SYNTHESIS & PHARMACOLOGICAL EVAL OF POTENTIAL ANTI-CANCER & ANTI MICROBIAL AGENT

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 摘要 这个研究项目建立了初级调查员(库珀伍德)和高级调查员(杜、雷达和阿布洛德佩)之间的合作，他们在研究方面拥有丰富的知识。近年来，通过早期发现和辅助系统治疗，乳腺癌的治疗取得了一定的成功，但乳腺癌的发病率仍呈稳步上升趋势。内分泌治疗已被证明是通过拮抗雌激素受体对雌激素受体(ER)阳性的乳腺癌有效的。我们计划使用类固醇碱基化合物和黄酮类化合物来靶向ER。我们已经设计和合成了几个化合物，它们对MCF-7乳腺癌细胞具有类似于4-羟基他莫昔芬的抑制活性。另一种令人感兴趣的靶向疾病状态是MRSA感染。Coperwood、Du和Ablordepey博士参与了关于设计治疗MRSA和其他感染的潜在药物的研究。引起医院感染的主要病原体是金黄色葡萄球菌。抗生素对金黄色葡萄球菌的效果已经变得不那么有效，因为这种细菌会发生突变，从而抵抗目前的治疗方法。虽然获得疫苗的努力正在进行中，但有必要开发针对金黄色葡萄球菌的新药，更具体地说，针对MRSA。 假设：抗乳腺癌药物的设计和合成是基于我们的Flexx分子模型。所有具有MCF-7抑制生长活性的受试化合物都具有刚性结构(初步研究中提到的类固醇)，含有两个羟基，其分离距离与雌二醇相似，其中一个羟基形成烷基氨基醚。我们设想有可能通过延长烷基氨基侧链来提高MCF-7的生长抑制活性。此外，我们的Flexx分子模型强烈表明，这些概念可以应用于其他刚性结构，如类黄酮类和查尔酮类。抗甲氧西林耐药金黄色葡萄球菌(MRSA)细菌剂的设计和合成是基于先前合成的具有活性的化合物。我们设想，通过改变N-烷基3-苯基上取代基的电子和疏水特性， 苯硫代喹啉将提高药效并降低细胞毒性。这项试验的目标是设计、合成和开发具有抗乳腺癌和抗MRSA药物活性的候选药物。 为了实现这些目标，我们将动员对各种疾病状态感兴趣的个人进行合作，以实现以下具体目标：(1)设计、合成和评估作为潜在抗乳腺癌、抗甲氧西林耐药金黄色葡萄球菌(MRSA)的化合物的药理活性；(2)基于药理活性和分子建模研究优化先导化合物(S)。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT This research project forges collaborations between a junior investigator (Cooperwood) and senior investigators (Du, Redda and Ablordeppey) who have vast knowledge in research. While some success in the treatment of breast cancer have been attained in the recent years through early detection and adjuvant systemic treatment, the incidence of this disease has steadily been on the incline. Endocrine therapy has been proven to be effective against estrogen receptor (ER) positive breast cancer through antagonism of estrogen at its receptor. We plan to target the ER using steroidal base compounds and flavonoids. We have several compounds, which have been designed and synthesized with inhibitory activity against MCF-7 breast cancer cells similar to that 4-hydroxytamoxifen. Another drug targeted disease state of interest is MRSA infections. Drs. Cooperwood, Du and Ablordeppey are involved in research concerning design of potential drugs for the treatment of MRSA and other infections. Among the major pathogens responsible for nosocomial infections is Staphylococcus aureus. Antibiotics have become less effective against S. aureus because the bacteria mutate to resist current treatments. While attempts to obtain vaccines are in the works, there is a need to develop new drugs against S. aureus, and more specifically against MRSA. Hypotheses: The design and synthesis of anti-breast cancer agents are based upon our FlexX molecular model. All of test compounds with MCF-7 inhibitory growth activity have rigid structures (steroids mentioned in preliminary studies) bearing two hydroxyl groups with a separation distance similar to that of estradiol with one hydroxyl group forming an alkylamino ether. We conceptualize that it may be possible to improve MCF-7 inhibitory growth activity by extension of alkylamino side chain. Furthermore, our FlexX molecular model strongly suggests that these concepts can be applied to other rigid structures such as flavonoids and chalcones. The design and synthesis of anti-Methicillin Resistant Staphylococcus aureus (MRSA) bacteria agents are based upon previously synthesized compounds that displayed activity. We conceptualize that by changing the electronic and hydrophobic characteristic of substituents on the phenyl portion of N-alkyl 3- Phenylthioquinolinium will improve potency and reduce cytotoxicity. The goals of this pilot are to design synthesis and develop drug candidates with activities against breast cancer and anti-MRSA agents. To achieve these goals, we will elicit the collaboration of individuals who have an invested interest in various disease states to carry out the specific aims which are to (1) design, synthesize and evaluate the pharmacological activities of compounds as potential anti-breast cancer, anti-Methicillin-Resistant Staphylococcus aureus (MRSA); and (2) lead compound(s) optimization based upon pharmacological activities and molecular modeling studies.