Molecular design, synthesis and biological characterization of novel Resveratrol derivative as potential anticancer agent targeting NF-κB.

IF 2 4区 医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL
Journal of applied biomedicine Pub Date : 2020-03-01 Epub Date: 2020-02-10 DOI:10.32725/jab.2020.001
Zuhier Awan, Hussam Ibrahim Kutbi, Aftab Ahmad, Rabbani Syed, Faten A S Alsulaimany, Noor Ahmad Shaik
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引用次数: 3

Abstract

Resveratrol (RESV), an anticancer nutraceutical compound, is known to show poor bioavailability inside the human body. Therefore, this study has designed multiple chemical analogs of RESV compound for improving its pharmacokinetic as well as its anti-cancer properties. Initially, the drug likeliness and ADME-toxicity properties of these new chemical analogs were tested with the help of diverse computational approaches. Then the best predicted RESV derivative is synthesized by the organic method, and its NF-κB mediated anti-tumor activity assessed on histiocytic lymphoma U-937 cells. The new synthetic RESV analog, i.e. (E)-3-(prop-2-yn-1-yloxy)-5-(4-(prop-2-yn-1-yloxy) styryl) phenol has shown a rapid, persistent and better dose-dependent (IC50 of 7.25 μM) decrease in the viability of U937 cells than the native (IC50 of 30 μM) RESV compound. This analog has also demonstrated its potential ability in inducing apoptosis through DNA ladder formation. At 10 µg/ml concentration, this chemical derivative has shown a better NF-κB inhibition (IC50 is 2.45) compared to the native RESV compound (IC50 is 1.95). Molecular docking analysis found that this analog exerts its anti- NF-κB activity (binding energy of -6.78 kcal/mol and Ki 10 µM) by interacting with DNA binding residues (Arg246, Lys444, and Gln606) of p50 chain NF-κB. This study presents a novel RESV analog that could further develop as a potential anti-NF-κB mediated tumor inhibitor.

靶向NF-κB的新型白藜芦醇衍生物的分子设计、合成及生物学特性研究。
白藜芦醇(RESV)是一种抗癌营养化合物,在人体内的生物利用度很差。因此,本研究设计了多种RESV化合物的化学类似物,以改善其药代动力学和抗癌性能。最初,这些新的化学类似物的药物可能性和adme毒性特性在不同计算方法的帮助下进行了测试。然后采用有机方法合成预测效果最好的RESV衍生物,并对其NF-κB介导的组织细胞性淋巴瘤U-937细胞的抗肿瘤活性进行评价。新合成的RESV类似物(E)-3-(prop-2-yn-1-yloxy)-5-(4-(prop-2-yn-1-yloxy)苯乙烯基)苯酚与天然RESV化合物(IC50为30 μM)相比,对U937细胞的生存能力有快速、持久和较好的剂量依赖性降低(IC50为7.25 μM)。这种类似物也证明了其通过DNA阶梯形成诱导细胞凋亡的潜在能力。在10µg/ml浓度下,该化学衍生物对NF-κB的抑制作用(IC50为2.45)优于天然RESV化合物(IC50为1.95)。分子对接分析发现,该类似物通过与p50链NF-κ b的DNA结合残基(Arg246、Lys444和Gln606)相互作用发挥抗NF-κ b活性(结合能-6.78 kcal/mol, Ki 10µM)。本研究提出了一种新的RESV类似物,可能进一步发展为潜在的抗nf -κB介导的肿瘤抑制剂。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of applied biomedicine
Journal of applied biomedicine PHARMACOLOGY & PHARMACY-
CiteScore
2.40
自引率
7.70%
发文量
13
审稿时长
>12 weeks
期刊介绍: Journal of Applied Biomedicine promotes translation of basic biomedical research into clinical investigation, conversion of clinical evidence into practice in all medical fields, and publication of new ideas for conquering human health problems across disciplines. Providing a unique perspective, this international journal publishes peer-reviewed original papers and reviews offering a sensible transfer of basic research to applied clinical medicine. Journal of Applied Biomedicine covers the latest developments in various fields of biomedicine with special attention to cardiology and cardiovascular diseases, genetics, immunology, environmental health, toxicology, neurology and oncology as well as multidisciplinary studies. The views of experts on current advances in nanotechnology and molecular/cell biology will be also considered for publication as long as they have a direct clinical impact on human health. The journal does not accept basic science research or research without significant clinical implications. Manuscripts with innovative ideas and approaches that bridge different fields and show clear perspectives for clinical applications are considered with top priority.
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