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

合成

基本信息

批准号：
7959139
负责人：
John S Cooperwood
金额：
$ 11.73万
依托单位：
FLORIDA AGRICULTURAL AND MECHANICAL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7959139
关键词：
4-Hydroxy-Tamoxifen Adjuvant Antibiotics Bacteria Breast Cancer Cell Breast Cancer Treatment Chalcone Chalcones Characteristics Collaborations Computer Retrieval of Information on Scientific Projects Database Disease Drug Delivery Systems Early Diagnosis Electronics Estradiol Estrogen Receptors Estrogen receptor positive Estrogens Ethers Flavonoids Funding Goals Grant Growth Incidence Individual Infection Institution Knowledge Lead MCF7 cell Malignant Neoplasms Molecular Models Mutate Nosocomial Infections Pharmaceutical Preparations Research Research Personnel Research Project Grants Resources Side Source Staphylococcus aureus State Interests Steroids Structure Testing United States National Institutes of Health Vaccines Work abstracting antimicrobial drug base cytotoxicity design drug candidate forging hormone therapy hydroxyl group improved interest malignant breast neoplasm methicillin resistant Staphylococcus aureus molecular modeling pathogen receptor success

项目摘要

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.

该子项目是利用该技术的众多研究子项目之一资源由 NIH/NCRR 资助的中心拨款提供。子项目和研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金，因此可以在其他 CRISP 条目中表示。列出的机构是对于中心来说，它不一定是研究者的机构。抽象的该研究项目在初级研究员 (Cooperwood) 和拥有丰富研究知识的高级研究员 (Du、Redda 和 Ablordeppey) 之间建立了合作关系。尽管近年来通过早期发现和辅助全身治疗在乳腺癌治疗方面取得了一些成功，但该疾病的发病率却一直在稳步上升。内分泌治疗已被证明通过拮抗雌激素受体（ER）受体来有效对抗雌激素受体（ER）阳性乳腺癌。我们计划使用类固醇化合物和类黄酮来靶向 ER。我们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。另一种令人关注的药物靶向疾病状态是 MRSA 感染。博士。 Cooperwood、Du 和 Ablordeppey 参与了有关治疗 MRSA 和其他感染的潜在药物设计的研究。金黄色葡萄球菌是造成医院感染的主要病原体之一。抗生素对抗金黄色葡萄球菌的效果已经减弱，因为细菌会发生突变以抵抗当前的治疗方法。虽然正在尝试获得疫苗，但仍需要开发针对金黄色葡萄球菌，尤其是针对 MRSA 的新药物。假设：抗乳腺癌药物的设计和合成基于我们的 FlexX 分子模型。所有具有MCF-7抑制生长活性的测试化合物都具有刚性结构（初步研究中提到的类固醇），带有两个羟基，其间隔距离类似于雌二醇与一个羟基形成烷基氨基醚的距离。我们认为，通过延长烷基氨基侧链可能会提高 MCF-7 的抑制生长活性。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，例如类黄酮和查耳酮。抗甲氧西林金黄色葡萄球菌 (MRSA) 细菌制剂的设计和合成基于先前合成的具有活性的化合物。我们认为，通过改变 N-烷基 3-Phenylthioquinolinium 苯基部分取代基的电子和疏水特性，将提高效力并降低细胞毒性。该试点项目的目标是设计合成并开发具有抗乳腺癌活性和抗 MRSA 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，以实现以下具体目标：（1）设计、合成和评估化合物作为潜在抗乳腺癌的药理活性，抗甲氧西林金黄色葡萄球菌 (MRSA) 和 (2) 基于药理活性和分子模型研究的先导化合物优化。