2. Academic Validation
  3. Development of a metabolically stable topoisomerase I poison as anticancer agent

Development of a metabolically stable topoisomerase I poison as anticancer agent

  • Eur J Med Chem. 2020 Sep 15;202:112551. doi: 10.1016/j.ejmech.2020.112551.
Biswajit Kundu 1,  Dipayan Sarkar 2,  Srijita Paul Chowdhuri 3,  Sourav Pal 2,  Subhendu K Das 3,  Benu Brata Das 4,  Arindam Talukdar 5
Affiliations

Affiliations

  • 1 Department of Organic and Medicinal Chemistry, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata, 700032, WB, India.
  • 2 Department of Organic and Medicinal Chemistry, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata, 700032, WB, India; Academy of Scientific and Innovative Research, Ghaziabad, 201002, India.
  • 3 Laboratory of Molecular Biology, School of Biological Sciences, Indian Association for the Cultivation of Science, 2A & 2B, Raja S. C. Mullick Road, Kolkata, 700032, WB, India.
  • 4 Laboratory of Molecular Biology, School of Biological Sciences, Indian Association for the Cultivation of Science, 2A & 2B, Raja S. C. Mullick Road, Kolkata, 700032, WB, India. Electronic address: [email protected].
  • 5 Department of Organic and Medicinal Chemistry, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata, 700032, WB, India; Academy of Scientific and Innovative Research, Ghaziabad, 201002, India. Electronic address: [email protected].
PMID: 32682183 DOI: 10.1016/j.ejmech.2020.112551
Abstract

We have recently reported a new chemotype of a potent Topoisomerase I poison with compound 1 as a potential Anticancer chemotherapeutic agent. During further optimization, it has been observed that compound 1 suffers from high intrinsic clearance in human liver microsomes. To overcome the metabolic instability of compound 1, we report design and synthesis of metabolically stable Top1 poison 3. Newly identified Top1 poison 3 exhibits t1/2 of 69.1 min in human liver microsomes in comparison to compound 1 with t1/2 of 9.9 min. Molecular dynamic study of the newly optimized Top1 poison 3 was performed to get the insight into the stability of the binding pose in the active site. Compound 3 was able to trap DNA-Top1 cleavage complex and found to be less cytotoxic in non-cancerous cell line as compared to compound 1.

Keywords

Camptothecin; In vitro pharmacokinetics; Metabolic stability; Molecular dynamics; Poison; Topoisomerase 1.

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