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

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 Pt C 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 = OCH 3 ) 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. • Novel class of anticancer drugs have been developed (aza-PLADIPYs). • They possess a unique Pt C bond as part of their porphyrin-like structure. • Compounds displayed superior cytotoxicity over cisplatin. • Compounds had virtually no nephrotoxicity.