ABSTRACT
A series of hybrid aza heterocycles containing pyrazolo[3,4-d]pyrimidin-4(5H)-ones tethered to 1,2,3-triazole scaffold were synthesized from 1,3-dipolar cycloaddition reaction of pyrazolopyrimidinone based alkyne with azides using Cu(II) catalyst in presence of sodium ascorbate and evaluated for their anticancer efficacy in vitro against C6 rat and U87 human glioma cell lines. These compounds induced a concentration dependent inhibition of C6 rat and U87 human glioma cell proliferation. Compound 5f arrested the cells at S-phase of the cell cycle and induced apoptosis in U87 GBM cell lines. Further, apoptosis was evidenced by the cleavage of Caspase-3, PARP and up regulation of p53. In silico docking studies reveal that the compounds 5a, 5f and 5l were more effective in binding with TGFBR2 than other compounds.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Brain Neoplasms/drug therapy , Glioma/drug therapy , Pyrimidinones/chemistry , Pyrimidinones/pharmacology , Triazoles/chemistry , Triazoles/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Apoptosis/drug effects , Brain Neoplasms/metabolism , Brain Neoplasms/pathology , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Chemistry Techniques, Synthetic/methods , Drug Screening Assays, Antitumor , Glioma/metabolism , Glioma/pathology , Humans , Molecular Docking Simulation , Protein Serine-Threonine Kinases/metabolism , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyrazoles/pharmacology , Pyrimidinones/chemical synthesis , Rats , Receptor, Transforming Growth Factor-beta Type II , Receptors, Transforming Growth Factor beta/metabolism , Triazoles/chemical synthesisABSTRACT
A facile DABCO promoted one-pot three component synthesis of a new series of C-C linked bis-heterocycle containing dihydropyrano[c]chromene as highly fused oxa-heteryl group at C-2 position of quinazoline was developed. Quinazoline-2-carbaldehyde, substituted 4-hydroxycoumarin and ethyl cyanoacetate were used as key components in the Knoevenagel-Michael addition reaction to get the titled compounds. These compounds were screened for anti-cancer activity against the breast cancer cell lines of MDA-MB 231, and MDA-MB 453.
