Practical Chemical Synthesis of Complex Alkaloids

描述（由申请人提供）：我们的HL研究计划的目标是开发立体和对映体控制的方法，用于构建复杂的胍和其他强碱性分子。这些结构是靶向的，因为胍和胺官能团在药理活性天然产物和现有药物和药物候选物中的比例不成比例地高，并且它们的化学合成方法比其他有机合成工具开发得更少。如果这一应用的目标得以实现，生物医学研究人员将拥有新的工具来制备和修饰含有基本官能团的复杂有机分子的结构。从长远来看，我们正在开发的新的有机合成方法的可用性将有助于发现和生产用于治疗医学疾病的改进的化学试剂 全合成研究将在四个结构不同的领域进行：hetisine生物碱，帕劳'胺和同系物，massadine和sarain A。在每种情况下，都不存在这些结构复杂和新颖的分子的合成条目。这些分子被靶向的部分原因是它们不寻常的生物学特性。海桐碱类生物碱具有抗肿瘤作用和低毒性，海桐碱类生物碱关附甲素目前正在中国进行III期临床试验。帕劳胺是一种非常无毒的免疫抑制剂。Massadine是致病真菌白色念珠菌的香叶基香叶基转移酶I的抑制剂，由于白色念珠菌的香叶基香叶基转移酶I与人的相应酶的同源性仅为30%，因此Massadine在寻找新的抗真菌药物方面具有重要意义。 我们正在进行的研究crambescidin和batzelladine生物碱领域的重点是确定结构简单的同系物显示有前途的抗癌和抗艾滋病毒的活动，可以作为药物开发的实际先导化合物。 拟议的调查是建立在当前项目期间的新策略，用于制备复杂的生物碱通过环缩合和环加成反应，和效用的batzelladine生物碱的栓系双胍类似物，以抑制蛋白质-蛋白质相互作用，涉及大的表面接触的发现。

DESCRIPTION (provided by applicant): The objective of our HL research program is to develop stereo- and enantiocontrolled methods for constructing complex guanidines and other strongly basic molecules. These structures are targeted because guanidine and amine functional group are found in a disproportionately high percentage of pharmacologically-active, natural products and existing drugs and drug candidates, and methods for their chemical synthesis are less developed than other organic synthesis tools. If the aims of this application are realized, biomedical researchers will have new tools for preparing and modifying the structure of complex organic molecules containing basic functional groups. In the long term, the availability of the new organic synthesis methods that we are developing will facilitate discovery and production of improved chemical agents for treating medical disorders Total synthesis investigations will be carried out in four structurally distinct areas: hetisine alkaloids, palau'amine and congeners, massadine and sarain A. In each case, no synthesis entries to these structurally intricate and novel molecules exist. These molecules are targeted in part because of their unusual biological properties. Alkaloids of the hetisine type possess antiarrhythmic properties and low toxicity; the hetisine alkaloid guan-fu base A is currently undergoing Phase III clinical trials in China. Palau'amine is a remarkably non-toxic immunosuppressive agent. Massadine is an inhibitor of geranyl geranyl transferase I of the pathogenic fungus Candida albicans, as geranyl geranyl transferase I of Candida albicans shares only 30% homology with the corresponding human enzyme, it represents a novel lead in the search for new antifungal agents. Our ongoing studies in the crambescidin and batzelladine alkaloid areas focus on identifying structurally simple congeners displaying promising anti-cancer and anti-HIV activities that could serve as practical lead compounds for drug development. The proposed investigations are founded on discoveries made during the current project period of new strategies for preparing complex alkaloids by cyclocondensation and cycloaddition reactions, and the utility of tethered bisguanidine analogs of batzelladine alkaloids to inhibit protein-protein interactions involving large surface contacts.