Indenone derivatives as inhibitor of human DNA dealkylation repair enzyme AlkBH3

Nigam, Richa and Babu, Kaki Raveendra and Ghosh, Topi and Kumari, Bhavini and Akula, Deepa and Rath, Subha Narayan and Das, Prolay and Roy, Anindya and Khan, Faiz Ahmed (2018) Indenone derivatives as inhibitor of human DNA dealkylation repair enzyme AlkBH3. Bioorganic & Medicinal Chemistry. ISSN 0968-0896 (In Press)

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Abstract

The mammalian AlkB homologue-3 (AlkBH3) is a member of the dioxygenase family of enzymes that in humans is involved in DNA dealkylation repair. Because of its role in promoting tumor cell proliferation and metastasis of cancer, extensive efforts are being directed in developing selective inhibitors for AlkBH3. Here we report synthesis, screening and evaluation of panel of arylated indenone derivatives as new class of inhibitors of AlkBH3 DNA repair activity. An efficient synthesis of 2,3-diaryl indenones from 2,3-dibromo indenones was achieved via Suzuki-Miyaura cross-coupling. Using a robust quantitative assay, we have obtained an AlkBH3 inhibitor that display specific binding and competitive mode of inhibition against DNA substrate. Finally, we established that this compound could prevent the proliferation of lung cancer cell line and enhance sensitivity to DNA damaging alkylating agent.

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