Dipartimento di Scienze del Farmaco, Università di Catania, Viale A. Doria 6, 95125 Catania, Italy.
Org Biomol Chem. 2019 May 15;17(19):4892-4905. doi: 10.1039/c9ob00651f.
A series of 2,3,4-triaryl-substituted 1,2,4-oxadiazole-5-ones have been prepared as fixed-ring analogues of tamoxifen (TAM), a drug inhibitor of Estradiol Receptor (ER) used in breast cancer therapy, by an efficient synthetic protocol based on a 1,3-dipolar cycloaddition of nitrones to isocyanates. Some of the newly synthesized compounds (14d-f, 14h and 14k) show a significant cytotoxic effect in a human breast cancer cell line (MCF-7) possessing IC50 values between 15.63 and 31.82 μM. In addition, compounds 14d-f, 14h and 14k are able to increase the p53 expression levels, activating also the apoptotic pathway. Molecular modeling studies of novel compounds performed on the crystal structure of ER reveal the presence of strong hydrophobic interactions with the aromatic rings of the ligands similar to TAM. These data suggest that 1,2,4-oxadiazole-5-ones can be considered analogues of TAM, and that their anticancer activity might be partially due to ER inhibition.
已经通过一种基于硝酮与异氰酸酯的 1,3-偶极环加成的有效合成方案，制备了一系列作为他莫昔芬（TAM）的固定环类似物的 2,3,4-三芳基取代的 1,2,4-噁二唑-5-酮，TAM 是一种用于乳腺癌治疗的雌激素受体（ER）药物抑制剂。一些新合成的化合物（14d-f、14h 和 14k）在具有 IC50 值在 15.63 和 31.82 μM 之间的人乳腺癌细胞系（MCF-7）中显示出显著的细胞毒性作用。此外，化合物 14d-f、14h 和 14k 能够增加 p53 表达水平，还激活了凋亡途径。对 ER 晶体结构上的新型化合物进行的分子建模研究表明，与 TAM 类似，配体的芳环上存在强烈的疏水相互作用。这些数据表明，1,2,4-噁二唑-5-酮可以被认为是 TAM 的类似物，并且它们的抗癌活性可能部分归因于 ER 抑制。
