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

合成

• 批准号: 8357114
• 负责人: John S Cooperwood
• 金额: $ 9.36万
• 依托单位: FLORIDA AGRICULTURAL AND MECHANICAL UNIV
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357114
• 关键词: 4-Hydroxy-Tamoxifen; Adjuvant; Antibiotics; Bacteria; Breast Cancer Cell; Breast Cancer Treatment; Chalcones; Characteristics; Collaborations; Disease; Drug Delivery Systems; Early Diagnosis; Electronics; Estradiol; Estrogen Receptors; Estrogen receptor positive; Estrogens; Ethers; Flavonoids; Funding; Goals; Grant; Growth; Incidence; Individual; Infection; Knowledge; Lead; MCF7 cell; Malignant Neoplasms; Molecular Models; Mutate; National Center for Research Resources; Nosocomial Infections; Pharmaceutical Preparations; Pharmacologic Substance; Principal Investigator; Research; Research Infrastructure; Research Personnel; Research Project Grants; Resources; Side; Source; Staphylococcus aureus; State Interests; Steroids; Structure; Testing; United States National Institutes of Health; Vaccines; Work; antimicrobial drug; base; cost; cytotoxicity; design; drug candidate; forging; hormone therapy; hydroxyl group; improved; interest; malignant breast neoplasm; methicillin resistant Staphylococcus aureus; molecular modeling; pathogen; receptor; success

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.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 抽象的 该研究项目为初级研究员（库珀伍德）与高级研究人员（DU，Redda和Ablordeppey）之间的合作提供了合作。 尽管近年来通过早期发现和辅助系统治疗获得了乳腺癌治疗方面的成功，但这种疾病的发生率一直在倾斜上。事实证明，内分泌疗法通过雌激素在其受体上的拮抗作用而有效地抵抗雌激素受体（ER）阳性乳腺癌。我们计划使用类固醇碱化合物和类黄酮靶向ER。 我们有几种化合物，这些化合物已通过抑制活性对MCF-7乳腺癌细胞进行设计和合成，类似于4-羟基氧法。另一个针对药物的疾病感兴趣状态是MRSA感染。 博士。 Cooperwood，Du和Ablordeppey参与了有关用于治疗MRSA和其他感染的潜在药物设计的研究。 在负责医院感染的主要病原体中，是金黄色葡萄球菌。抗生素对金黄色葡萄球菌的有效性降低了，因为细菌突变以抵抗当前治疗。尽管正在尝试获取疫苗的尝试，但仍有必要针对金黄色葡萄球菌开发新药，更具体地说是针对MRSA的。 假设：抗胸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均具有刚性结构（初步研究中提到的类固醇），其分离距离具有与雌二醇相似的两个羟基，其中一个羟基形成烷基氨基醚。 我们概念化认为，通过烷基氨基侧链的扩展，有可能改善MCF-7抑制性生长活性。此外，我们的Flexx分子模型强烈建议这些概念可以应用于其他刚性结构，例如类黄酮和chalcones。 抗甲基霉素抗葡萄球菌金黄色葡萄球菌（MRSA）细菌的设计和合成是基于先前合成的化合物，这些化合物表现出活性。我们通过更改N-烷基苯基部分的取代基的电子和疏水特性来概念化这一点。 苯噻喹啉将提高效力并降低细胞毒性。该试点的目标是设计合成并开发针对乳腺癌和抗MRSA剂的活动的候选药物。 为了实现这些目标，我们将引起对各种疾病国家有投资兴趣的个人的合作，以执行（1）设计，合成和评估化合物的药理学活动作为潜在的抗乳腺癌，抗甲基甲基甲基抗素的葡萄球菌（MRSA）； （2）基于药理活性和分子建模研究的铅化合物优化。