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（由申请人提供）：实现生物功能分子结构的优化设计需要发明化学选择性、区域选择性、非对映选择性和对映选择性的新方法，以允许以省时的方式获得设计的分子靶点，无论其结构复杂性如何。另一个重要的方面是设计同样具有原子经济性的方法——即最大限度地利用有价值的原材料并最大限度地减少废物的产生。此外，在单个罐中形成多个键的方法的开发，其中分子复杂性被快速组装，提供了减少步骤数的机会。多键形成反应在单个步骤中引入更多的结构复杂性，从而缩短步骤数。金属催化环加成的优点是使用金属及其伴随配体来控制选择性，特别是非对映选择性和对映选择性。金属络合物控制选择性的能力在烯丙基烷基化中提供了独特的令人难以置信的机会，因为完全相同的催化剂适用于形成多种键类型 - C-H、C-O、C-N、C-F、C-S、C-P 和 C-C 等，以及多种对映体歧视机制。这些靶标具有主要作为抗癌和抗病毒剂的生物活性。 Citrinadin A 具有细胞毒性 抗小鼠白血病 L1210 和人表皮样癌 KB 细胞。简单的合成将证实立体化学，并且重要的是，可以为进一步的生物学评估提供更大的数量。 Welwistatin（N-甲基welwitindolinone C 异硫氰酸酯）是一种有效的 MDR 逆转剂，可将许多抗癌药物的 IC50 降低 90 倍。丝氨酸蛋白酶抑制剂铜绿素具有作为抗病毒剂的潜力。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、抗真菌和镇痛，引发了结构变化如何产生选择性的问题。六环海鞘类过佛脒通过 PARP 裂解诱导细胞凋亡，更复杂的通讯素是微丝破坏剂。蜘蛛精型吲哚生物碱 kopimaline A 可逆转长春新碱耐药 KB 细胞的多重耐药性，之前尚未合成。