New prodigiosin derivatives – chemoenzymatic synthesis and physiological evaluation against cisplatin-resistant cancer cells

Prodigiosin and its derivatives from the prodiginine family are a natural class of secondary metabolite alkaloids of bacterial origin. They are well known for multifarious biological activities against a broad range of bacteria, pathogenic fungi, parasites, and several cancer cell lines. Biosynthesis of natural derivatives is based on a converging route with a final ATP- and enzyme-dependent condensation reaction between the bipyrrole precursor MBC and miscellaneously substituted monopyrroles. Although these ligating enzymes have been recognised for promiscuity regarding monopyrroles, minor studies were exerted to investigate promiscuity for MBC derivatives. To overcome the current lack of structural knowledge, we synthesised six 5′-n-alkyl derivatives of MBC and validated their suitability for condensation with monopyrroles by the ligating enzymes PigC, TreaP, and TamQ to probe their active site experimentally. Moreover, chemically synthesised prodiginines with 5-n-alkylation on the A-ring were subjected to systematic cell viability screening with the urothelial cancer cell lines RT-112 (cisplatin-sensitive) and RT-112res (cisplatin-resistant) to fathom the effect of electron-donating substituents on cytotoxicity. Alongside an overall broad acceptance of short- and medium-chain alkylated MBC derivatives by the enzymes PigC, TreaP, and TamQ, we identified the A-ring substituted prodiginines with methyl substituents as superior anticancer agents against cisplatin-resistant RT-112res after 72 h (15.7–18.8 nM) compared to prodigiosin (41.1 nM) and the former phase II clinical candidate obatoclax mesylate (36.0 nM).