Inhibition of IGF-1R and lipoxygenase by nordihydroguaiaretic acid (NDGA) analogs
Inhibition of IGF-1R and lipoxygenase by nordihydroguaiaretic acid (NDGA) analogs
复制标题
DOI：
10.1016/j.bmcl.2007.04.092
复制
发表时间：
2007-07-15
影响因子：
2.7
通讯作者：
Berkman, Clifford E.
中科院分区：
文献类型：
--
作者：
Blecha, Joseph E.;Anderson, Marc O.;Berkman, Clifford E.
在此，我们追求的假设，去甲二氢愈创木酸（NDGA）的结构可以细化对胰岛素样生长因子1受体（IGF-1 R）作为乳腺癌的潜在治疗靶点，同时减少其对其他细胞靶点的作用的选择性效力。因此，制备了一组NDGA类似物（7a-7 h），并检查了对IGF-1 R激酶和替代靶标15-脂氧合酶（15 LOX）的抑制效力。这些化合物的抗癌作用通过它们抑制IGF-1介导的MCF-7乳腺癌细胞生长的能力来确定。类似物的设计是基于粗略的Topliss方法，其中NDGA的芳香环之一被各种取代基修饰。发现NDGA的两个儿茶酚环之一的结构修饰对IGF-1 R和IGF-1介导的MCF-7细胞的细胞生长的激酶活性的抑制效力几乎没有影响。15-LOX被认为是最敏感的NDGA的结构修饰。从所检查的有限系列的NDGA类似物中，与15-LOX抑制相比，对IGF-1介导的生长表现出最大选择性的化合物是具有类似于从Larrea divaricata分离的天然产物的框架的环状类似物7 h。7小时的结果是显著的，因为虽然NDGA显示生物混杂性，但7小时对乳腺癌靶点IGF-IR表现出更大的特异性，并具有针对15-LOX（一种据称在乳腺癌中具有肿瘤抑制作用的酶）的10倍弱效力的额外益处。随着特异性和效力的增加，7 h可能成为开发乳腺癌新型治疗药物的新领导者。(C)2007爱思唯尔有限公司保留所有权利。
Herein, we pursue the hypothesis that the structure of nordihydroguaiaretic acid (NDGA) can be refined for selective potency against the insulin-like growth factor 1 receptor (IGF-1R) as a potential therapeutic target for breast cancer while diminishing its action against other cellular targets. Thus, a set of NDGA analogs (7a-7h) was prepared and examined for inhibitory potency against IGF-1R kinase and an alternative target, 15-lipoxygenase (15 LOX). The anti-cancer effects of these compounds were determined by their ability to inhibit IGF-1 mediated cell growth of MCF-7 breast cancer cells. The design of the analogs was based upon a cursory Topliss approach in which one of NDGA's aromatic rings was modified with various substituents. Structural modification of one of the two catechol rings of NDGA was found to have little effect upon the inhibitory potency against both kinase activity of the IGF-1R and IGF-1 mediated cell growth of MCF-7 cells. 15-LOX was found to be most sensitive to structural modifications of NDGA. From the limited series of NDGA analogs examined, the compound that exhibited the greatest selectivity for IGF-1 mediated growth compared to 15-LOX inhibition was a cyclic analog 7h with a framework similar to a natural product isolated from Larrea divaricata. The results for 7h are significant because while NDGA displays biological promiscuity, 7h exhibits greater specificity toward the breast cancer target IGF-IR with that added benefit of possessing a 10-fold weaker potency against 15-LOX, an enzyme which has a purported tumor suppressing role in breast cancer. With increased specificity and potency, 7h may serve as a new lead in developing novel therapeutic agents for breast cancer. (C) 2007 Elsevier Ltd. All rights reserved.