Two Directional Benzyne Ring Annulation in the Total Synthesis of Sch 47554

合成有机化学是一门对生物医学研究和药物创新至关重要的学科。它直接影响到新药发现和开发过程的所有阶段。新的HIT活性化合物的发现及其生产药物先导结构的优化依赖于药物设计、迭代合成和生物学评价。2006年可能不太明显的是，天然产物分离、全合成和半合成对于发现未来商业上成功的药物至关重要。在传染病领域，目前医学上使用的药物中有31%以上是直接或通过天然产物铅结构的半合成获得的。此外，天然产品占所有医学领域所有药物的20%以上，主要侧重于治疗癌症和移植手术的药物。医学界对真菌病有相当大的警觉。白念珠菌、新生隐球菌、卡氏肺孢子虫和烟曲霉等病原体是免疫功能低下患者相当大的发病率和死亡率的原因。这些患者包括艾滋病患者，移植手术的接受者，他们需要接受终身免疫抑制药物的治疗，以防止组织排斥反应，以及接受癌症化疗的患者，他们的免疫系统因抗癌药物的副作用而受损。目前治疗严重系统性真菌感染的方法是不足的，因为现在唑类抗真菌药物存在耐药性问题，而更有效的杀菌剂多烯类药物是有毒的。因此，迫切需要针对严重真菌疾病的新疗法，以及对大量局部真菌感染的管理。拨款申请者正在寻求资金支持一名博士后研究助理的研究，他将进行SCH 47554和SCH 47555的全合成，这两种药物都是有效的抗真菌药物。两种化合物对白色念珠菌、热带念珠菌、星形念珠菌、须毛癣菌、红色毛霉菌、汤氏毛霉菌和犬小孢子菌都有较强的抑制作用，SCH 47554显示出较强的活性。这些生物活性天然产物与具有抗肿瘤、抗病毒活性的水那霉素密切相关，它们是色氨酸5-单加氧酶和酪氨酸水解酶的抑制剂，并具有抑制血小板聚集的作用。因此，SCH 47554和SCH 47555是极佳的HIT化学结构，可作为设计治疗人类真菌感染的新型抗真菌药物的基础。为了实现这些目标，有必要开发新的合成化学，用于阐述天然产物的高度官能化的核心结构。新的方法应适用于类似物结构的合成，并在药物合成和发现中普遍使用。

Synthetic organic chemistry is a discipline of paramount importance to biomedical research and pharmaceutical innovation. It impacts directly on all stages of the discovery and development process for new medicines. The discovery of new hit active compounds and their optimisation to produce pharmaceutical lead structures depend on drug design, iterative synthesis and biological evaluation. What may be less apparent in 2006 is the vital importance of natural product isolation, total synthesis and semi-synthesis for the discovery of the commercially successful drugs of the future. In the area of infectious disease, over 31% of the drugs in current use in medicine are derived either directly or via semi-synthesis from natural product lead structures. In addition, natural products constitute over 20% of all drugs in all areas of medicine with major emphasis on drugs to treat cancer and in transplant surgery. There is considerable alarm amongst the medical profession regarding fungal disease. Pathogens such as Candida albicans, Cryptococcus neoformans, Pneumocystis carinii and Aspergillus fumigatus are the cause of considerable morbidity and mortality in immuno-compromised patients. These include patients with fully blown AIDS, recipients of transplant surgery, who need to be treated for life with immuno-suppressants to prevent tissue rejection, and patients undergoing cancer chemotherapy, whose immune system is impaired by the side effects of their anti-cancer drugs. Current therapies for the treatment of serious systemic fungal infection are deficient since there now are resistance problems with azole fungistatic agents and the more potent fungicidal polyene drugs are toxic. As such, there is urgent need for novel therapies for serious fungal disease and for the management of the legions of topical fungal infections. The grant applicant is seeking funding to support the research by one postdoctoral research associate who will carry out the total synthesis of both Sch 47554 and Sch 47555, which are potent antifungal agents. Both compounds show activities against the pathogens Candida albicans, C. tropicalis, C. stellatoidea, Trichophyton mentagrophytes, T. rubrum, T. tonsurans and Microsporum canis with the greater activity shown by Sch 47554. These bioactive natural products are closely related to the aquayamycins, which show antitumour effects, antiviral activities, are inhibitors of tryptophan 5-monooxygenase and tyrosine hydrolase and display inhibition of blood platelet aggregation. As such, Sch 47554 and Sch 47555 are excellent hit chemical structure on which to base the design of new antifungal agents for the treatment of fungal infections in man. In order to achieve these goals, it is necessary to develop new synthetic chemistry for the elaboration of the highly functionalised core structures of the natural products. The new methodology should be amenable for the synthesis of analogues structures and be of general use in pharmaceutical synthesis and discovery.