Synthesis and Evaluation of DIM-like Analogues Targeting PI3K/Akt Pathway

项目总结(见说明)： 研究项目3-针对PI3K/Akt通路的Dim类类似物的合成和评价： 约翰·库珀伍德、卡尔·B·古德曼和赫尔南·A·弗洛雷斯-罗萨斯：最近的调查显示，非裔美国女性患上了高度侵袭性的乳腺肿瘤，死亡率是其他人群的三倍左右。大多数非裔美国女性患有雌激素受体阴性(ER-)、孕激素受体阴性(PR-)和人类表皮生长因子受体-2阴性(HER-2-)肿瘤。当前食品和药物管理局(FDA)批准的乳腺癌治疗方法 用于治疗雌激素阳性(ER)的乳腺肿瘤，包括选择性雌激素受体调节剂(SERM)和芳香酶抑制剂。SERM和芳香酶抑制剂都可以缓解雌激素对ER乳腺癌进展的影响。然而，缺乏对三阴性(ER-、PR-和HER-2-)乳腺癌的治疗，这种癌症压倒性地影响着非裔美国妇女。这项建议的重点是针对一种自然产生的潜在化学预防和/或化疗药物，吲哚-3-甲醇，已发现它既显示出 预防和治疗乳腺癌的活动在各种研究中，吲哚-3-甲醇是十字花科蔬菜中的一种产品，目前正作为膳食补充剂在保健食品店销售。吲哚-3-甲醇的关键代谢物是其酸形式，可转化为其他中间体，如3，3‘-吲哚甲烷(DIM)。我们的假设是，DIM通过在活性部位拮抗磷脂酰肌醇3-激酶(PI3K)/丝氨酸苏氨酸激酶(Akt)信号通路而诱导细胞凋亡，该作用涉及雌二醇刺激乳腺癌生长的三重负性。这一假设已经被初步的分子模拟研究所证实，这些研究表明DIM类似物的化学结构与雌二醇相似。我们将通过以下具体目标来验证我们的假设：1.羟基化、苯并呋喃和苯并噻吩二胺类似物的合成。 2.利用雌激素受体三重阴性的乳腺癌细胞株MDA-MB-231、MDA-MB-435和MDA-MB-435进行的抗增殖研究，以及免疫印迹分析对Akt信号通路的抑制作用；3.优化乳腺癌生长抑制活性的计算研究。

PROJECT SUMMARY (See instructions): Research Project 3 - Synthesis and Evaluation of DIM-like Analogues Targeting PI3K/Akt Pathway: John Cooperwood, Carl B. Goodman and Hernan A. Flores-Rozas: Recent surveys have shown that African-American women develop highly aggressive breast tumors and experience about three-time higher mortality rates in comparison with other populations. Most African-American women have estrogen receptor negative (ER-), progesterone receptor negative (PR-) and human epidermal growth factor receptor-2 negative (HER-2-) tumors. Current Food and Drug Administration (FDA)-approved breast cancer therapies are geared toward the treatment of estrogen positive (ER+) breast tumors, which include Selective Estrogen Receptor Modulators (SERMs) and Aromatase inhibitors. Both SERMs and aromatase inhibitors serve to alleviate the estrogen effect upon the progression of ER+ breast cancers. Nevertheless, there is a lack of treatment for triple negative (ER-, PR- and HER-2- ) breast cancer which overwhelmingly affects African-American women. This proposal's emphasis is directed toward a natural occurring potential chemopreventive and/or chemotherapeutic agent, indole-3-carbinol, which has been found to display both preventive and therapeutic anti-breast cancer activities in various studies, lndole-3-carbinol is a product found in cruciferous vegetables, and it is being marketed in health food stores as a dietary supplement. The key metabolite of lndole-3-carbinol is its acid form which is converted to other intermediates, such as 3, 3'dlindolylmethane (DIM). Our hypothesis is that DIM induces apoptosis by the inhibition of phosphatidylinositol 3-kinase (PI3K)/serine-threonine kinase (Akt,) signaling pathway by antagonism at active site which is involved the stimulation of triple negative breast cancer growth by estradiol. This hypothesis has been substantiated by preliminary molecular modeling studies which indicate that there is similarity between the chemical structures of DIM analogues and estradiol. We will validate our hypothesis by the following specific aims: 1. Synthesis of hydroxlyated, benzofuran and benzothiophene DIM analogues. 2. Anti-proliferation Studies using MDA-MB-231, MDA-MB-435 and MDA-MB-435 estrogen receptor triple negative breast cancer cell lines, and Inhibition of Akt signal pathway using Immunoblot analysis, 3. Computational Studies for optimization of breast cancer growth inhibitory activity.