设计、合成 Rho/MKL1 转录通路抑制剂 CCG-1423 的类似物，并基于前列腺癌细胞进行研究。
Design, synthesis and prostate cancer cell-based studies of analogs of the Rho/MKL1 transcriptional pathway inhibitor, CCG-1423.
机构信息
Department of Pharmacology, University of Michigan Medical School, University of Michigan, Ann Arbor, MI 48109, USA.
出版信息
Bioorg Med Chem Lett. 2010 Jan 15;20(2):665-72. doi: 10.1016/j.bmcl.2009.11.056. Epub 2009 Nov 18.
Abstract
We recently identified bis(amide) CCG-1423 (1) as a novel inhibitor of RhoA/C-mediated gene transcription that is capable of inhibiting invasion of PC-3 prostate cancer cells in a Matrigel model of metastasis. An initial structure-activity relationship study focusing on bioisosteric replacement of the amides and conformational restriction identified two compounds, 4g and 8, with improved selectivity for inhibition of RhoA/C-mediated gene transcription and attenuated cytotoxicity relative to 1. Both compounds were also capable of inhibiting cell invasion with equal efficacy to 1 but with less attendant cytotoxicity.
摘要
我们最近发现双（酰胺）CCG-1423（1）是一种新型的 RhoA/C 介导的基因转录抑制剂，能够在基质胶转移模型中抑制 PC-3 前列腺癌细胞的侵袭。一项最初的构效关系研究集中在酰胺的生物等排体取代和构象限制上，确定了两种化合物 4g 和 8，它们对 RhoA/C 介导的基因转录抑制具有更好的选择性，并且相对于 1 降低了细胞毒性。这两种化合物也能够以与 1 相同的功效抑制细胞侵袭，但伴随的细胞毒性较小。
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