2. Academic Validation
  3. Novel Pyrimidine-5-Carbonitriles as potential apoptotic and antiproliferative agents by dual inhibition of EGFRWT/T790M and PI3k enzymes; Design, Synthesis, biological Evaluation, and docking studies

Novel Pyrimidine-5-Carbonitriles as potential apoptotic and antiproliferative agents by dual inhibition of EGFRWT/T790M and PI3k enzymes; Design, Synthesis, biological Evaluation, and docking studies

  • Bioorg Chem. 2024 Apr:145:107185. doi: 10.1016/j.bioorg.2024.107185.
Nada Reda 1,  Khaled O Mohamed 2,  Kareem Abdou 3,  Amira A Helwa 4,  Ahmed Elshewy 5
Affiliations

Affiliations

  • 1 Pharmaceutical Organic Chemistry Department, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology (MUST), 6th of October City, Egypt. Electronic address: [email protected].
  • 2 Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo 11562, Egypt; Pharmaceutical Chemistry Department, Faculty of Pharmacy. Sinai University (Arish branch), El Arish, Egyptzip code 45511. Electronic address: [email protected].
  • 3 Biochemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt. Electronic address: [email protected].
  • 4 Pharmaceutical Organic Chemistry Department, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology (MUST), 6th of October City, Egypt. Electronic address: [email protected].
  • 5 Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo 11562, Egypt; Department of Medicinal Chemistry, Faculty of Pharmacy, Galala University, New Galala 43713, Egypt. Electronic address: [email protected].
PMID: 38350273 DOI: 10.1016/j.bioorg.2024.107185
Abstract

A new series of 6-(4-fluorophenyl)-2-(methylthio) pyrimidine-5-carbonitrile derivatives were designed and synthesized as EGFR/PI3K dual inhibitors, and potential antiproliferative agents. The new 22 compounds were screened by DTP-NCI against all NCI60 cell lines. Almost all compounds showed cytotoxic activity. Compound 7c showed a promising antitumour activity on CNS Cancer (SNB-75), and ovarian Cancer (OVAR-4) with IC50 < 0.01, and 0.64 µM, respectively. Fortunately, 7c exhibited a better safety profile on normal cells (WI-38) than doxorubicin by 2.2-fold. Compound 7c displayed selective inhibitory activity on EGFRt790m over EGFRWT with IC50 = 0.08, and 0.13 µM, respectively, wherefore it might overcome EGFR-TKIs resistance. In addition to its remarkable inhibitory activity on all PI3K isoforms, specifically PI3K-δ with IC50 = 0.64 µM Compared with LY294002 IC50 = 7.6 µM. Compound 7c arrested the cell cycle of SNB-75 & OVAR-4 at the G0-G1 phase coupled with Apoptosis induction. The western blotting analysis approved decreasing the expression level of p-AKT coupled with an increase in Casp3, Casp9, and Bax proteins in the SNB-75 & OVAR-4 after being treated with 7c which may support the suggested mechanism of action of 7c as EGFR/PI3K dual inhibitor. Physicochemical parameters were forecasted using SwissADME online tool. MD showed the interaction of 7c with the crucial Amino acids of the active domain of both EGFR/PI3K which may explain its potent inhibitory activities. In vivo study disclosed a significant decrease in tumor weight and the number of nodules in the group of mice treated with 7c compared with the control group.

Keywords

Anticancer; EGFR(WT)/PI3k inhibition; In vivo study; Molecular Docking study; Pyrimidine-5-carbonitrile Synthesis; Western Blot analysis.

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