Concise Syntheses of Vinylcitrate, Isocitrate and Citrafungin A, a Potent Inhibitor of Fungal Geranylgeranyltranferase I

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各个阶段。新的命中活性化合物的发现和它们的优化以产生药物先导结构依赖于药物设计、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的至关重要性。医学界对真菌病有相当大的担忧。病原体如白色念珠菌、新型隐球菌、卡氏肺孢子虫和烟曲霉是免疫功能低下患者相当高的发病率和死亡率的原因。这些包括患有完全爆发的艾滋病的患者，移植手术的接受者，他们需要终身接受免疫抑制剂治疗以防止组织排斥，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。目前用于治疗严重的全身性真菌感染的疗法是有缺陷的，因为现在存在唑类抑真菌剂的耐药性问题，并且更有效的杀真菌多烯药物是有毒的。因此，迫切需要用于严重真菌疾病的新疗法和用于大量局部真菌感染的管理。其次，结核病是全世界因传染病而导致死亡的主要原因，其严重程度已使世界卫生组织（世卫组织）宣布全球处于紧急状态。世卫组织预测，如果不迅速开发新的抗结核药物，到2020年将有10亿新感染者。大约90%的感染者最初会逃避疾病的症状。在这些具有健康免疫系统的个体中，杆菌进入非复制（NRP）状态，可以持续数十年而没有明显的疾病迹象，但仍保持感染潜力。目前结核病（TB）的一线药物治疗虽然对活动性疾病有效，但对NRP状态无效。这不可避免地造成全世界发病率和死亡率大幅上升，而这场灾难对撒哈拉以南非洲尤其不祥。赠款申请人正在寻求资金，以支持一名博士生的培训和研究，该博士生将进行有效的抗真菌剂柠檬芬净A的全合成。这种具有生物活性的天然产物作为一种关键真菌酶，香叶基香叶基转移酶I的抑制剂。这种酶对真菌细胞壁的生物合成至关重要。因此，citrafungin A是一个很好的化学结构，它是设计用于治疗人类真菌感染的新型抗真菌药物的基础。此外，这些研究与发现用于治疗潜伏状态疾病的新型抗结核药物有关。柠檬芬净A的类似物可能对异柠檬酸裂解酶（ICL）显示出很好的活性，ICL是NRP状态下结核分枝杆菌的关键酶。这些研究将导致合成一系列用于生物测定的天然产物的类似物，并鉴定出用于进一步开发的上级化合物。

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. 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. Secondly, TB is the principal cause of death due to an infectious disease worldwide and has reached such proportions that the World Health Organisation (WHO) has declared a global emergency. WHO predicts 1 billion newly infected people by the year 2020 if new anti-TB drugs are not rapidly developed. Approximately 90% of individuals who are infected initially escape symptoms of the disease. In these individuals with healthy immune systems, the bacilli enter a non-replicating (NRP) state that can persist for decades without overt signs of disease, yet maintaining an infectious potential. Current first-line drug treatments for tuberculosis (TB), while effective toward active disease, are impotent towards the NRP state. This has the inevitable consequence of significantly elevated levels of morbidity and mortality worldwide with the catastrophe being especially ominous for sub-Saharan Africa. The grant applicant is seeking funding to support the training and research of one PhD student who will carry out the total synthesis of citrafungin A, a potent antifungal agent. This bioactive natural product acts as an inhibitor of a key fungal enzyme, geranylgeranyltransferase I. This enzyme is crucial for the biosynthesis of the fungal cell wall. As such, citrafungin A is an excellent hit chemical structure on which to base the design of new antifungal agents for the treatment of fungal infections in man. In addition, these studies are relevant to the discovery of new anti-tuberculosis agents for the treatment of the disease in its latent state. Analogues of citrafungin A may well show activity against isocitrate lyase (ICL), which is a critical enzyme for Mycobacterium tuberculosis in the NRP state. The studies should lead to this synthesis of a range of analogues of the natural products for bioassay and the identification of superior compounds for further development.