Synthesis and evaluation of Aza-PLADIPYs: A novel class of cytotoxic agents

IF 2.5 Q2 CHEMISTRY, MULTIDISCIPLINARY Results in Chemistry Pub Date : 2025-02-13 DOI:10.1016/j.rechem.2025.102114

Tanvi A. Desphande , Andi Zeng , Michelle Young , Terrence Nicholson , Karen Luo , Sudip Timilsina , Bryan Q. Spring , Peter Müller , Neha Kulkarni , Swati Betharia , Ronny Priefer

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Abstract

A novel class of platinum containing anticancer agents, specifically aza‑platinum-dipyrromethenes (aza-PLADIPYs) has been developed and assessed. These were synthesized with the aim of being dual-acting anticancer agents, hypothesized to produce both DNA crosslinking chemotoxicity and phototoxicity. The aza-PLADIPYs displayed a distorted square planar structure, which unexpectedly included a PtC bond. We compared the activity of these agents to that of Photofrin® (a photodynamic therapy (PDT) agent) and cisplatin (a DNA crosslinking agent). These compounds did not exhibit any PDT activity. However, they demonstrated promising cytotoxicity against partial cisplatin-resistant human ovarian carcinoma (OVCAR5) cells. Among the tested compounds, Compound 4 (R = OCH₃) exhibited the highest cytotoxicity, achieving approximately 78 % cell death at 250 μM, which is significantly higher than the 54 % cell death observed with cisplatin at the same concentration. Impressively, the aza-PLADIPYs displayed virtually no nephrotoxicity at concentrations up to 250 μM, when tested on HK-2 kidney proximal tubule cells, overcoming one of the major dose-limiting side effects of platinum containing anticancer agents.

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