Cancer, Environmental and Petroleum Pollutants Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Department of Medicinal Chemistry, School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
Department of Medicinal Chemistry, School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
Comput Biol Chem. 2019 Jun;80:128-137. doi: 10.1016/j.compbiolchem.2019.03.008. Epub 2019 Mar 28.
Phenylbutyrate (PB), a small aromatic fatty acid, has been known as an interesting compound with the ability of anti-proliferation and cell growth inhibition in cancer cells. In the present study, a series of PB derivatives were synthesized by Passerini multicomponent reaction and their cytotoxic activities against various human cancer cell lines including A549 (non-small cell lung cancer), MDA-MB-231 (breast cancer), and SW1116 (colon cancer) were evaluated. The results revealed that B9, displayed significantly higher in vitro cytotoxicity with IC of 6.65, 8.44 and 24.71 μM, against A549, MDA-MB-231 and, SW1116, respectively, in comparison to PB. The effects of these compounds on the proliferation of MCF-10A as non-tumoral breast cell line, showed good selectivity of the compounds between tumorigenic and non-tumorigenic cell lines. Moreover, B9 has indicated apoptosis-inducing activities to MDA-MB-231 cancer cell line in a dose-dependent manner. The molecular docking studies of the synthesized compounds on pyruvate dehydrogenase kinase 2 (PDK2; PDB ID: 2BU8) and histone deacetylase complex (HDAC; PDB ID: 1C3R), as the main targets of PB were applied to predict the binding sites and binding orientation of the compounds to these targets.
苯丁酸钠（PB），一种小分子芳香脂肪酸，具有抗增殖和抑制癌细胞生长的能力，是一种很有趣的化合物。在本研究中，通过 Passerini 多组分反应合成了一系列 PB 衍生物，并评估了它们对各种人类癌细胞系（包括 A549（非小细胞肺癌）、MDA-MB-231（乳腺癌）和 SW1116（结肠癌））的细胞毒性。结果表明，B9 对 A549、MDA-MB-231 和 SW1116 的体外细胞毒性分别为 6.65、8.44 和 24.71 μM，比 PB 显著更高。与肿瘤细胞系相比，这些化合物对 MCF-10A（非肿瘤性乳腺细胞系）增殖的影响显示出化合物在肿瘤发生和非肿瘤细胞系之间的良好选择性。此外，B9 以剂量依赖的方式对 MDA-MB-231 癌细胞系表现出诱导凋亡的活性。还应用了合成化合物对丙酮酸脱氢酶激酶 2（PDK2；PDB ID：2BU8）和组蛋白去乙酰化酶复合物（HDAC；PDB ID：1C3R）的分子对接研究，作为 PB 的主要靶点，以预测化合物与这些靶点的结合位点和结合取向。
