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

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 摘要 这个研究项目建立了初级研究员（库珀伍德）和高级研究员（杜，Redda和Alberodeppey）之间的合作，他们在研究方面拥有丰富的知识。 虽然近年来通过早期发现和辅助系统治疗在治疗乳腺癌方面取得了一些成功，但这种疾病的发病率一直在稳步上升。内分泌治疗已被证明是有效的对雌激素受体（ER）阳性乳腺癌通过拮抗雌激素在其受体。我们计划使用甾体碱化合物和类黄酮来靶向ER。 我们已经设计和合成了几种化合物，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。另一种药物靶向的感兴趣的疾病状态是MRSA感染。 Cooperwood，Du和Eschordeppey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。 金黄色葡萄球菌是引起医院感染的主要病原体之一。抗生素对S.金黄色葡萄球菌，因为细菌突变，以抵抗目前的治疗。虽然疫苗的研制工作正在进行中，但仍需要开发新的抗沙门氏菌的药物。金黄色葡萄球菌，更具体地针对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。 具有MCF-7抑制生长活性的所有测试化合物具有刚性结构（在初步研究中提到的类固醇），其带有两个羟基，其分离距离与雌二醇的分离距离相似，其中一个羟基形成烷基氨基醚。 我们的概念是，它可能是可能的，以提高MCF-7的抑制生长活性的烷氨基侧链的延伸。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，如黄酮类化合物和查尔酮。 抗耐甲氧西林金黄色葡萄球菌（MRSA）细菌药剂的设计和合成是基于先前合成的显示活性的化合物。我们认为，通过改变N-烷基3-苯基硫代喹啉的苯基部分取代基的电子和疏水特性，可以提高效力并降低细胞毒性。该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，我们将引起对各种疾病状态有投资兴趣的个人的合作，以实现以下特定目标：（1）设计，合成和评估化合物的药理活性，作为潜在的抗乳腺癌，抗甲氧西林耐药金黄色葡萄球菌（MRSA）和（2）基于药理活性和分子建模研究的先导化合物优化。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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 than 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 (1) to 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.