2. Academic Validation
  3. Synthesis and Biological Evaluation of Calothrixins B and their Deoxygenated Analogues

Synthesis and Biological Evaluation of Calothrixins B and their Deoxygenated Analogues

  • J Med Chem. 2018 Feb 8;61(3):1285-1315. doi: 10.1021/acs.jmedchem.7b01797.
Bose Muthu Ramalingam 1,  Nachiappan Dhatchana Moorthy 2 3,  Somenath Roy Chowdhury 4,  Thiyagarajan Mageshwaran 1,  Elangovan Vellaichamy 2,  Sourav Saha 4,  Karthikeyan Ganesan 3,  B Navin Rajesh 3,  Saleem Iqbal 5,  Hemanta K Majumder 4,  Krishnasamy Gunasekaran 5,  Ramamoorthy Siva 6,  Arasambattu K Mohanakrishnan 1
Affiliations

Affiliations

  • 1 Department of Organic Chemistry, University of Madras , Guindy Campus, Chennai 600 025, India.
  • 2 Department of Biochemistry, University of Madras , Guindy Campus, Chennai 600 025, India.
  • 3 Research and Development Centre, Orchid Pharma Ltd , Sholinganallur, Chennai 600 119, India.
  • 4 Division of Infectious Diseases & Immunology, Indian Institute of Chemical Biology , 4 Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, India.
  • 5 CAS in Crystallography & Biophysics, University of Madras , Chennai 600 025, India.
  • 6 School of Bio Sciences and Technology, VIT University , Vellore 632 014, India.
PMID: 29313676 DOI: 10.1021/acs.jmedchem.7b01797
Abstract

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.

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