Synthesis and Biological Evaluation of Calothrixins B and their Deoxygenated Analogues

A 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. T...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2018-02, Vol.61 (3), p.1285-1315
Main Authors: Muthu Ramalingam, Bose, Dhatchana Moorthy, Nachiappan, Chowdhury, Somenath Roy, Mageshwaran, Thiyagarajan, Vellaichamy, Elangovan, Saha, Sourav, Ganesan, Karthikeyan, Rajesh, B. Navin, Iqbal, Saleem, Majumder, Hemanta K, Gunasekaran, Krishnasamy, Siva, Ramamoorthy, Mohanakrishnan, Arasambattu K
Format: Article
Language:English
Subjects:
Carbazoles - chemistry
Cell Line, Tumor
Cell Proliferation - drug effects
Chemistry Techniques, Synthetic
DNA Damage
DNA Topoisomerases, Type II - metabolism
Drug Evaluation, Preclinical
Humans
Indole Alkaloids - chemical synthesis
Indole Alkaloids - chemistry
Indole Alkaloids - pharmacology
Models, Molecular
Nucleic Acid Conformation
Oxygen - chemistry
Topoisomerase II Inhibitors - chemical synthesis
Topoisomerase II Inhibitors - chemistry
Topoisomerase II Inhibitors - pharmacology
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Summary:A 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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.7b01797