Investigation of Nucleic Acid Based Derived Tamoxifen Analogues for Breast Cancer

基于核酸的他莫昔芬类似物治疗乳腺癌的研究

• 批准号: 7667285
• 负责人: Shashikant K Phadtare
• 金额: $ 17.85万
• 依托单位: XAVIER UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7667285
• 关键词: 6-Mercaptopurine; 6-chloropurine; Adverse effects; Agonist; Antineoplastic Agents; Breast; Breast Cancer Treatment; Cancer cell line; Cause of Death; Complex; Data; Development; Diethylstilbestrol; Dose; Estrogen Antagonists; Estrogen Receptors; Estrogens; Evaluation; Exhibits; Future; Genetic Transcription; Goals; Grant; Guanine; In Vitro; Investigation; Journals; Ligands; Louisiana; Malignant Neoplasms; Minor; Modification; National Cancer Institute; New Agents; Nucleic Acids; Peer Review; Pharmaceutical Preparations; Pharmacy facility; Property; Publishing; Purines; Pyrimidine; Pyrimidines; Research; Screening procedure; Signal Transduction; Structure-Activity Relationship; Tamoxifen; Thioguanine; Thymine; Universities; Uracil; Woman; analog; anticancer activity; base; cancer cell; chemotherapy; college; design; improved; malignant breast neoplasm; pre-clinical; purine; pyrimidine analog

DESCRIPTION (provided by applicant): INVESTGATION OF NUCLEIC ACID BASE DERIVED TAMOXIFEN ANALOGUES FOR BREAST CANCER: In the USA, breast cancer is one of the major causes of death in women and a systemic approach such as chemotherapy is required for effective cancer management. It has been established that one of the primary causes of breast cancer is high levels of estrogen in women. Breast cancer drugs such asTamoxifen reduces the estrogen levels by blocking the estrogen receptor. Tamoxifen and other chemotherapeutic treatments for breast cancer also have serious toxic side effects due to their lack of selectivity to cancer cells. Therefore, there is a need for the development of newer agents with more selective and potent anticancer properties for the treatment of breast cancer. Tamoxifen, an estrogen antagonist, is a structural analogue of an earlier discoved drug, Diethystibestrol (DES), with estrogen agonist properties. Minor structural modifications in diethylstilbestrol led to the discovery of tamoxifen with antiestrogenic properties. Therefore, over the past decade we have been investigating nucleic acid base (purine or pyrimidine) derived diethystibestrol (DES) analogues as potential and selective anticancer agents with antiestrogenic properties similar to tamoxifen. Our biomedical investigation of these DES-purine and DES-pyrimidine analogues has yielded several 'leads' such as N9-(butenyl)purine, N9-(aryl)purine and N1- (aryl)pyrimidine compounds that have shown consistant preclinical anticancer activity at micromolar/nanomolar concentrations in several breast and other cancer cell lines. This promising anticancer activity may be due to the antagonist properties of DES-purines and DES-pyrimidines at the estrogen receptor. Therefore, we hypothesized that a nucleic acid base derived tamoxifen-purine and tamoxifen-pyrimidine analogues may exhibit a better ability to form an estrogen receptor-'purine' or 'pyrimidine' ligand complex that can repress gene transcription by signaling through the estrogen receptors and thus may exhibit improved anticancer activity than our current DES-nucleic acid base analogues. Therefore, in this project we describe the design, development and screening of new tamoxifen analogues with different pyrimidine and purine nucleic acid bases as potential estrogen receptor anatgonists for the treatment of breast cancer. The synthesis and characterization of all the proposed compounds will be carried out at the Xavier University of Louisiana, College of Pharmacy, New Orleans, LA. The screening of proposed compounds will be carried out at the National Cancer Institute (NCI), Bethesda, MD. The information gained in this project will be valuable not only in determining the structure-activity-relationship of this new class of compounds, but may also result in the development of a selective and potent agents for the treament of breast cancer.

描述（由申请方提供）：核苷酸碱基衍生的他莫昔芬类似物治疗乳腺癌的研究：在美国，乳腺癌是女性死亡的主要原因之一，有效的癌症管理需要全身性方法（如化疗）。乳腺癌的主要原因之一是女性体内雌激素水平过高。乳腺癌药物如他莫昔芬通过阻断雌激素受体来降低雌激素水平。他莫昔芬和其他用于乳腺癌的化疗药物由于缺乏对癌细胞的选择性，也具有严重的毒副作用。因此，需要开发用于治疗乳腺癌的具有更高选择性和更有效抗癌特性的新型药剂。他莫昔芬是一种雌激素拮抗剂，是早期发现的具有雌激素激动剂特性的药物己烯雌酚（DES）的结构类似物。对己烯雌酚的微小结构修饰导致发现了具有抗雌激素特性的他莫昔芬。因此，在过去的十年中，我们一直在研究核酸碱基（嘌呤或嘧啶）衍生的二乙基雌酚（DES）类似物作为潜在的和选择性的抗癌药物与他莫昔芬类似的抗雌激素性质。我们对这些DES-嘌呤和DES-嘧啶类似物的生物医学研究已经产生了几种“先导化合物”，如N9-（丁烯基）嘌呤、N9-（芳基）嘌呤和N1-（芳基）嘧啶化合物，它们在几种乳腺癌和其他癌细胞系中以微摩尔/纳摩尔浓度显示出一致的临床前抗癌活性。这种有希望的抗癌活性可能是由于DES-嘌呤和DES-嘧啶在雌激素受体上的拮抗剂性质。因此，我们假设核酸碱基衍生的他莫昔芬-嘌呤和他莫昔芬-嘧啶类似物可以表现出更好的形成雌激素受体-“嘌呤”或“嘧啶”配体复合物的能力，所述复合物可以通过雌激素受体的信号传导抑制基因转录，因此可以表现出比我们目前的DES-核酸碱基类似物改善的抗癌活性。因此，在这个项目中，我们描述了设计，开发和筛选新的他莫昔芬类似物与不同的嘧啶和嘌呤核酸碱基作为潜在的雌激素受体拮抗剂治疗乳腺癌。所有拟定化合物的合成和表征将在Xavier University of Louisiana，College of Pharmacy，New Orleans，LA进行。拟定化合物的筛选将在马里兰州贝塞斯达的国家癌症研究所（NCI）进行。本项目所获得的信息不仅在确定这类新化合物的构效关系方面有价值，而且还可能导致开发用于治疗乳腺癌的选择性和有效的药物。