Novel Approaches for Antitumor and Antiviral Agents

抗肿瘤和抗病毒药物的新方法

基本信息

批准号：
9128446
负责人：
BARRY M TROST
金额：
$ 39.08万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1987
资助国家：
美国
起止时间：
1987-04-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9128446
关键词：
Adverse effects Alkaloids Alkylation Analgesics Antifungal Agents Antineoplastic Agents Antiviral Agents Apoptosis Aspidosperma Biological Chemicals Complex Coupling Cyclization Distant Drug Design Economics Evaluation Exhibits Family Generations Goals Health Human Indole Alkaloids Isothiocyanates KB Cells Laboratories Lactams Lead Ligands Malignant Neoplasms Metals Methodology Microfilaments Molecular Molecular Structure Molecular Target Mus Palladium Pharmacologic Substance Process Property Protocols documentation Reaction Reagent Reducing Agents Research Resistance Route Serine Proteinase Inhibitors Squamous cell carcinoma Structure System Testing Time Translating Twin Multiple Birth Vincristine Vindoline Viral antitumor agent ascidian base catalyst communesin B cycloaddition cytotoxicity design insight invention leukemia member metal complex method development novel novel strategies novel therapeutics perophoramidine programs stereochemistry wasting welwitindolinone C isothiocyanate

项目摘要

DESCRIPTION (provided by applicant): Enabling the optimal design of molecular structure for biologic function requires the invention of new methodologies that are chemo-, regio-, diastereo-, and enantio-selective to allow access to the designed molecular target in a time-efficient manner regardless of its structural complexity. Another aspect of importance is to design such methodologies that also are atom economic - ie to maximize the use of valuable raw materials and to minimize the generation of waste. Furthermore, the development of methods that form multiple bonds in a single pot wherein molecular complexity is rapidly assembled offers the opportunity to reduce step count. Multi-bond forming reactions introduce more structural complexity in a single step and thereby shortens step count. Metal catalyzed cycloadditions has the advantage of using the metal and its attendant ligands to control selectivity, notably diastereo- and enantioselectivity. This latter ability of metal complexes to control selectivity provides incredible opportunity uniquely in allylic alkylations because the exact same catalysts are applicable to formation of a wide diversity of bond types - C-H, C-O, C-N, C-F, C-S, C-P, and C-C, etc., and a wide diversity of mechanisms for enantiodiscrimination. The targets have biological activity mainly as anti-cancer and anti-viral agents. Citrinadin A exhibits cytotoxicity against murine leukemia L1210 and human epidermoid carcinoma KB cells. A facile synthesis will confirm stereochemistry and, importantly, supply larger quantities for further biological evaluation. Welwistatin (N-methylwelwitindolinone C isothiocyanate) is a potent MDR reversing agent reducing the IC50 by 90 fold for many anticancer agents. The serine protease inhibitors, the aeruginosins, have potential as antiviral agents. The cyclotryptamine alkaloids exhibit a broad range of biological properties including antitumor, antiviral, antifungal, and analgesic triggering the question of how structural changes may beget selectivity. The hexacyclic ascidian perophoramidines induce apoptosis by PARP cleavage and the more complicated communesins are microfilament disrupters. The aspidosperma type indole alkaloid, kopimaline A reverses multidry resistance in vincristine-resistant KB cells and has not been synthesized previously.

描述（由申请人提供）：实现生物学功能的分子结构的最佳设计，需要发明新的方法论，这些方法是化学，区域，映射和对映选择性的，以允许以时间效率的方式访问设计的分子目标，无论其结构复杂性如何。重要性的另一个方面是设计也是原子经济的方法 - 即最大程度地利用有价值的原材料并最大程度地减少废物的产生。此外，在单个锅中形成多个键的方法的发展，其中迅速组装的分子复杂性提供了减少步骤计数的机会。多键形成反应在单个步骤中引入了更大的结构复杂性，从而缩短了步骤计数。金属催化的环加成的优点是使用金属及其伴随的配体来控制选择性，尤其是映射性和对映选择性。金属配合物控制选择性的后一种能力为烯丙基烷基化提供了令人难以置信的机会，因为完全相同的催化剂适用于形成广泛的粘结类型的多样性-C-H，C-O，C-N，C-N，C-F，C-S，C-S，C-S，C-P，C-C和C.等，以及用于EnantioDisodiscrimination的机制多样性。靶标主要作为抗癌和抗病毒药物的生物学活性。柠檬酸磷脂A表现出细胞毒性针对鼠白血病L1210和人表皮癌KB细胞。便利的合成将确认立体化学，重要的是，供应更多的生物学评估。 Welwistatin（N-甲基韦替丁酮C C C）是一种有效的MDR反转剂，可为许多抗癌药减少IC50倍数90倍。丝氨酸蛋白酶抑制剂，铜绿素具有抗病毒剂的潜力。环丙酰胺生物碱表现出广泛的生物学特性，包括抗肿瘤，抗病毒，抗真菌和镇痛，这会触发结构变化如何具有选择性的问题。己二环鞘磷脂通过PARP裂解诱导细胞凋亡，而更复杂的公认为是微丝脱落的。 aspidosperma型吲哚生物碱，Kopimaline A逆转抗Vincristine耐药的KB细胞中的多种耐药性，并且先前尚未合成。