Department of Pharmaceutical Chemistry, College of Pharmacy, University of Kirkuk, Kirkuk, Iraq.
Department of Pharmaceutical Chemistry, College of Pharmacy, University of Baghdad, Bagdad, Iraq.
Anticancer Agents Med Chem. 2023;23(11):1336-1348. doi: 10.2174/1871520623666230227153449.
The indole backbone is encountered in a class of N-heterocyclic compounds with physiological and pharmacological effects such as anti-cancer, anti-diabetic, and anti-HIV. These compounds are becoming increasingly popular in organic, medicinal, and pharmaceutical research. Nitrogen compounds' hydrogen bonding, dipole- dipole interactions, hydrophobic effects, Van der Waals forces, and stacking interactions have increased their relevance in pharmaceutical chemistry due to their improved solubility. Indole derivatives, such as carbothioamide, oxadiazole, and triazole, have been reported to act as anti-cancer drugs due to their ability to disrupt the mitotic spindle and prevent human cancer cell proliferation, expansion, and invasion.
To synthesize new 5-bromoindole-2-carboxylic acid derivatives that function as EGFR tyrosine kinase inhibitors as deduced through molecular docking studies.
Different derivatives of indole (carbothioamide, oxadiazole, tetrahydro pyridazine-3,6-dione, and triazole) were synthesized and evaluated through different chemical, spectroscopic methods (IR, HNMR, CNMR, and MS) and assessed in silico and in vitro for their antiproliferative activities against A549, HepG2, and MCF-7 cancer cell lines.
According to molecular docking analyses, compounds 3a, 3b, 3f, and 7 exhibited the strongest EGFR tyrosine kinase domain binding energies. In comparison to erlotinib, which displayed some hepatotoxicity, all of the evaluated ligands displayed good in silico absorption levels, did not appear to be cytochrome P450 inhibitors, and were not hepatotoxic. The new indole derivatives were found to decrease cell growth of three different types of human cancer cell lines (HepG2, A549, and MCF-7), with compound 3a being the most powerful while still being cancer-specific. Cell cycle arrest and the activation of apoptosis were the results of compound 3a's inhibition of EGFR tyrosine kinase activity.
The novel indole derivatives, compound 3a in particular, are promising anti-cancer agents which inhibit cell proliferation by inhibiting EGFR tyrosine kinase activity.
吲哚骨架存在于一类具有生理和药理作用的 N-杂环化合物中，如抗癌、抗糖尿病和抗 HIV 药物。这些化合物在有机、医药和制药研究中越来越受欢迎。由于其溶解度的提高，含氮化合物的氢键、偶极-偶极相互作用、疏水效应、范德华力和堆积相互作用增加了它们在药物化学中的相关性。吲哚衍生物，如碳硫酰胺、恶二唑和三唑，已被报道具有抗癌作用，因为它们能够破坏有丝分裂纺锤体并阻止人类癌细胞的增殖、扩张和侵袭。
通过分子对接研究，合成新型 5-溴吲哚-2-羧酸衍生物作为 EGFR 酪氨酸激酶抑制剂。
合成了不同的吲哚衍生物（碳硫酰胺、恶二唑、四氢哒嗪-3,6-二酮和三唑），并通过不同的化学、光谱方法（IR、HNMR、CNMR 和 MS）进行了评估，并在计算机和体外评估了它们对 A549、HepG2 和 MCF-7 癌细胞系的抗增殖活性。
根据分子对接分析，化合物 3a、3b、3f 和 7 与 EGFR 酪氨酸激酶结构域的结合能最强。与显示出一些肝毒性的厄洛替尼相比，所有评估的配体都显示出良好的计算机吸收水平，似乎不是细胞色素 P450 抑制剂，也没有肝毒性。新的吲哚衍生物被发现能够降低三种不同类型的人类癌细胞系（HepG2、A549 和 MCF-7）的细胞生长，其中化合物 3a 最为有效，同时仍然具有癌症特异性。化合物 3a 抑制 EGFR 酪氨酸激酶活性导致细胞周期停滞和凋亡激活。
新型吲哚衍生物，特别是化合物 3a，是有前途的抗癌药物，通过抑制 EGFR 酪氨酸激酶活性抑制细胞增殖。
