Marine Fatty Acids as New Antifungal, Antimycobacterial, and Topo-l Agents

描述(申请人提供)：脂肪酸在人类健康中起着至关重要的作用。我们的研究小组一直在积极地从海洋生物中发现新的脂肪酸，其结构与通常在陆地生物中遇到的脂肪酸有很大的不同。我们的目标是进一步研究这些新型脂肪酸，以便更好地了解它们的生物化学及其在健康相关问题上的潜在用途。我们特别希望回答以下问题：1)新型海洋脂肪酸的结构特征是否与常见脂肪酸中的结构特征有足够的不同，从而显著改变其在原核和真核细胞中的生物发生？2)海洋脂肪酸对真菌和/或分枝杆菌等病原体的毒性是否与更常见和研究得更好的脂肪酸有足够的不同？3)海洋脂肪酸是否有助于预防和/或控制由真菌和分枝杆菌引起的疾病？如果最不寻常的海洋脂肪酸对传染病的病原体有毒，那么我们可以将它们用于食品配方和补充剂中，以帮助预防、减少和/或治疗真菌感染和/或更复杂的疾病，如结核病。因此，我们的长期目标是确定可能有助于预防、减少和/或治疗传染病的新型海洋脂肪酸。这项应用的目的是探索2-甲氧基化5，9-二不饱和脂肪酸、中链甲氧基化脂肪酸和4，5-亚甲基脂肪酸的化学和毒性：(1)首次合成外消旋和准2-甲氧基化5，9-二不饱和脂肪酸，并测定它们的抗分枝杆菌、inha和拓扑异构酶-L抑制活性；(2)合成一系列中链甲氧基化脂肪酸并研究它们的烯醇基还原酶(EcFabl)抑制活性。(3)首次合成外消旋和光学活性的4，5-亚甲基脂肪酸，并测定其抗真菌和抗分枝杆菌的潜力；(4)实施发展计划，以实现PI在非得分支持方面的竞争力。在这个项目结束时，我们将提供新的脂肪酸，供生物化学家、细胞生物学家和药剂学家用于治疗这些疾病。新型抗真菌化合物还可用作食品中的酵母菌和霉菌抑制剂以及系统抗真菌药物。

DESCRIPTION (provided by applicant): Fatty acids play a critical role in human health. Our research group has been active in discovering new fatty acids from marine biota whose structures differ significantly from those of fatty acids normally encountered in terrestrial organisms. It is our aim to study further these novel fatty acids so as to better understand their biochemistry and their potential use in health related problems. In particular, we wish to answer the following questions: 1) Are the structural features of the novel marine fatty acids sufficiently different from those present in common fatty acids so as to significantly alter their biogenesis in prokaryotic and eukaryotic cells? 2) Will the marine fatty acids be sufficiently different from the more common and better studied fatty acids in their toxicity towards pathogenic agents such as fungi and/or mycobacteria? 3) Will the marine fatty acids be useful in helping to prevent and/or control diseases arising from fungi and mycobacteria? If the most unusual marine fatty acids are toxic to the causative agents of infectious diseases, then we can use them in food formulations and supplements that could help in the prevention, reduction, and/or treatment of fungal infections and/or more complex diseases such as tuberculosis. Our long-range goal, therefore, is to identify novel marine fatty acids with the potential of helping in the prevention, reduction, and/or treatment of infectious diseases. The objective of this application, which is the next step toward attainment of our long-range goal, is to explore the chemistry and toxicity of 2-methoxylated 5,9-diunsaturated fatty acids, mid-chain methoxylated fatty acids, and 4,5-methylene fatty acids by: (1) developing the first synthesis for racemic and quiral 2-methoxylated 5,9-diunsaturated fatty acids and determining their antimycobacterial, InhA, and topoisomerase-l inhibitory activities, (2) synthesizing a series of mid-chain methoxylated fatty acids and study their enoyl reductase (EcFabl) inhibitory activity, (3) developing the first synthesis for racemic and optically active 4,5-methylene fatty acids and determining their antifungal and antimycobacterial potential, and (4) carrying out a developmental plan to achieve competitiveness of the PI for non-SCORE support. At the end of this project we will provide new fatty acids that will be made available to biochemists, cell biologists, and pharmacologists to be used against these diseases. The novel antifungal compounds could also be used as yeast and mold inhibitors in food stuffs and as systematic antifungals.