Synthesis of new pyridothienopyrimidinone and pyridothienotriazolopyrimidine derivatives as pim-1 inhibitors.
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ABSTRACT:
SUBMITTER: El-Nassan HB
PROVIDER: S-EPMC6009955 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Pim kinases (proviral integration site for Moloney murine leukemia virus kinases) are overexpressed in various types of hematological malignancies and solid carcinomas, and promote cell proliferation and survival. Thus, Pim kinases are validated as targets for antitumor therapy. In this context, our combined efforts in natural product-inspired library generation and screening furnished very promising dibenzo[b,d]furan derivatives derived from cercosporamide. Among them, lead compound 44 was highlighted as a potent Pim-1/2 kinases inhibitor with an additional nanomolar IC50 value against CLK1 (cdc2-like kinases 1) and displayed a low micromolar anticancer potency towards the MV4-11 (AML) cell line, expressing high endogenous levels of Pim-1/2 kinases. The design, synthesis, structure–activity relationship, and docking studies are reported herein and supported by enzyme, cellular assays, and Galleria mellonella larvae testing for acute toxicity.
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Project description:BackgroundHesperitin, a naturally occurring flavonoid was hybridized with phenolic acids to evaluate its potential to inhibit the activity of xanthine oxidase (XO), a key enzyme which catalyses xanthine to uric acid which is found to be associated with gout and many life style related disorders.ObjectiveTo develop new xanthine oxidase inhibitors from natural constituents along with antioxidant potential.MethodIn this report, we designed and synthesized hesperitin derivatives hybridized with natural phenolic acids to form ester linkage with the help of molecular docking. The synthesized compounds were evaluated for their antioxidant and xanthine oxidase inhibitory potential.ResultsThe in vitro xanthine oxidase inhibitory activity and enzyme kinetics studies showed that hesperitin derivatives displayed a potential inhibition against XO in competitive manner with IC50 value ranging from 9.0 to 23.15 µM and HET4 was revealed as most active derivative. Molecular simulation revealed that new hesperitin derivatives interacted with the amino acid residues SER1080, PHE798, GLN1194, ARG912, THR1083, ALA1078 and MET1038 located within the active cavity of XO. Results of antioxidant activity revealed that all the derivatives showed very good antioxidant potential.ConclusionTaking advantage of molecular docking, this hybridization of two natural constituent could lead to desirable xanthine oxidase inhibitors with improved activity.
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