期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 22, 期 5, 页码 -出版社
MDPI
DOI: 10.3390/ijms22052742
关键词
pyrazolopyrimidinone; hydrazide-hydrazone; antitumor lead compound; cytotoxic activity; antiproliferative activity; molecular docking; epidermal growth factor receptor; G-quadruplex DNA; KRAS; circular dichroism
资金
- Italian Ministry of Health
- OncoLab, Regione Campania, PO FESR 2014-2020, O.S. Project Campania Oncoterapie, Italy [BG1G18000470007]
Chemotherapy is commonly used for cancer treatment, but there is a need for novel and effective anticancer drugs due to chemoresistance and tumor relapses. A series of pyrazolo[3,4-d]pyrimidin-4(5H)-ones tethered with hydrazide-hydrazones were synthesized and showed promising antiproliferative effects, with certain compounds exhibiting cytotoxic activity through apoptosis induction and cell-cycle arrest. Molecular docking studies confirmed high binding affinity of these compounds towards epidermal growth factor receptor (EGFR) and G-quadruplex DNA structures.
Chemotherapy represents the most applied approach to cancer treatment. Owing to the frequent onset of chemoresistance and tumor relapses, there is an urgent need to discover novel and more effective anticancer drugs. In the search for therapeutic alternatives to treat the cancer disease, a series of hybrid pyrazolo[3,4-d]pyrimidin-4(5H)-ones tethered with hydrazide-hydrazones, 5a-h, was synthesized from condensation reaction of pyrazolopyrimidinone-hydrazide 4 with a series of arylaldehydes in ethanol, in acid catalysis. In vitro assessment of antiproliferative effects against MCF-7 breast cancer cells, unveiled that 5a, 5e, 5g, and 5h were the most effective compounds of the series and exerted their cytotoxic activity through apoptosis induction and G0/G1 phase cell-cycle arrest. To explore their mechanism at a molecular level, 5a, 5e, 5g, and 5h were evaluated for their binding interactions with two well-known anticancer targets, namely the epidermal growth factor receptor (EGFR) and the G-quadruplex DNA structures. Molecular docking simulations highlighted high binding affinity of 5a, 5e, 5g, and 5h towards EGFR. Circular dichroism (CD) experiments suggested 5a as a stabilizer agent of the G-quadruplex from the Kirsten ras (KRAS) oncogene promoter. In the light of these findings, we propose the pyrazolo-pyrimidinone scaffold bearing a hydrazide-hydrazone moiety as a lead skeleton for designing novel anticancer compounds.
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