噻唑基 N-苄基取代的乙酰胺衍生物：合成、Src 激酶抑制和抗癌活性。
Thiazolyl N-benzyl-substituted acetamide derivatives: synthesis, Src kinase inhibitory and anticancer activities.
机构信息
Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran 14176, Iran.
出版信息
Eur J Med Chem. 2011 Oct;46(10):4853-8. doi: 10.1016/j.ejmech.2011.07.050. Epub 2011 Aug 4.
KX2-391 (KX-01/Kinex Pharmaceuticals), N-benzyl-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetamide, is a highly selective Src substrate binding site inhibitor. To understand better the role of pyridine ring and N-benzylsubstitution in KX2-391 and establish the structure-activity relationship, a number of N-benzyl substituted (((2-morpholinoethoxy)phenyl)thiazol-4-yl)acetamide derivatives containing thiazole instead of pyridine were synthesized and evaluated for Src kinase inhibitory activities. The unsubstituted N-benzyl derivative (8a) showed the inhibition of c-Src kinase with GI(50) values of 1.34 μM and 2.30 μM in NIH3T3/c-Src527F and SYF/c-Src527F cells, respectively. All the synthesized compounds were evaluated for inhibition of cell proliferation of human colon carcinoma (HT-29), breast carcinoma (BT-20), and leukemia (CCRF-CEM) cells. 4-Fluorobenzylthiazolyl derivative 8b exhibited 64-71% inhibition in the cell proliferation of BT-20 and CCRF cells at concentration of 50 μM.
KX2-391（KX-01/金奈克斯制药），N-苄基-2-（5-（4-（2-吗啉乙氧基）苯基）吡啶-2-基）乙酰胺，是一种高度选择性Src 底物结合位点抑制剂。为了更好地了解吡啶环和 N-苄基取代在 KX2-391 中的作用，并建立构效关系，我们合成了一系列含有噻唑而不是吡啶的 N-苄基取代的（（2-吗啉乙氧基）苯基）噻唑-4-基）乙酰胺衍生物，并对其Src 激酶抑制活性进行了评价。未取代的 N-苄基衍生物（8a）在 NIH3T3/c-Src527F 和 SYF/c-Src527F 细胞中对 c-Src 激酶的抑制作用分别为 GI（50）值为 1.34 μM 和 2.30 μM。所有合成的化合物均用于评价对人结肠癌细胞（HT-29）、乳腺癌细胞（BT-20）和白血病细胞（CCRF-CEM）增殖的抑制作用。4-氟苄基噻唑基衍生物 8b 在浓度为 50 μM 时对 BT-20 和 CCRF 细胞的增殖抑制率为 64%-71%。
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