发现新的萘醌-萘酮分子构型作为强效FGFR1酪氨酸激酶抑制剂：合成、生物评价和分子模型化研究。
Discovery of Novel Naphthoquinone-Chalcone Hybrids as Potent FGFR1 Tyrosine Kinase Inhibitors: Synthesis, Biological Evaluation, and Molecular Modeling.
发表日期：2023 Sep 12
作者：
Ronnakorn Leechaisit, Panupong Mahalapbutr, Pornthip Boonsri, Kun Karnchanapandh, Thanyada Rungrotmongkol, Veda Prachayasittikul, Supaluk Prachayasittikul, Somsak Ruchirawat, Virapong Prachayasittikul, Ratchanok Pingaew
来源：
Environmental Technology & Innovation
摘要：
本研究通过亲核取代法从易得的氨基香豆醌和2,3-二氯-1,4-萘醌中合成了10个新型萘醌-查尔酮衍生物（1-10）。所有化合物在所有经过测试的癌细胞系（即HuCCA-1，HepG2，A549，MOLT-3，T47D和MDA-MB-231）中表现出广谱细胞毒性活性，其IC50值在0.81-62.06 μM范围内，尤其是四种最有效的化合物1、3、8和9。对成纤维细胞生长因子受体1（FGFR1）的体外研究表明，八种衍生物（1-2，4-5和7-10）是FGFR1的活性抑制剂（IC50 = 0.33-3.13 nM），其活性比已知的FGFR1抑制剂AZD4547（IC50 = 12.17 nM）更高。有希望的是，化合物5（IC50 = 0.33 ± 0.01 nM）、9（IC50 = 0.50 ± 0.04 nM）和7（IC50 = 0.85 ± 0.08 nM）是三种最有效的FGFR1抑制剂。分子对接、分子动力学模拟和基于MM/GBSA的自由能计算揭示了化合物5、7和9与靶点FGFR1蛋白结合所涉及的关键氨基酸残基与AZD4547的相似性（即Val492、Lys514、Ile545、Val561、Ala640和Asp641）。这些发现表明新合成的萘醌-查尔酮骨架是一种有前景的结构特征，可以有效抑制FGFR1。©2023 The Authors. Published by American Chemical Society.
This work presents a flexible synthesis of 10 novel naphthoquinone-chalcone derivatives (1-10) by nucleophilic substitution of readily accessible aminochalcones and 2,3-dichloro-1,4-naphthoquinone. All compounds displayed broad-spectrum cytotoxic activities against all the tested cancer cell lines (i.e., HuCCA-1, HepG2, A549, MOLT-3, T47D, and MDA-MB-231) with IC50 values in the range of 0.81-62.06 μM, especially the four most potent compounds 1, 3, 8, and 9. The in vitro investigation on the fibroblast growth factor receptor 1 (FGFR1) inhibitory effect indicated that eight derivatives (1-2, 4-5, and 7-10) were active FGFR1 inhibitors (IC50 = 0.33-3.13 nM) with more potency than that of the known FGFR1 inhibitor, AZD4547 (IC50 = 12.17 nM). Promisingly, compounds 5 (IC50 = 0.33 ± 0.01 nM), 9 (IC50 = 0.50 ± 0.04 nM), and 7 (IC50 = 0.85 ± 0.08 nM) were the three most potent FGFR1 inhibitors. Molecular docking, molecular dynamics simulations, and MM/GBSA-based free energy calculation revealed that the key amino acid residues involved in the binding of the compounds 5, 7, and 9 and the target FGFR1 protein were similar with those of the AZD4547 (i.e., Val492, Lys514, Ile545, Val561, Ala640, and Asp641). These findings revealed that the newly synthesized naphthoquinone-chalcone scaffold is a promising structural feature for an efficient inhibition of FGFR1.© 2023 The Authors. Published by American Chemical Society.