Novel Approaches for Antitumor and Antiviral Agents

抗肿瘤和抗病毒药物的新方法

• 批准号: 8494200
• 负责人: BARRY M TROST
• 金额: $ 38.14万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 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/8494200
• 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; Human; Indole Alkaloids; Inhibitory Concentration 50; Isothiocyanates; KB Cells; Laboratories; Lactams; Lead; Ligands; Malignant Neoplasms; Metals; Methodology; Microfilaments; Molecular; Molecular Structure; Molecular Target; Mus; Palladium; Pharmaceutical Preparations; 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; leukemia; member; metal complex; method development; novel; novel strategies; perophoramidine; programs; public health relevance; stereochemistry; wasting; welwitindolinone C isothiocyanate

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(申请人提供)：为了实现生物功能的分子结构的最佳设计，需要发明具有化学选择性、区域选择性、非对映选择性和对映体选择性的新方法，以允许以时间高效的方式访问所设计的分子靶标，而不考虑其结构的复杂性。另一个重要的方面是设计这样的方法，也是原子经济的--即最大限度地利用有价值的原材料，最大限度地减少废物的产生。此外，在一个锅中形成多个键的方法的发展，其中分子复杂性被快速组装，提供了减少步骤计数的机会。多键形成反应在单步反应中引入了更多的结构复杂性，从而缩短了步数。金属催化的环加成反应具有利用金属及其伴生配体控制选择性，特别是非对映选择性和对映体选择性的优点。金属络合物的这种控制选择性的能力在烯丙基烷基化反应中提供了绝佳的机会，因为完全相同的催化剂适用于各种键类型的形成-C-H、C-O、C-N、C-F、C-S、C-P和C-C等，以及各种各样的对映歧视机制。这些靶标具有生物活性，主要作为抗癌和抗病毒药物。Citrinadin A具有细胞毒性 对小鼠白血病L1210和人表皮样癌KB细胞的作用。简便的合成将证实立体化学，重要的是，为进一步的生物学评价提供更多的数量。Welwistatin(N-甲基韦林酮C异硫氰酸酯)是一种有效的多药耐药逆转剂，可使许多抗癌药物的IC50降低90倍。丝氨酸蛋白酶抑制剂，即铜绿球蛋白，具有作为抗病毒药物的潜力。环色胺生物碱表现出广泛的生物学特性，包括抗肿瘤、抗病毒、抗真菌和止痛剂，这引发了结构变化如何产生选择性的问题。六环海鞘亚胺类化合物通过PARP裂解诱导细胞凋亡，而更复杂的共生素是微丝破碎物。紫草型吲哚生物碱Kopimaline A逆转长春新碱耐药KB细胞的多重耐药，以前还没有合成过。