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 cross-links 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 platinumcarbazole conjugate (carbazoplatin). The 2.5 Å crystal structure of carbazoplatin-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 carbazoplatin 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 carbazoplatin might be different from those of cisplatin; carbazoplatin was 5-8 times more cytotoxic than cisplatin against PANC-1 and MDA-MB-231 cancer cell lines. K E Y W O R D Scancer therapy, cisplatin, DNA damage, nucleotide excision repair, X-ray crystallography

A miR‐15a related polymorphism affects NSCLC prognosis via altering ERCC1 repair to platinum‐based chemotherapy

“…As known, there are at least several DNA repair systems in the human body, such as nucleotide excision repair (NER), base excision repair (BER) and mismatch repair (MMR) 9 . Among them, NER is the most significant and flexible one for excising platinum‐DNA adducts 10 . The main repair steps of NER include the separation of double helix at lesion sites, the excision of the lesion‐containing single stranded DNA fragment, the synthesis of a new DNA fragment to replace the gap and the ligation of the remaining single‐stranded nick 11 .…”

“…9 Among them, NER is the most significant and flexible one for excising platinum-DNA adducts. 10 The main repair steps of NER include the separation of double helix at lesion sites, the excision of the lesioncontaining single stranded DNA fragment, the synthesis of a new DNA fragment to replace the gap and the ligation of the remaining single-stranded nick. 11 Therefore, the NER pathway plays a pivotal role in repairing platinum-DNA adducts and may affect the sensitivity of individuals to platinum chemotherapy potentially.…”

Platinum complexes as inhibitors of DNA repair protein Ku70 and topoisomerase IIα in cancer cells

“…21,22 Carbazole derivatives may exert antitumor effects by inhibiting topoisomerases. 23–25 For example, ellipticine (5,11-dimethyl-6 H -pyrido[4,3- b ]carbazole) with carbazole as the main pharmacophore is a clinically approved topoisomerase inhibitor, and its derivatives exhibit inhibitory activity in several tumor types. 26…”

“…It was reported that a monofunctional platinum–carbazole conjugate with an ethylene diamine linker was more cytotoxic than CDDP. 23 The conjugate exerted different physical and biological effects depending on the platinum core, the topoisomerase inhibitor, and the linker. Recently we found that monofunctional Pt II complexes containing pyridine and –CH 2 Ph 3 P + moieties not only disrupt the function of mitochondria, 29 but also inhibit the activity of DNA topoisomerases.…”