Synthesis, Structure, and Biological Evaluation of a Platinum-Carbazole Conjugate

Abstract

Cisplatin resistance is caused, in part, by the efficient removal of the helix-distorting cisplatin 1,2-intrastrand crosslinks by nucleotide excision repair (NER) machinery. To make a platinum-DNA adduct that causes less helical distortion than the cisplatin 1,2-intrastrand adduct, we designed and synthesized a monofunctional platinum-carbazole conjugate (carbazoleplatin). The 2.5Å crystal structure of carbazoleplatin-DNA adduct revealed both the monoplatination of the N7 of a guanine (G) base and the intercalation into two G:C base pairs while causing a minor distortion of the DNA helix. A 50-mer dsDNA containing a single carbazoleplatin lesion was poorly processed by UvrABC endonuclease, the prokaryotic NER machinery that detects helical distortion and performs dual incision around the lesion. Our cell viability assay indicated that the cytotoxic pathways of carbazoleplatin might be different from those of cisplatin; carbazoleplatin was 5 to 8 times more cytotoxic than cisplatin against PANC-1 and MDA-MB-231 cancer cell lines.

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We designed and synthesized a monofunctional platinum-carbazole conjugate (carbazoleplatin). The crystal structure of carbazoleplatin-DNA adduct showed that carbazoleplatin modified N7 of a guanine (G) base and intercalated into two G:C base pairs without significantly distorting the double helix. UvrABC removed the carbazoleplatin-containing DNA less efficiently than the cisplatin 1,2-intrastrand crosslink-containing DNA. Carbazoleplatin was several-fold more cytotoxic than cisplatin in PANC-1 and MDA-MB-231 cell lines.

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