jm7b01797_si_001.pdf (5.11 MB)
Synthesis and Biological Evaluation of Calothrixins B and their Deoxygenated Analogues
journal contribution
posted on 2018-01-09, 00:00 authored by Bose Muthu Ramalingam, Nachiappan Dhatchana Moorthy, Somenath Roy Chowdhury, Thiyagarajan Mageshwaran, Elangovan Vellaichamy, Sourav Saha, Karthikeyan Ganesan, B. Navin Rajesh, Saleem Iqbal, Hemanta K. Majumder, Krishnasamy Gunasekaran, Ramamoorthy Siva, Arasambattu K. MohanakrishnanA series
of calothrixin B (2) analogues bearing substituents
at the ‘E’ ring and their corresponding deoxygenated
quinocarbazoles lacking quinone unit were synthesized. The cytotoxicities
of calothrixins 1, 2, and 15b–p and quinocarbazole analogues were investigated
against nine cancer cell lines. The quinocarbazoles 21a and 25a inhibited the catalytic activity of human topoisomerase
II. The plasmid DNA cleavage abilities of calothrixins 1, 2, and 15b–p identified
compound 15h causing DNA cleavage comparable to that
of calothrixin A (1). Calothrixin A (1),
3-fluorocalothrixin 15h and 4-fluoroquinocarbazole 21b 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 15h with low toxicity
in animal model and its deoxygenated derivative 4-fluoroquinocarbazole 21b as having potent cytotoxicity against NCI-H460 cell line
with a GI50 of 1 nM.