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Human dihydrofolate reductase inhibition effect of 1-Phenylpyrazolo [3,4–d]pyrimidines: Synthesis, antitumor evaluation and molecular modeling study
Faculty
Pharmacy
Year:
2022
Type of Publication:
ZU Hosted
Pages:
13
Authors:
Osama Ibrahim Abdou Elsabagh
Staff Zu Site
Abstract In Staff Site
Journal:
Bioorganic Chemistry Elsevier
Volume:
0045-2068/© 2022
Keywords :
Human dihydrofolate reductase inhibition effect , 1-Phenylpyrazolo
Abstract:
A new series of pyrazolo[3,4–d]pyrimidine analogues bearing different amino acid conjugates 10a-m were synthesized with the aim to evaluate their antitumor effect through simultaneous inhibition of human dihydrofolate reductase (hDHFR). All novel compounds were tested to screen their enzyme inhibition activity against (hDHFR) beside their in vitro cytotoxicity against six human MTX resistant cancer cell lines namely, human prostate cancer (PC-3), pancreatic human cancer cell lines (BxPC-3), colorectal carcinoma (HCT-116), human hepatocellular carcinoma (HepG-2), cervical carcinoma (HeLa), and mammary gland breast cancer (MCF-7), besides normal immortalized pancreatic cell line (HPDE). Compounds 10e, 10f, 10g inhibited DHFR at considerable low (IC50 < 1 µM) in comparison to MTX (IC50 = 5.61 µM) beside their characteristic cytotoxic effects on different resistant cancer cell lines. Flow cytometry was done for the most active candidate compound 10e against MCF-7 breast cancer cell line. The results illustrated that compound 10e induced apoptosis and arrested MCF-7 cell cycle in the G1/S phase. Western blot for visualization and quantification was used to confirm the capability of compound 10e to induce the expression of proapoptotic caspases and Bax proteins in MCF-7 breast cancer cell line beside its ability to reduce the expression of antiapoptotic Bcl-2 protein. Molecular modeling studies demonstrated that compound 10e elucidated binding energy of (S= − 8.4390 Kcal/mol) that exceed that of the normal ligand MTX (S= − 8.3951Kcal/mol) in addition to several favorable binding interactions with the active site residues
Author Related Publications
Osama Ibrahim Abdou Elsabagh, "Design, synthesis and antitumor evaluation of novel pyrazolo[3,4-d]pyrimidines incorporating different amino acid conjugates as potential DHFR inhibitors", Taylor & Francis Group, 2022
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Osama Ibrahim Abdou Elsabagh, "Synthesis of Some New Benzisothiazolone and Benzenesulfonamide Derivatives of Biological Interest Starting from Saccharin Sodium", 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim, 2013
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Osama Ibrahim Abdou Elsabagh, "Synthesis and Biological Evaluation of Some N-Arylpyrazoles and Pyrazolo[3,4-d]pyridazines as Anti-Inflammatory Agents", 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim, 2013
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Osama Ibrahim Abdou Elsabagh, "Synthesis of new benzotriazepin-5(2H)-one derivatives of expected antipsychotic activity", springer, 2012
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Osama Ibrahim Abdou Elsabagh, "Synthesis and pharmacological studies for some new benzotriazole and dibenzodiazepine derivatives as antipsychotic agents", KOREAN CHEMICAL SOC, 2009
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Department Related Publications
Etedaal Hassan Mohamed Abdulaal, "18. In situ annelation of enaminones by reaction with methyleneiminium intermediates", لايوجد, 1900
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Hanan Abdelraziek Abdelfattah Ali Hamied, "synthesis of some new imidazolones of expected antimicrobial activity", لايوجد, 1900
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Azza Mohamed Kadry , "35. Synthesis and potentiometric study of some dioxadiaza ionophores in ion selective electrodes", لايوجد, 1900
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Azza Mohamed Kadry , "16. Chemistry of quinazolines: Reinvestigation of the action of hydrazine on thioxo derivatives", لايوجد, 1900
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Azza Mohamed Kadry , "2. Reaction and rearrangement of 2,4-quinazolinediones", لايوجد, 1900
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