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

项目总结（见说明）： 研究项目3 -靶向PI 3 K/Akt通路的DIM样类似物的合成和评价： 约翰·库珀伍德卡尔B。Goodman和Hernan A.弗洛雷斯-罗萨斯：最近的调查显示，非洲裔美国妇女患上高度侵袭性的乳腺肿瘤，死亡率比其他人群高出约三倍。大多数非洲裔美国妇女患有雌激素受体阴性（ER-）、孕激素受体阴性（PR-）和人表皮生长因子受体-2阴性（HER-2-）肿瘤。目前美国食品药品监督管理局（FDA）批准的乳腺癌治疗 用于治疗雌激素阳性（ER+）乳腺肿瘤，包括选择性雌激素受体调节剂（SERM）和芳香化酶抑制剂。SERM和芳香酶抑制剂都有助于减轻雌激素对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，这极大地影响了非洲裔美国妇女。该建议的重点是针对天然存在的潜在化学预防和/或化学治疗剂，吲哚-3-甲醇，已发现其表现出两种 在各种研究中，吲哚-3-甲醇是一种在十字花科蔬菜中发现的产品，它作为膳食补充剂在保健食品商店销售。吲哚-3-甲醇的关键代谢物是其酸形式，其转化为其他中间体，如3，3 '-二吲哚基甲烷（DIM）。我们的假设是，DIM诱导细胞凋亡的磷脂酰肌醇3-激酶（PI 3 K）/丝氨酸-苏氨酸激酶（Akt）信号通路的活性位点，这涉及雌二醇刺激三阴性乳腺癌生长的拮抗作用的抑制。这一假设已被初步的分子模拟研究所证实，表明DIM类似物和雌二醇的化学结构之间存在相似性。我们将通过以下具体目标来验证我们的假设：1。羟基化的苯并呋喃和苯并噻吩DIM类似物的合成。 2.使用MDA-MB-231、MDA-MB-435和MDA-MB-435雌激素受体三阴性乳腺癌细胞系的抗增殖研究，以及使用免疫印迹分析的Akt信号通路的抑制。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.