A monofunctional platinum(II)-based anticancer agent from a salicylanilide derivative: Synthesis, antiproliferative activity, and transcription inhibition

• A salicylanilide–Pt conjugate, SA–Pt, was synthesized and biologically evaluated.
• The complexes showed identical cytotoxicities compared with cisplatin.
• SA–Pt entered cells efficiently, arrested cell cycle, and triggered apoptosis.
• SA–Pt weakly inhibited transcription, indicating a distinct mechanism of action.

Cationic monofunctional platinum(II)-based anticancer agents with a general formula of cis-[Pt(NH3)2(N-donor)Cl]+ have recently drawn significant attention due to their unique mode of action, distinctive anticancer spectrum, and promising antitumor activity both in vitro and in vivo. Understanding the mechanism of action of novel monofunctional platinum compounds through rational drug design will aid in the further development of active agents. In this study, we synthesized and evaluated a monofunctional platinum-based anticancer agent SA–Pt containing a bulky salicylanilide moiety. The antiproliferative activity of SA–Pt was close to that of cisplatin. Mechanism studies revealed that SA–Pt entered HeLa cells more efficiently than cisplatin, blocked the cell cycle at the S-phase, and induced apoptosis. The compound bound to DNA as effectively as cisplatin, but did not block RNA polymerase II-mediated transcription as strongly as cisplatin, indicating that once the compound formed Pt-DNA lesions, the salicylanilide group was more easily recognized and removed. This study not only enriches the family of monofunctional platinum-based anticancer agents but also guides the design of more potent monofunctional platinum complexes.

A unique monofunctional Pt(II) anticancer agent (SA–Pt) containing a bulky salicylanilide moiety was synthesized. SA–Pt showed cytotoxicity against a panel of human cancer cells. The compound entered HeLa cells more efficiently than cisplatin, induced apoptosis, but had a weaker transcription inhibitory effect.Figure optionsDownload as PowerPoint slide