Novel thienopyrimidine analogues as potential metabotropic glutamate receptors inhibitors and anticancer activity: Synthesis, In-vitro, In-silico, and SAR approaches

• Published in: Bioorganic chemistry 2021-04, Vol.109, p.104729-104729, Article 104729
• Main Authors: Khedr, Mohammed A., Abu-Zied, Khadiga M., Zaghary, Wafaa A., Aly, Ahmed S., Shouman, Dina N., Haffez, Hesham
• Format: Article
• Language: English
• Subjects: Anticancer; Apoptosis; Docking; mGluR-1 inhibitor; Molecular dynamics; Thienopyrimidines
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2021.104729

[Display omitted] •Novel theinopyrimidines were synthesized and chemical structures were confirmed.•Antiproliferation was performed using MCF-7, A-549, PC-3 and WI-38 cell lines.•Antiproliferation was confirmed by apoptosis, cell cycle and genetic analysis.•Glutamate assay and docking study revealed glutamate inhibitory capabilities.•Molecular dynamic confirmed the stability of compound 7b with the highest activity.•Compound 7b is a promising mGluR-1 lead scaffold in breast cancer therapy. There is a continuous need in drug development approach for synthetic anticancer analogues with new therapeutic targets to diminish chemotherapeutic resistance of cancer cells. This study presents new group of synthetic thienopyrimidine analogues (1–9) aims as mGluR-1 inhibitors with anticancer activity. In-vitro antiproliferative assessment was carried out using viability assay against cancer cell lines (MCF-7, A-549 and PC-3) compared to WI-38 normal cell line. Analogues showed variable anticancer activity with IC50 ranging from 6.60 to 121 µg/mL with compound 7b is the most potent analogue against the three cancer cell lines (MCF-7; 6.57 ± 0.200, A-549; 6.31 ± 0.400, PC-3;7.39 ± 0.500 µg/mL) compared to Doxorubicin, 5-Flurouracil and Riluzole controls. Selected compounds were tested as mGluR-1 inhibitors in MCF-7 cell line and results revealed compound 7b induced significant reduction in extracellular glutamate release (IC50; 4.96 ± 0.700 µM) compared to other analogues and next to Riluzole (IC50; 2.80 ± 0.500 µM) of the same suggested mode of action. Furthermore, both cell cycle and apoptosis assays confirmed the potency of compound 7b for early apoptosis of MCF-7 at G2/M phase and apoptotic positive cell shift to (91.4%) compared to untreated control (19.6%) and Raptinal positive control (51.4%). On gene expression level, compound 7b induced over-expression of extrinsic (FasL, TNF-α and Casp-8), intrinsic (Cyt-C, Casp-3, Bax) apoptotic genes with down-regulation of anti-apoptotic Bcl-2 gene with boosted Bax/Bcl-2 ratio to 2.6-fold increase. Molecular docking and dynamic studies confirmed the biological potency through strong binding and stability modes of 7b where it was faster in reaching the equilibrium point and achieving the stability than Riluzole over 20 ns MD. These results suggest compound 7b as a promising mGluR inhibitory scaffold with anticancer activity that deserves further optimization and in-depth In-vivo and clinical investigations.