Design, Synthesis, In Vitro Biological Evaluation, and In Silico Studies of Novel Imidazo[4,5-b]Pyridine-Acrylonitrile-Based Derivatives as VEGFR-2 Inhibitors Against Breast Cancer and Hepatocellular Carcinoma.

چکیده اصلی

Vascular endothelial growth factor receptor-2 (VEGFR-2) is a vital mediator of angiogenesis. Therefore, VEGFR-2 inhibition is considered a promising therapeutic target to combat cancer. In the present study, a series of 22 imidazo[4,5-b]pyridine-acrylonitrile-based derivatives was designed and synthesized. All compounds were evaluated for their VEGFR-2 inhibitory activity. Seven of the tested compounds showed high inhibitory activity against VEGFR-2 with IC50 (0.029-0.087 µM) compared to reference drug sorafenib IC50 = 0.091 µM. Four of these derivatives were selected for in vitro cytotoxic activity against breast cancer (MCF-7) and hepatocellular (HepG2) carcinoma cell lines, showing IC50 (0.073-0.196 µM) and (0.20-0.21 µM), respectively, relative to sorafenib IC50 0.16 and 0.19 µM, respectively. Compound 2f exhibiting a superior VEGFR-2 inhibition (IC50 = 0.029 µM compared to sorafenib IC50 = 0.091 µM) and cytotoxicity against MCF-7 and HepG2 (IC50 = 0.073 µM and IC50 = 0.09 µM, respectively), was subjected to cell cycle analysis, apoptosis assay, and molecular modeling studies, which strongly supported the results. It caused cell cycle arrest at G2/M phase by 13.67% and a promising apoptosis induction. 2f exhibited a promising binding score and pose inside the VEGFR-2 active sites. It also showed a good safety profile with a moderate selectivity index. Based on the prediction of physicochemical and pharmacokinetic properties for 2f, it showed excellent prediction results to be orally bioavailable.

ترجمه فارسی چکیده

رگ‌زایی توسط فاکتور رشد عروق هموگلوبین-۲ (VEGFR-2) یک میانجی حیاتی است. بنابراین مهار VEGFR-2 یک هدف درمانی امیدوارکننده برای مبارزه با سرطان است. در این مطالعه، یک سری از ۲۲ مشتق مبتنی بر ایمیدازو[4,5-b]پیریدین-آکریلونیتریل طراحی و سنتز شدند. تمام ترکیبات برای فعالیت مهارکنندگی VEGFR-2 ارزیابی شدند. هفت ترکیب تست شده فعالیت مهارکنندگی بالا علیه VEGFR-2 با IC50 (۰.۰۲۹-۰.۰۸۷ میکرومولار) نشان دادند که مقایسه‌ای با داروی مرجع سورافنib با IC50 = ۰.۰۹۱ میکرومولار است. چهار مشتق از این ترکیبات برای فعالیت سیتوتوکسیک در vitro علیه خطوط سلولی سرطان پستان (MCF-7) و کارسینومای کبد سلولی (HepG2) انتخاب شدند که IC50 (۰.۰۷۳-۰.۱۹۶ میکرومولار) و (۰.۲۰-۰.۲۱ میکرومولار) را به ترتیب نشان دادند که مقایسه‌ای با سورافنib با IC50 ۰.۱۶ و ۰.۱۹ میکرومولار به ترتیب است. ترکیب 2f که مهار VEGFR-2 برتری (IC50 = ۰.۰۲۹ میکرومولار مقایسه با سورافنib IC50 = ۰.۰۹۱ میکرومولار) و سیتوتوکسیسیته علیه MCF-7 و HepG2 (IC50 = ۰.۰۷۳ میکرومولار و IC50 = ۰.۰۹ میکرومولار به ترتیب) را نشان داد، subjected to cell cycle analysis, apoptosis assay, and molecular modeling studies, which strongly supported the results. It caused cell cycle arrest at G2/M phase by 13.67% and a promising apoptosis induction. 2f exhibited a promising binding score and pose inside the VEGFR-2 active sites. It also showed a good safety profile with a moderate selectivity index. Based on the prediction of physicochemical and pharmacokinetic properties for 2f, it showed excellent prediction results to be orally bioavailable.

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