Synthesis and biological evaluation of diaryl urea derivatives designed as potential anticarcinoma agents using de novo structure-based lead optimization approach

Synthesis and biological evaluation of diaryl urea derivatives designed as potential anticarcinoma agents using de novo structure-based lead optimization approach


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نویسندگان: فرشته عظیمیان , مریم حمزه میوه رود , جاوید شهبازی , سالار همتی , سیاوش دستمالچی

کلمات کلیدی: Lead optimization; de novo drug design; diaryl urea; synthesis; docking; antiproliferative activity

نشریه: 55150 , 112461 , 201 , 2020

اطلاعات کلی مقاله
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نویسنده ثبت کننده مقاله سیاوش دستمالچی
مرحله جاری مقاله تایید نهایی
دانشکده/مرکز مربوطه مرکز تحقیقات بیوتکنولوژی(زیست فناوری)
کد مقاله 73377
عنوان فارسی مقاله Synthesis and biological evaluation of diaryl urea derivatives designed as potential anticarcinoma agents using de novo structure-based lead optimization approach
عنوان لاتین مقاله Synthesis and biological evaluation of diaryl urea derivatives designed as potential anticarcinoma agents using de novo structure-based lead optimization approach
ناشر 5
آیا مقاله از طرح تحقیقاتی و یا منتورشیپ استخراج شده است؟ بلی
عنوان نشریه (خارج از لیست فوق)
نوع مقاله Original Article
نحوه ایندکس شدن مقاله ایندکس شده سطح یک – ISI - Web of Science
آدرس لینک مقاله/ همایش در شبکه اینترنت

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To develop inhibitors blocking VEGFR2 and the Raf/MEK/ERK mitogen-activated protein kinase signaling pathway new compounds based on sorafenib were designed, synthesized and biologically evaluated. Using de novo design method, a library of new ligands was generated and expanded. Considering in silico binding affinity towards VEGFR2, synthetic feasibility, and drug-likeness property, some of the designed ligands were selected for synthesis and screening for their in vitro antiproliferative activities against two cancer cell lines (HT-29 and A549). Four compounds (13a, 14a, 14l and 15b) exhibited stronger antiproliferative activity (with IC50 values of 13.27, 6.62, 12.74, 3.38 µM, respectively) against HT-29 cells compared to that of the positive reference drug sorafenib (IC50 = 17.28 µM). Notably, compound 15b demonstrated the highest activity, and in particular, it induced HT-29 apoptosis, increased intracellular reactive oxygen species level, arrested cell cycle at G0/G1 phase, and influenced the expression of apoptosis- and cell cycle-related proteins. 15b compound can effectively block the Raf/MEK/ERK pathway and inhibit VEGFR2 phosphorylation. Molecular docking revealed that 15b can bind well to the active site of VEGFR2 receptor. Collectively, 15b may be considered as a promising compound amenable for further investigation for the development of new anticancer agents.

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نویسنده نفر چندم مقاله
فرشته عظیمیاناول
مریم حمزه میوه روددوم
جاوید شهبازیسوم
سالار همتیچهارم
سیاوش دستمالچیپنجم

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Synthesis and biological evaluation of diaryl urea derivatives designed.pdf1399/07/082524205دانلود