Abstract：
Applying various drug design strategies including ring variation, substituents variation, and ring fusion, two series of 2-(alkylthio)-5-(arylidene/heteroarylidene)imidazolones and imidazo[1,2-a]thieno[2,3-d]pyrimidines were designed and prepared as dual potential Chk1 and Chk2 inhibitors. The newly synthesized hybrids were screened in NCI 60 cell line panel where the most active derivatives 4b, d-f, and 6a were further estimated for their five dose antiproliferative activity against the most sensitive tumor cells including breast MCF-7 and MDA-MB-468 and non-small cell lung cancer EKVX as well as normal WI-38 cell. Noticeably, increasing the carbon chain attached to thiol moiety at C-2 of imidazolone scaffold elevated the cytotoxic activity. Hence, compounds 4e and 4f, containing S-butyl fragment, exhibited the most antiproliferative activity against the tested cells where 4f showed extremely potent selectivity toward them. As well, compound 6a, containing imidazothienopyrimidine core, exerted significant cytotoxic activity and selectivity toward the examined cells. The mechanistic investigation of the most active cytotoxic analogs was achieved through the evaluation of their inhibitory activity against Chk1 and Chk2. Results revealed that 4f displayed potent dual inhibition of both Chk1 and Chk2 with IC50 equal 0.137 and 0.25 μM, respectively. It also promoted its antiproliferative and Chk suppression activity via EKVX cell cycle arrest at S phase through stimulating the apoptotic approach. The apoptosis induction was also emphasized by elevating the expression of Caspase-3 and Bax, that are accompanied by Bcl-2 diminution. The in silico molecular docking and ADMET profiles of the most active analogs have been carried out to evaluate their potential as significant anticancer drug candidates.
摘要：
应用各种药物设计策略，包括环变异，取代基变异，和环形融合，设计并制备了两个系列的2-（烷硫基）-5-（亚芳基/杂亚芳基）咪唑酮和咪唑并[1,2-a]噻吩并[2,3-d]嘧啶作为双重潜在的Chk1和Chk2抑制剂。在NCI60细胞系面板中筛选新合成的杂种，其中最具活性的衍生物4b，d-f,和6a进一步估计了它们对最敏感的肿瘤细胞，包括乳腺MCF-7和MDA-MB-468和非小细胞肺癌EKVX以及正常WI-38细胞的五剂量抗增殖活性。值得注意的是，增加与咪唑酮支架的C-2处的硫醇部分连接的碳链提高了细胞毒性活性。因此，化合物4e和4f，含有S-丁基片段，对测试细胞表现出最大的抗增殖活性，其中4f对它们表现出极其有效的选择性。同样,化合物6a,含有咪唑并噻吩并嘧啶核心，对被检查的细胞产生显著的细胞毒活性和选择性。通过评估其对Chk1和Chk2的抑制活性，可以对最具活性的细胞毒性类似物进行机理研究。结果显示，4f对Chk1和Chk2均表现出有效的双重抑制作用，IC50等于0.137和0.25μM，分别。它还通过刺激凋亡途径，通过EKVX细胞周期停滞在S期促进其抗增殖和Chk抑制活性。通过提高Caspase-3和Bax的表达也强调了细胞凋亡的诱导。伴随着Bcl-2的减少。已经进行了最有活性的类似物的计算机分子对接和ADMET谱以评估它们作为重要的抗癌药物候选物的潜力。
