结合薰衣草素C与基于5-烯基噻唑-4-酮的多靶点抗癌杂化物的设计、合成与优化

Combining lavendustin C and 5-arylidenethiazolin-4-one-based pharmacophores toward multitarget anticancer hybrids

BIOORGANIC CHEMISTRY

影响因子:4.7

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

DOI: 10.1016/j.bioorg.2024.107884

摘要

薰衣草素C是一种源自天然产物的抗癌先导化合物，通过酯化或酰胺化（化合物6-10）对其羧基进行修饰，以及引入5-烯基噻唑-4-酮（14a-c至17a-c，18a和18b）在其氨基上，采用两种策略结合这些部分以优化产率。新合成的这些化合物在九种癌细胞系的增殖抑制活性方面进行了评价。结果显示，5-烯基噻唑-4-酮部分对活性贡献显著。甲基酯比酰胺更具活性，而N-乙酰酰胺在酰胺中最具活性。化合物14b在所有测试的癌细胞系中展现出最高的活性，IC50为1.4-2.5 μM，而对正常细胞系的IC50>50 μM。14b在G0/G1和S期阻滞HeLa细胞，并减少G2/M期细胞比例。此外，14b通过诱导凋亡引起HeLa癌细胞死亡。其对EGFR的抑制能力与厄洛替尼相当。进行了计算机对接和体内药代动力学研究，并进行了讨论。总之，14b可能作为多靶点先导化合物，推动抗癌药物的进一步开发。

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.