将Lavendustin C和5-芳基苯甲烷-4-4-4-4-One Pharmacocotors与多坐Multitarget抗癌杂种相结合
Combining lavendustin C and 5-arylidenethiazolin-4-one-based pharmacophores toward multitarget anticancer hybrids
影响因子:4.70000
分区:医学2区 / 有机化学1区 生化与分子生物学2区
发表日期:2024 Dec
作者:
Shimaa A Othman, Ola F Abou-Ghadir, Varsha Menon, Wafaa S Ramadan, Yaser A Mostafa, Raafat El-Awady, Hajjaj H M Abdu-Allah
摘要
Lavendustin C是一种自然产物衍生的抗癌铅化合物，通过酯化或胺化（化合物6-10）在其羧基及其氨基组进行了修饰，并通过引入5-氨基乙烯乙醇素-4-酮（14a-C至17A-C，18A和18B）。使用了两种策略来结合这些部分并优化产量。对这些新化合物的抗增殖活性评估了，针对九个癌细胞系的小组。结果清楚地表明，5-芳基甲二唑林-4-一个部分对该活动产生了重大贡献。同样，甲基酯比酰胺更有效，而N-乙酰基是酰胺中最有效的。 14b在所有测试的癌细胞系具有IC50 1.4-2.5 µm的效力最高，而对正常细胞系IC50> 50 µm。它显示在G0/G1，S相和G2/m中细胞百分比的降低时，HeLa细胞停滞。此外，14B通过凋亡诱导引发了HeLa癌细胞的死亡。发现EGFR的抑制作用14b与厄洛替尼相当。进行了计算对接和计算机药代动力学研究。总之，14B可能是多坐杆菌铅化合物，以进一步开发抗癌剂。
Abstract
Lavendustin C, a natural-product derived anticancer lead compound, was modified at its carboxylic group by esterification or amidation (compounds 6-10) and at its amino group by introducing 5-arylidenethiazolin-4-ones (14a-c to 17a-c, 18a and 18b). Two strategies were used to combine these moieties and to optimize the yield. These new compounds were evaluated for their antiproliferative activities against a panel of nine cancer cell lines. The results clearly show that 5-arylidenethiazolin-4-one moiety contributes substantially to the activity. Also, methyl esters are more potent than amides, while N-ethylamides are the most potent among amides. 14b showed the highest potency against all tested cancer cell lines with IC50 1.4-2.5 µM, while against normal cell line IC50 > 50 µM. It showed arrest of HeLa cells at G0/G1, S phases and reduction of the percent of cells in G2/M. Moreover, 14b triggered death of HeLa cancer cells via apoptosis induction. EGFR inhibitory potency of 14b was found to be comparable to that of erlotinib. Computational docking and in silico pharmacokinetic studies were performed and discussed. In conclusion, 14b might serve as a multitarget lead compound for further development of anticancer agents.