Department of Chemistry, Faculty of Science, King Abdulaziz University, Jeddah, 21589, Saudi Arabia.
Department of Pharmaceutical Sciences, College of Pharmacy, Shaqra University, Al Dwadmi, 11961, Saudi Arabia.
ChemMedChem. 2023 Apr 17;18(8):e202200641. doi: 10.1002/cmdc.202200641. Epub 2023 Mar 1.
A new series of tetrasubstituted imidazole derivatives carrying pyrimidine sulfonamide pharmacophores has been synthesized and evaluated for their anticancer activities. In-vitro screening of these hybrids against a full 60-cell-line panel at a single dose of 10 μM showed significant growth inhibition of up to 95 %. The most active compound showed in-vitro anticancer activities against (i) abnormal HER2 and (ii) two mutants for EGFR. Apoptotic gene expression revealed that lead compounds induced MCF-7 cell line apoptosis together with considerable change in the Bax/Bcl-2 expression ratio. One lead compound led to a significant cell-cycle S-phase arrest, while another blocked the cell cycle at G1/S-phase causing the accumulation of cells. Docking analysis of these two hybrids adopted the orientation and binding interactions with a higher liability to enter the active side pocket of HER2, L858R, and T790 M, preferable to that of co-crystallized ligands. Modelling simulation was consistent with the acquired biological evaluation.
已经合成了一系列带有嘧啶磺酰胺药效团的四取代咪唑衍生物，并对其进行了抗癌活性评估。这些杂种在 10μM 的单剂量下对全 60 细胞系进行体外筛选，显示出高达 95%的显著生长抑制。最活跃的化合物对异常 HER2 和 EGFR 的两个突变体表现出体外抗癌活性。凋亡基因表达表明，先导化合物诱导 MCF-7 细胞系凋亡，同时 Bax/Bcl-2 表达比值发生相当大的变化。一种先导化合物导致细胞周期 S 期显著停滞，而另一种则阻止细胞周期在 G1/S 期，导致细胞积累。这两种杂种的对接分析采用了与 HER2、L858R 和 T790M 的活性侧袋进入更高亲和力的取向和结合相互作用，优于共结晶配体。建模模拟与获得的生物学评价一致。
