Synthesis of Caerulomycins E and A Analogs for Studying Cytotoxic Activity

Abstract

Caerulomycin A, a marine-derived natural product featuring a bipyridinic core and a substituted oxime functional group, was originally isolated from Streptomyces caeruleus and is known for its antibiotic, antifungal, and cytotoxic properties. In this study, we report the efficient synthesis of caerulomycin A and a series of novel analogs via a five-step synthetic route using readily available reagents. The structural diversification focused on the replacing the methoxy group with various benzyl ether substituents at C-4 and subsequent oxidation and condensation steps at C-6 to generate caerulomycin E and caerulomycin A analogs. These compounds were evaluated for their cytotoxic activity against six human cancer cell lines. Notably, several benzyl ether derivatives exhibited significantly enhanced cytotoxicity compared to the parent compound, with some analogs demonstrating greater potency than the reference drug ellipticine. The structure–activity relationship (SAR) analysis revealed that halogenated substituted benzyl ether groups at C-4 positions played a critical role in modulating cytotoxic activity and selectivity. These findings underscore the potential of synthetic caerulomycin derivatives as promising lead compounds for further development in cancer therapeutics.