School of Chemical Sciences, Swami Ramanand Teerth Marathwada University, Nanded-431 606, MS, India.
Gramin Science (Vocational) College, Vishnupuri, Nanded-431 606, MS, India.
Comput Biol Chem. 2021 Jun;92:107484. doi: 10.1016/j.compbiolchem.2021.107484. Epub 2021 Apr 8.
N-(4-(substituted)-3-(trifluoromethyl) phenyl) isobutyramides and their N-ethyl analogues (flutamides) are versatile scaffolds with a wide spectrum of biological activities. A series of new N-(4-(substituted)-3-(trifluoromethyl) phenyl) isobutyramides (8a-t) and their N-ethyl analogous (9a-t) were synthesized and characterized. The inhibitory potential of the synthesized compounds on the viability of three human cancer cell lines HEP3BPN 11 (liver), MDA-MB 453 (breast), and HL 60 (leukemia) were assessed. Among all the compounds 8 L, 8q, 9n and 9p showed higher inhibitory activity on the viability of HL 60 than the standard methotrexate. These lead molecules were then tested for their potential to inhibit the activity of proangiogenic cytokines. The compound 9n showed significantly better inhibition against two cytokines viz. TNFα and Leptin as compared to the standard suramin, while 9p has activity comparable to suramin against IGF1, VEGF, FGFb, and Leptin. The 8q is found to be strong antiangiogenic agent against IGF1, VEGF and TGFβ; while 8 L has showed activity against TNFα, VEGF, and Leptin inhibition. Furthermore antioxidant potential of 8a-t and 9a-t compounds was screened using DPPH, OH and SOR radical scavenging activities. The OH radical scavenging activity of 8c and DPPH activities of 9n as well as 9o are significant as compared to respective standards ascorbic acid and α-tocopherol. The 8c, 9p and 9 h have also exhibited potential antioxidant activity. Additionally, we present in silico molecular docking data to provide the structural rationale of observed TNFα inhibition against newly synthesized compounds. Overall, the synthesized flutamide derivatives have not only anticancer activity, but also possess dual inhibitory effect (anti-angiogenesis and antioxidant) and hence can act as a promising avenue to develop further anticancer agents.
N-(4-(取代)-3-(三氟甲基)苯基)异丁酰胺及其 N-乙基类似物（氟他胺）是具有广泛生物活性的多功能支架。我们合成并表征了一系列新的 N-(4-(取代)-3-(三氟甲基)苯基)异丁酰胺（8a-t）及其 N-乙基类似物（9a-t）。评估了合成化合物对三种人类癌细胞系 HEP3BPN 11（肝）、MDA-MB 453（乳腺）和 HL 60（白血病）活力的抑制潜力。在所有化合物中，8L、8q、9n 和 9p 对 HL 60 活力的抑制活性高于标准甲氨蝶呤。然后，这些先导分子被测试其抑制促血管生成细胞因子活性的潜力。与标准苏拉明相比，化合物 9n 对两种细胞因子 TNFα 和 Leptin 的抑制作用明显更好，而 9p 对 IGF1、VEGF、FGFb 和 Leptin 的活性与苏拉明相当。8q 被发现是一种针对 IGF1、VEGF 和 TGFβ 的强大抗血管生成剂；而 8L 则对 TNFα、VEGF 和 Leptin 的抑制表现出活性。此外，还使用 DPPH、OH 和 SOR 自由基清除活性筛选了 8a-t 和 9a-t 化合物的抗氧化潜力。与相应的标准抗坏血酸和α-生育酚相比，8c 的 OH 自由基清除活性和 9n 以及 9o 的 DPPH 活性具有显著意义。8c、9p 和 9h 也表现出潜在的抗氧化活性。此外，我们提供了基于计算机的分子对接数据，以提供对新合成化合物观察到的 TNFα 抑制作用的结构合理性。总的来说，合成的氟他胺衍生物不仅具有抗癌活性，而且还具有双重抑制作用（抗血管生成和抗氧化），因此可以作为开发进一步抗癌药物的有前途的途径。
