Wilson Robert J, Jecs Edgars, Miller Eric J, Nguyen Huy H, Tahirovic Yesim A, Truax Valarie M, Kim Michelle B, Kuo Katie M, Wang Tao, Sum Chi Shing, Cvijic Mary E, Paiva Anthony A, Schroeder Gretchen M, Wilson Lawrence J, Liotta Dennis C
Department of Chemistry, Emory University, 1515 Dickey Drive NE, Atlanta, Georgia 30322, United States.
Bristol-Myers Squibb Research & Development, Princeton, New Jersey 08543, United States.
ACS Med Chem Lett. 2017 Dec 8;9(1):17-22. doi: 10.1021/acsmedchemlett.7b00381. eCollection 2018 Jan 11.
CXCR4 is the most common chemokine receptor expressed on the surface of many cancer cell types. In comparison to normal cells, cancer cells overexpress CXCR4, which correlates with cancer cell metastasis, angiogenesis, and tumor growth. CXCR4 antagonists can potentially diminish the viability of cancer cells by interfering with CXCL12-mediated pro-survival signaling and by inhibiting chemotaxis. Herein, we describe a series of CXCR4 antagonists that are derived from ()-5,6,7,8-tetrahydroquinolin-8-amine that has prevailed in the literature. This series removes the rigidity and chirality of the tetrahydroquinoline providing 2-(aminomethyl)pyridine analogs, which are more readily accessible and exhibit improved liver microsomal stability. The medicinal chemistry strategy and biological properties are described.
CXCR4是在许多癌细胞类型表面表达的最常见趋化因子受体。与正常细胞相比，癌细胞过度表达CXCR4，这与癌细胞转移、血管生成和肿瘤生长相关。CXCR4拮抗剂可通过干扰CXCL12介导的促生存信号和抑制趋化作用来潜在地降低癌细胞的活力。在此，我们描述了一系列源自文献中常见的（）-5,6,7,8-四氢喹啉-8-胺的CXCR4拮抗剂。该系列消除了四氢喹啉的刚性和手性，提供了2-（氨基甲基）吡啶类似物，其更容易获得且具有改善的肝微粒体稳定性。描述了药物化学策略和生物学特性。
