Synthesis and Biological Evaluation of Calothrixins B and their Deoxygenated Analogues

A series of calothrixin B (<b>2</b>) analogues bearing substituents at the ‘E’ ring and their corresponding deoxygenated quinocarbazoles lacking quinone unit were synthesized. The cytotoxicities of calothrixins <b>1</b>, <b>2</b>, and <b>15b</b>–<b>p</b> and quinocarbazole analogues were investigated against nine cancer cell lines. The quinocarbazoles <b>21a</b> and <b>25a</b> inhibited the catalytic activity of human topoisomerase II. The plasmid DNA cleavage abilities of calothrixins <b>1</b>, <b>2</b>, and <b>15b</b>–<b>p</b> identified compound <b>15h</b> causing DNA cleavage comparable to that of calothrixin A (<b>1</b>). Calothrixin A (<b>1</b>), 3-fluorocalothrixin <b>15h</b> and 4-fluoroquinocarbazole <b>21b</b> induced extensive DNA damage followed by apoptotic cell death. Spectral and plasmid unwinding studies demonstrated an intercalative mode of binding for quinocarbazoles. We identified two promising drug candidates, the 3-fluorocalothrixin B <b>15h</b> with low toxicity in animal model and its deoxygenated derivative 4-fluoroquinocarbazole <b>21b</b> as having potent cytotoxicity against NCI-H460 cell line with a GI₅₀ of 1 nM