Department of Pharmaceutical Sciences, School of Pharmacy, University of Puerto Rico, San Juan, PR 00936, United States.
Department of Pathology and Laboratory Medicine, School of Medicine, Universidad Central del Caribe, Bayamon, PR 00960, United States.
Bioorg Med Chem. 2018 Feb 15;26(4):884-890. doi: 10.1016/j.bmc.2018.01.003. Epub 2018 Jan 11.
Based on the efficacy of EHop-016 as an inhibitor of migration and Rac1 activation, a new series of carbazole derivatives has been synthesized. Cytotoxic and anti-migratory effects of these compounds were evaluated in MCF-7 and MDA-MB-231 breast cancer cell lines. Preliminary investigations of their anticancer activity demonstrated that several compounds have moderate antiproliferative effects on cancer cell lines with GI values in the range of 13-50 µM. Furthermore, compounds 3b and 11b inhibit migration activity of metastatic cell line MDA-MB-231 by 32% and 34%, respectively. Compound 11b was shown to inhibit activation of the Rho GTPase Rac1 by 55% at 250 nM in both MDA-MB-231 and MDA-MB-435 cell lines. Compared with the IC of Rac1 inhibition by lead compound EHop-016 of 1.1 µM, compound 11b demonstrates 4X improved in vitro efficacy.
基于 EHop-016 作为迁移和 Rac1 激活抑制剂的功效，合成了一系列新的咔唑衍生物。在 MCF-7 和 MDA-MB-231 乳腺癌细胞系中评估了这些化合物的细胞毒性和抗迁移作用。初步研究表明，几种化合物对癌细胞系具有中等的增殖抑制作用，GI 值在 13-50 µM 范围内。此外，化合物 3b 和 11b 分别抑制转移性细胞系 MDA-MB-231 的迁移活性 32%和 34%。在 MDA-MB-231 和 MDA-MB-435 细胞系中，化合物 11b 在 250 nM 时可抑制 Rac1 GTPase 的激活，抑制率为 55%。与 Rac1 抑制的先导化合物 EHop-016 的 IC 为 1.1 µM 相比，化合物 11b 在体外的功效提高了 4 倍。
