Investigation of Nucleic Acid Based Derived Tamoxifen Analogues for Breast Cancer

描述(申请人提供)：针对乳腺癌的核酸衍生三苯氧胺类似物的研究：在美国，乳腺癌是导致女性死亡的主要原因之一，有效的癌症管理需要化疗等系统性方法。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。像他莫昔芬这样的乳腺癌药物通过阻断雌激素受体来降低雌激素水平。他莫昔芬和其他乳腺癌化疗药物也有严重的毒副作用，因为它们对癌细胞缺乏选择性。因此，有必要开发具有更高选择性和更强抗癌特性的新药物来治疗乳腺癌。他莫昔芬是一种雌激素拮抗剂，是一种早期发现的药物己烯雌酚的结构类似物，具有雌激素激动剂的特性。己烯雌酚的微小结构修改导致了具有抗雌激素特性的他莫昔芬的发现。因此，在过去的十年里，我们一直在研究核酸碱基(嘌呤或嘧啶)衍生的己烯雌酚(DES)类似于他莫昔芬的潜在和选择性抗癌药物。我们对这些去嘌呤和去嘧啶类似物的生物医学研究已经产生了几个‘先导’，例如N9-(丁烯基)嘌呤、N9-(芳基)嘌呤和N1-(芳基)嘧啶化合物，它们在几个乳腺和其他癌细胞株中显示出一致的微摩尔/纳摩尔浓度的临床前抗癌活性。这种有希望的抗癌活性可能是由于去嘌呤和去嘧啶类化合物在雌激素受体上的拮抗作用。因此，我们假设核酸碱基的他莫昔芬-嘌呤和他莫昔芬-嘧啶类似物可能表现出更好的形成雌激素受体-嘌呤或嘧啶配体复合体的能力，该复合体可以通过雌激素受体发出信号来抑制基因转录，从而表现出比我们目前的去核酸碱基类似物更好的抗癌活性。因此，在本项目中，我们描述了具有不同的嘧啶和嘌呤核酸碱基的三苯氧胺类似物的设计、开发和筛选，作为潜在的雌激素受体拮抗剂用于乳腺癌的治疗。所有拟议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。建议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。该项目中获得的信息不仅对确定这类新化合物的结构-活性-关系有价值，而且还可能导致开发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.