Novel Approaches for Antitumor and Antiviral Agents

描述（由申请人提供）：为了实现生物功能分子结构的最佳设计，需要发明新的化学、区域、非映体和对映体选择性方法，以便无论其结构复杂性如何，都能以时间高效的方式访问所设计的分子靶标。另一个重要的方面是设计这样的方法，同时也是最经济的，即最大限度地利用有价值的原材料，并尽量减少废物的产生。此外，在单个锅中形成多个键的方法的发展，其中分子复杂性的快速组装提供了减少步数的机会。多键形成反应在单个步骤中引入了更多的结构复杂性，从而缩短了步骤数。金属催化环加成的优点是利用金属及其伴随的配体来控制选择性，特别是非映体和对映体选择性。金属配合物的后一种控制选择性的能力为烯丙基烷基化提供了独特的机会，因为完全相同的催化剂适用于形成多种不同的键类型- C-H， C-O, C-N, C-F, C-S， C-P和C-C等，以及多种不同的对映辨别机制。这些靶点主要具有抗癌和抗病毒的生物活性。Citrinadin A具有细胞毒性

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.