Department of Chemistry and Biochemistry, Université de Moncton, Moncton, NB, Canada.
Eur J Med Chem. 2011 Sep;46(9):4010-24. doi: 10.1016/j.ejmech.2011.05.074. Epub 2011 Jun 12.
A series of bis- and mono-benzonitrile or phenyl analogues of letrozole 1, bearing (1,2,3 and 1,2,5)-triazole or imidazole, were synthesized and screened for their anti-aromatase activities. The unsubstituted 1,2,3-triazole 10a derivative displayed inhibitory activity comparable with that of the aromatase inhibitor, letrozole 1. Compound 10a, bearing a 1,2,3-triazole, is also 10000-times more tightly binding than the corresponding analogue 25 bearing a 1,2,5-triazole, which confirms the importance of a nitrogen atom at position 3 or 4 of the 5-membered ring needed for high activity. The effect on human epithelial adrenocortical carcinoma cell line (H295R) proliferation was also evaluated. The compound 10j (IC(50) = 4.64 μM), a letrozole 1 analogue bearing para-cyanophenoxymethylene-1,2,3-triazole decreased proliferation rates of H295R cells by 76 and 99% in 24 and 72 h respectively. Computer calculations, using quantum ab initio structures, suggest a possible correlation between anti-aromatase activity and the distance between the nitrogen in position 3 or 4 of triazole nitrogen and the cyano group nitrogen.
一系列的双和单苯并腈或苯并类似物来曲唑 1，具有（1,2,3 和 1,2,5）-三唑或咪唑，被合成并筛选其芳香酶抑制活性。未取代的 1,2,3-三唑 10a 衍生物显示出与芳香酶抑制剂来曲唑 1 相当的抑制活性。化合物 10a，具有 1,2,3-三唑，也比相应的类似物 25 （具有 1,2,5-三唑）结合更紧密 10000 倍，这证实了 5 元环中位置 3 或 4 上需要氮原子对于高活性的重要性。对人上皮肾上腺皮质癌细胞系（H295R）增殖的影响也进行了评估。化合物 10j（IC（50）= 4.64 μM），是来曲唑 1 的类似物，带有对氰苯氧基亚甲基-1,2,3-三唑，分别在 24 和 72 小时使 H295R 细胞的增殖率降低了 76%和 99%。使用量子从头计算结构的计算机计算表明，抗芳香酶活性与三唑氮 3 或 4 位的氮与氰基之间的距离之间可能存在相关性。
