Novel Antitumor Cisplatin and Transplatin Derivatives Containing 1‑Methyl-7-Azaindole: Synthesis, Characterization, and Cellular Responses

• Published in: Journal of medicinal chemistry 2015-01, Vol.58 (2), p.847-859
• Main Authors: Pracharova, Jitka, Saltarella, Teresa, Radosova Muchova, Tereza, Scintilla, Simone, Novohradsky, Vojtech, Novakova, Olga, Intini, Francesco P, Pacifico, Concetta, Natile, Giovanni, Ilik, Petr, Brabec, Viktor, Kasparkova, Jana
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Cell Cycle - drug effects; Cisplatin - analogs & derivatives; DNA - metabolism; Humans; Indoles - chemistry; Organoplatinum Compounds - chemical synthesis; Organoplatinum Compounds - chemistry; Organoplatinum Compounds - pharmacology; Protein Binding; Tumor Suppressor Protein p53 - physiology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm501420k

The current work investigates the effect of new bifunctional and mononuclear Pt(II) compounds, the cis- and trans-isomers of [PtCl2(NH3)(L)] (L = 1-methyl-7-azaindole, compounds 1 and 2, respectively), on growth and viability of human carcinoma cells as well as their putative mechanism(s) of cytotoxicity. The results show that substitution of 1-methyl-7-azaindole for ammine in cisplatin or transplatin results in an increase of the toxic efficiency, selectivity for tumor cells in cisplatin-resistant cancer cells, and activation of the trans geometry. The differences in the cytotoxic activities of 1 and 2 were suggested to be due to their different DNA binding mode, different capability to induce cell cycle perturbations, and fundamentally different role of transcription factor p53 in their mechanism of action. Interestingly, both isomers make it possible to detect their cellular uptake and distribution in living cells by confocal microscopy without their modification with an optically active tag.