A Cytotoxic Indazole-based Gold(III) Carboxamide Pincer Complex Targeting DNA through Dual Binding Modes of Groove Binding and Alkylation.

Abstract

Gold(III) complexes have garnered increasing attention in drug delivery due to their structural and mechanistic similarities to cisplatin. This study investigates an indazole-based gold(III) carboxamide pincer complex, AuL, for its potential as an anticancer agent. Speciation analysis at physiological pH revealed that AuL predominantly exists as a neutral chlorinated species. The complex exhibited strong cytotoxicity against the MCF-7 breast cancer cell line, with an impressive IC50 value of 9 µM, while showing no significant activity against the HT-29 colon cancer cell line. Comprehensive analysis using electrophoresis, viscometry, UV-Vis, CD, LD spectroscopy, and biomolecular simulations demonstrated that AuL binds to DNA via a dual mechanism: minor groove binding and alkylation, with binding constants Ka1 =1.48 x109 M-1 and Ka2 = 6.59 x105 M-1, respectively. Our data indicates that AuL initially binds to the minor groove of DNA, at which point nucleobase substitute the Cl ion resulting in AuL alkylating to DNA In conclusion, the dual binding mode of AuL with DNA underscores its potential as a promising anticancer agent, which may open new avenues for drug discovery and development of metal-based therapeutics.