Synthesis of 2‐Chloro‐3‐amino indenone derivatives and their evaluation as inhibitors of DNA dealkylation repair

Nigam, Richa and Raveendra Babu, Kaki and Ghosh, Topi and Kumari, Bhavini and Das, Prolay and Anindya, Roy and Ahmed Khan, Faiz (2021) Synthesis of 2‐Chloro‐3‐amino indenone derivatives and their evaluation as inhibitors of DNA dealkylation repair. Chemical Biology & Drug Design, 97 (6). pp. 1170-1184. ISSN 1747-0277

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DNA alkylation damage, emanating from the exposure to environmental alkylating agents or produced by certain endogenous metabolic processes, affects cell viability and genomic stability. Fe(II)/2-oxoglutarate-dependent dioxygenase enzymes, such as Escherichia coli AlkB, are involved in protecting DNA from alkylation damage. Inspired by the natural product indenone derivatives reported to inhibit this class of enzymes, and a set of 2-chloro-3-amino indenone derivatives was synthesized and screened for their inhibitory properties against AlkB. The synthesis of 2-chloro-3-amino indenone derivatives was achieved from 2,3-dichloro indenones through addition–elimination method using alkyl/aryl amines under catalyst-free conditions. Using an in vitro reconstituted DNA repair assay, we have identified a 2-chloro-3-amino indenone compound 3o to be an inhibitor of AlkB. We have determined the binding affinity, mode of interaction, and kinetic parameters of inhibition of 3o and tested its ability to sensitize cells to methyl methanesulfonate that mainly produce DNA alkylation damage. This study established the potential of indenone-derived compounds as inhibitors of Fe(II)/2-oxoglutarate-dependent dioxygenase AlkB.

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IITH Creators:
IITH CreatorsORCiD
Item Type: Article
Uncontrolled Keywords: AlkB; dioxygenase; DNA alkylation; DNA repair; indenone
Subjects: Others > Biotechnology
Divisions: Department of Biotechnology
Depositing User: . LibTrainee 2021
Date Deposited: 08 Jul 2021 05:44
Last Modified: 08 Jul 2021 05:44
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