Hagras Mohamed, Mandour Asmaa A, Mohamed Esraa A, Elkaeed Eslam B, Gobaara Ibrahim M M, Mehany Ahmed B M, Ismail Nasser S M, Refaat Hanan M
Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy (Boys), Al-Azhar University Cairo Egypt.
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Future University in Egypt (FUE) Cairo 11835 Egypt
RSC Adv. 2021 Dec 13;11(63):39728-39741. doi: 10.1039/d1ra07922k.
Microtubules have become an appealing target for anticancer drug development including mainly colchicine binding site inhibitors (CBSIs). A new series of novel trimethoxypyridine derivatives were designed and synthesized as tubulin targeting agents. anti-proliferative activities of the tested compounds compared to colchicine against hepatocellular carcinoma (HepG-2), colorectal carcinoma (HCT-116), and breast cancer (MCF-7) was carried out. Most of compounds showed significant cytotoxic activities. Compounds Vb, Vc, Vf, Vj and VI showed superior anti-proliferative activities to colchicine. Where compound VI showed IC values of 4.83, 3.25 and 6.11 μM compared to colchicine (7.40, 9.32, 10.41 μM) against HCT 116, HepG-2 and MCF-7, respectively. The enzymatic activity against tubulin enzyme was carried out for the compounds that showed high anti-proliferative activity. Also, compound VI exhibited the highest tubulin polymerization inhibitory effect with an IC value of 8.92 nM compared to colchicine (IC value = 9.85 nM). Compounds Vb, Vc, Vf, Vj, & VIIIb showed promising activities with IC values of 22.41, 17.64, 20.39, 10.75, 31.86 nM, respectively. Cell cycle and apoptosis test for compound VI against HepG-2 cells, indicated that compound VI can arrest cell cycle at G2/M phase, and can cause apoptosis at pre-G1 phase, with high apoptotic effect 18.53%. Molecular docking studies of the designed compounds confirmed the essential hydrogen bonding with CYS241 beside the hydrophobic interaction at the binding site compared to reference compounds which assisted in the prediction of the structure requirements for the detected antitumor activity.
微管已成为抗癌药物开发的一个有吸引力的靶点，主要包括秋水仙碱结合位点抑制剂（CBSIs）。设计并合成了一系列新型三甲氧基吡啶衍生物作为微管蛋白靶向剂。对所测试的化合物与秋水仙碱相比针对肝癌（HepG-2）、结直肠癌（HCT-116）和乳腺癌（MCF-7）的抗增殖活性进行了研究。大多数化合物显示出显著的细胞毒活性。化合物Vb、Vc、Vf、Vj和VI显示出优于秋水仙碱的抗增殖活性。其中化合物VI针对HCT 116、HepG-2和MCF-7的IC值分别为4.83、3.25和6.11 μM，而秋水仙碱的IC值分别为7.40、9.32和10.41 μM。对显示出高抗增殖活性的化合物进行了针对微管蛋白酶的酶活性研究。此外，化合物VI表现出最高的微管蛋白聚合抑制作用，IC值为8.92 nM，而秋水仙碱的IC值为9.85 nM。化合物Vb、Vc、Vf、Vj和VIIIb显示出有前景的活性，IC值分别为22.41、17.64、20.39、10.75和31.86 nM。对化合物VI针对HepG-2细胞的细胞周期和凋亡测试表明，化合物VI可使细胞周期停滞在G2/M期，并可在G1期前诱导凋亡，凋亡率高达18.53%。与参考化合物相比，所设计化合物的分子对接研究证实了在结合位点除疏水相互作用外与CYS241的关键氢键，这有助于预测所检测到的抗肿瘤活性的结构要求。
