Investigation of Nucleic Acid Based Derived Tamoxifen Analogues for Breast Cancer

描述（由申请人提供）：核酸基衍生的他莫昔芬类似物用于乳腺癌的研究：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系统性的方法，如化疗。已经确定，乳腺癌的主要原因之一是女性体内雌激素水平过高。乳腺癌药物如阿司莫昔芬通过阻断雌激素受体来降低雌激素水平。由于对癌细胞缺乏选择性，他莫昔芬和其他治疗乳腺癌的化学疗法也有严重的毒副作用。因此，有必要开发具有更强选择性和更强抗癌特性的新药来治疗乳腺癌。他莫昔芬是一种雌激素拮抗剂，其结构类似于较早发现的药物己烯雌酚（DES），具有雌激素激动剂的特性。二乙基雌酚的微小结构修饰导致了他莫昔芬抗雌激素特性的发现。因此，在过去的十年中，我们一直在研究核酸基（嘌呤或嘧啶）衍生的二乙酯雌酚（DES）类似物作为潜在的和选择性的抗癌药物，具有类似于他莫昔芬的抗雌激素特性。我们对这些des -嘌呤和des -嘧啶类似物的生物医学研究已经获得了一些“线索”，如N9-（丁烯基）嘌呤、N9-（芳基）嘌呤和N1-（芳基）嘧啶化合物，这些化合物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嘧啶对雌激素受体的拮抗剂特性。因此，我们假设核酸基衍生的他莫昔芬嘌呤和他莫昔芬嘧啶类似物可能表现出更好的能力，形成雌激素受体-“嘌呤”或“嘧啶”配体复合物，通过雌激素受体的信号传导抑制基因转录，因此可能比我们目前的des核酸基类似物表现出更好的抗癌活性。因此，在本项目中，我们描述了设计、开发和筛选具有不同嘧啶和嘌呤核酸碱基的新型他莫昔芬类似物作为治疗乳腺癌的潜在雌激素受体拮抗剂。所有提议的化合物的合成和表征将在路易斯安那州新奥尔良的泽维尔大学药学院进行。这些化合物的筛选将在位于马里兰州Bethesda的美国国家癌症研究所（NCI）进行。在这个项目中获得的信息不仅对确定这类新化合物的结构-活性关系很有价值，而且可能会导致开发出一种选择性和有效的治疗乳腺癌的药物。

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.