Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia; Department of Applied Organic Chemistry, National Research Centre, Dokki, Giza, P.O. Box 12622, Egypt.
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia.
Eur J Med Chem. 2015 Nov 2;104:1-10. doi: 10.1016/j.ejmech.2015.09.023. Epub 2015 Sep 16.
In order to develop a potent anti-tumor agent that can target both cancer stem cells and the bulk of tumor cells, a series of 2-((benzimidazol-2-yl)thio)-1-arylethan-1-ones 5a-o was synthesized. All compounds were evaluated for their anti-proliferative activity towards colon HT-29 cancer cell line. In addition, their inhibitory effect against cell surface expression of CD133, a potent cancer stem cells (CSCs) marker, in the same cells was evaluated by flow cytometry at 10 μM. Compound 5l emerged as the most active anti-proliferative analog against HT-29 (IC50 = 18.83 ± 1.37 μM), that almost equipotent as 5-fluorouracil (IC50 = 15.83 ± 1.63 μM) with 50.11 ± 4.05% inhibition effect on CD133 expression, suggested dual targeted effect. Also, compounds 5h, 5j, 5k and 5m-o inhibited the expression of CD133 with more than 50%. The SAR study pointed out the significance of substitution of the pendent phenyl group with lipophilic electron-donating groups or replacing it by 2-thienyl or 2-furyl groups.
为了开发一种能够靶向肿瘤干细胞和肿瘤细胞群体的有效抗肿瘤剂，我们合成了一系列 2-((苯并咪唑-2-基)硫代)-1-芳基乙-1-酮 5a-o。所有化合物均针对结肠 HT-29 癌细胞系进行了抗增殖活性评估。此外，我们还通过流式细胞术在 10 μM 下评估了它们对同一细胞中 CD133 表面表达的抑制作用，CD133 是一种有效的肿瘤干细胞 (CSCs) 标志物。化合物 5l 作为最具活性的抗增殖类似物对 HT-29（IC50=18.83±1.37 μM）表现出最强的活性，其对 CD133 表达的抑制作用几乎与 5-氟尿嘧啶（IC50=15.83±1.63 μM）相当，抑制率为 50.11±4.05%，提示具有双重靶向作用。此外，化合物 5h、5j、5k 和 5m-o 对 CD133 的表达抑制率超过 50%。SAR 研究指出，取代带有脂溶性供电子基团的侧芳基苯基或用 2-噻吩基或 2-呋喃基取代具有重要意义。
