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

靶向 PI3K/Akt 通路的 DIM 类似物的合成和评价

• 批准号: 9002858
• 负责人: John S Cooperwood
• 金额: $ 15.57万
• 依托单位: FLORIDA AGRICULTURAL AND MECHANICAL UNIV
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9002858
• 关键词: 1-Phosphatidylinositol 3-Kinase; Acids; Active Sites; Affect; African American; Agonist; Aromatase Inhibitors; Benzofurans; Biological Assay; Breast Cancer Patient; Breast Cancer cell line; Breast Cancer therapy; Chemical Structure; Chemopreventive Agent; Collaborations; Community Services; Computer Simulation; Data; Development; ERBB2 gene; Epidermal Growth Factor Receptor; Estradiol; Estrogen Receptors; Estrogen receptor negative; Estrogen receptor positive; Estrogens; Evaluation; Goals; Growth; Health Food; Human; Immunoblot Analysis; Indole-3-Carbinol; Indoles; Inhibition of Apoptosis; Instruction; Lead; Literature; MDA MB 231; MDA MB 435; MDA-MB-468; Malignant Neoplasms; Mammary Neoplasms; Maps; Marketing; Methanol; Molecular; Molecular Models; Natural Products; PI3 gene; Pathway interactions; Population; Preventive; Protein-Serine-Threonine Kinases; Research Training; Selective Estrogen Receptor Modulators; Signal Pathway; Structure; Structure-Activity Relationship; Surveys; Therapeutic; Time; United States Food and Drug Administration; Vero Cells; Woman; analog; anticancer research; base; benzothiophene; cell growth; chemotherapeutic agent; comparative; computer studies; cruciferous vegetable; cytotoxicity; design; dietary supplements; diindolylmethane; experience; hydroxyl group; malignant breast neoplasm; molecular modeling; mortality; neoplastic cell; oxidation; pharmacophore; progesterone receptor negative; scaffold; triple-negative invasive breast carcinoma; tumor

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.

最近的调查显示，非洲裔美国女性患上高度侵袭性乳腺肿瘤，其死亡率是其他人群的三倍。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-) 和人表皮生长因子受体 2 阴性 (HER-2-) 肿瘤。当前美国食品和药物管理局 (FDA) 批准的乳腺癌疗法 旨在治疗雌激素阳性（ER+）乳腺肿瘤，其中包括选择性雌激素受体调节剂（SERM）和芳香酶抑制剂。 SERM 和芳香酶抑制剂均可减轻雌激素对 ER+ 乳腺癌进展的影响。然而，三阴性（ER-、PR-和HER-2-）乳腺癌缺乏治疗方法，这种乳腺癌主要影响非裔美国女性。该提案的重点是针对天然存在的潜在化学预防和/或化疗剂，吲哚-3-甲醇，已发现它具有以下两种作用： 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，具有预防和治疗抗乳腺癌的作用，它作为膳食补充剂在健康食品商店销售。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，例如 3, 3'd 吲哚基甲烷 (DIM)。我们的假设是，DIM 通过拮抗活性位点抑制磷脂酰肌醇 3 激酶 (PI3K)/丝氨酸-苏氨酸激酶 (Akt) 信号通路来诱导细胞凋亡，该活性位点涉及雌二醇刺激三阴性乳腺癌生长。这一假设已被初步分子模型研究证实，该研究表明 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验证我们的假设： 1. 羟基化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进行抗增殖研究，并使用免疫印迹分析抑制 Akt 信号通路，3. 优化乳腺癌生长抑制活性的计算研究。