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

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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.