الفهرس 
Mechanisms of repair of DNAOnly 14 pages are availabe for public view
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Abstract
RecQ helicases are a family of highly conserved ATP-dependent DNA helicases that play a crucial role in maintaining genomic integrity and participate in various cellular processes, such as DNA replication, recombination, repair, and transcription regulation. The upregulation of RecQ helicases has been associated with cancer cell survival and resistance to chemotherapy, making them attractive targets for therapeutic intervention. In this study, twenty-nine novel compounds including twenty-six quinazolinone derivatives (11a-w, 6a-c, and 4a-c) were designed and synthesized. The antiproliferative activity of all compounds was evaluated against 60 cancer cell lines at the National Cancer Institute Developmental Therapeutic Program, with six compounds (11f, 11g, 11k, 11n, 11p, and 11q) with mean GI%= 53, 60, 65, 68, 60 and 47%, respectively, being promoted to the five-dose screen. Compound 11g demonstrated high cytotoxic activity against most examined cell lines. Fifteen compounds were further assayed for Bloom syndrome (BLM) helicase inhibition, where 11g, 11q, and 11u showed moderate inhibitory activity with IC50 = 37.19, 21.78 and 15.17 μM, respectively. These compounds were counter-screened against WRN and RECQ1 helicases, where 11g moderately inhibited both isoforms with IC50 = 25.36 and 41.48 μM, respectively, i.e. compound 11g can be considered a pan RecQ helicase inhibitor. An ATP competition assay confirmed that the compounds act as ATP competitors binding to the ATP site of BLM helicase. Also, fluorescence-based DNA unwinding assay confirmed the inhibitory activity of the compounds on RecQ helicases represented by BLM-HD to unwind dsDNA. Molecular docking simulations were used to study the binding mode within the ATP site of BLM, WRN, and RECQ1 helicases. Compound 11g induced apoptosis in both HCT- 116 and MDA-MB-231 cell lines with greater efficacy in HCT-116 cells, but also caused cell cycle arrest in HCT-116 cells at G2/M phase.