cyclohexane; D010984:Platinum
antitumor agents; chemoresistance; colon cancer; cytotoxicity; platinum complexes