Search results for: DHFR

Authors: Yomna Ibrahim El-Gazzar, Hussien Ibrahim El-Subbagh, Hanan Hanaa Georgey, Ghada S. Hassan Hassan

Abstract:

Dihydrofolate reductase (DHFR) is an enzyme that has pivotal importance in biochemistry and medicinal chemistry. It catalyzes the reduction of dihydrofolate to tetrahydrofolate and intimately couples with thymidylate synthase. Thymidylate synthase is a crucial enzyme that catalyzes the reductive methylation of (dUMP) to (dTMP) utilizing N5, N10-methylenetetrahydrofolate as a cofactor. A new series of 2-substituted thio-quinazolin-4-one analogs was designed that possessed electron withdrawing or donating functional groups (Cl or OCH3) at position 6- or 7-, 4-methoxyphenyl function at position 3-.The thiol function is used to connect to either 1,2,4-triazole, or 1,3,4-thiadiazole via a methylene bridge. Most of the functional groups designed to be accommodated on the quinazoline ring such as thioether, alkyl to increase lipid solubility of polar compounds, a character very much needed in the nonclassical DHFR inhibitors. The target compounds were verified with spectral data and elemental analysis. DHFR inhibitions, as well as antitumor activity, were applied on three cell lines (MCF-7, CACO-2, HEPG-2).

Keywords: nonclassical antifolates, DHFR Inhibitors, antitumor activity, quinazoline ring

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Authors: Menna Ewida, Dalal Abou El-Ella, Dina Lasheen, Huessin El-Subbagh

Abstract:

Introduction: Vascular Endothelial Growth Factor receptor (VEGF) is a signal protein produced by cells that stimulates vasculogenesis to create new blood vessels. VEGF family binds to three trans-membrane tyrosine kinase receptors,Dihydrofolate reductase (DHFR) is an enzyme of crucial importance in medicinal chemistry. DHFR catalyzes the reduction 7,8 dihydro-folate to tetrahydrofolate and intimately couples with thymidylate synthase which is a pivotal enzyme that catalysis the reductive methylation of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) utilizing N5,N10-methylene tetrahydrofolate as a cofactor which functions as the source of the methyl group. Purpose: Novel substituted Thiazole agents were designed as DHFR and VEGF-TK inhibitors with increased synergistic activity and decreased side effects. Methods: Five series of compounds were designed with a rational that mimic the pharmacophoric features present in the reported active compounds that target DHFR & VEGFR. These molecules were docked against Methotrexate & Sorafenib as controls. An in silico ADMET study was also performed to validate the bioavailability of the newly designed compounds. The in silico molecular docking & ADMET study were also applied to the non-classical antifolates for comparison. The interaction energy comparable to that of MTX for DHFRI and Sorafenib for VEGF-TKI activity were recorded. Results: Compound 5 exhibited the highest interaction energy when docked against Sorafenib, While Compound 9 showed the highest interaction energy when docked against MTX with the perfect binding mode. Comparable results were also obtained for the ADMET study. Most of the compounds showed absorption within (95-99) zone which varies according to the type of substituents. Conclusions: The Substituted Thiazole Analogues could be a suitable template for antitumor drugs that possess enhanced bioavailability and act as DHFR and VEGF-TK inhibitors.

Keywords: anti-tumor agents, DHFR, drug design, molecular modeling, VEGFR-TKIs

Procedia PDF Downloads 196