Evaluation of the anti-proliferative activity of 2-oxo-pyridine and 1′H-spiro-pyridine derivatives as a new class of EGFRWt and VEGFR-2 inhibitors with apoptotic inducers. Issue 15 (3rd April 2023)

• Record Type: Journal Article
• Authors: Raslan, Reham R.; Ammar, Yousry A.; Fouad, Sawsan A.; Hessein, Sadia A.; Shmiess, Nadia A. M.; Ragab, Ahmed
• Is Part Of: RSC advances. Volume 13:Issue 15(2023)
• Page Start: 10440
• Page End: 10458
• Publication Date: 2023-04-03
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/d3ra00887h
• Languages: English
• ISSNs: 2046-2069

Abstract

Abstract : Design and synthesis a novel of 2-oxo-pyridine and 1′ H -spiro-pyridine derivatives as a new apoptotic inducers agents. Abstract : Developing new agents for cancer treatment remains a top priority because it is one of the deadliest worldwide. A new series of 2-oxo-pyridine and 1′ H -spiro-pyridine derivatives were designed and synthesized based on an N -(ethyl benzoate) moiety. The structure of the designed derivatives was confirmed by different spectroscopic techniques (FT-IR and NMR) and elemental analysis and then evaluated as antiproliferative against HepG-2 and Caco-2 cell lines compared with Doxorubicin. The spiro-pyridine derivatives 5, 7, and 8 exhibited a remarkably higher activity against Caco-2 cell lines than that of other derivatives. Additionally, these derivatives exhibited activation in the Bax and suppressed Bcl-2 expression with variable degrees. Interestingly, compound 7 showed the lowest cytotoxicity value on Caco-2 cells (IC50 = 7.83 ± 0.50 μM) compared with Doxorubicin (IC50 = 12.49 ± 1.10 μM). Additionally, this compound showed activation of the Bax gene (7.508-fold) and suppressed Bcl-2 (0.194-fold) compared to untreated Caco-2 cells, as revealed by the qRT-PCR technique. Moreover, compound 7 could inhibit EGFR and VEGFR-2 with sub-micromole values of 0.124 μM and 0.221 μM compared with Erlotinib (IC50 = 0.033 μM) and Sorafenib (IC50 = 0.043 μM), respectively. Further, cell cycle and apoptosis analysis demonstrated that compound 7 promoted apoptosis by increasing the apoptosis rate from 1.92 to 42.35% and the S cell accumulation ratio from 31.18 to 42.07% compared to untreated Caco-2 cells. Finally, the most active compound 7 showed good drug-likeness and toxicity profiles. Besides, molecular docking studies were performed to determine the binding mode, which is in agreement with the in vitro results.