Fatty Acid Analogs to treat Cancer/Infectious Diseases

传染病是一个严重的问题，寻找抗击这些疾病的新药仍然是药物化学家的主要目标。例如，结核病是世界范围内一种传染病致死的主要原因，而且由于新的耐多药结核分枝杆菌菌株的出现，其根除工作每天都变得更加复杂。另一方面，白色念珠菌是人类重要的机会性病原体，会感染皮肤和粘膜，但对免疫功能低下的患者来说，它是一个越来越大的威胁。然而，白色念珠菌也对药物产生了抗药性。因此，我们的长期目标是找到新的脂肪酸，可以用作前药的脂质成分，也称为药物-脂质结合物，有可能克服一些主要的药理限制。 目前许多候选药物面临多药耐药、吸收或释放不完全或药物毒性过大等问题。这项鉴定的目标是找到最好的抗白血病、抗真菌和抗分枝杆菌2-甲氧基化脂肪酸，这是实现我们长期目标的下一步。这项研究的中心假设是，由于2-甲氧基功能的存在，具有2-甲氧基取代的脂肪酸将比目前可用的脂肪酸表现出更强的抗白血病、抗真菌和抗分枝杆菌活性。为了实现我们的目标，我们正在追求四个具体的目标：(1)鉴定对白血病K-562细胞最有活性的异和/或反-2-甲氧基化脂肪酸，(2)合成(Z)-2-甲氧基-5-十四烯酸的两个对映体 (3)鉴定抗结核分枝杆菌H3zRv最具活性的2-甲氧基化脂肪酸，以及(4)合成含有异/反2-甲氧基官能团的新型抗白血病和/或抗分枝杆菌1-O-(2-甲氧基烷基)甘油。在这个项目结束时，我们有望提供新的探针，供生物化学家、细胞生物学家和药理学家使用，用于这些脂类可以共价结合的有问题的药物。此外，这些脂质可以与对抗抗生素耐药性病原体的药物协同使用，而不需要 被综合地依恋。可以想象，新的脂质还可以帮助减少一组选定的候选药物的副作用。

Infectious diseases are a serious problem and the search for new drugs to combat these diseases continues to be a major goal of medicinal chemists. For example, tuberculosis is the main cause of death worldwide by an infectious agent and its eradication is becoming more complicated everyday due to new isolates of multidrug-resistant Mycobacterium tuberculosis. On the other hand, Candida albicans is a significant opportunistic pathogen in humans and infects the skin and mucosas but it is an increasing threat in immunocompromised patients. However, C. albicans has also acquired resistance to drugs. Our long-range goal, therefore, is to find novel fatty acids that could be used as the lipid component of a prodrug, also called a drug-lipid conjugate, with the potential of overcoming some of the major pharmacological limitations presently encountered by many drug candidates, such as multidrug resistance, incomplete absorption or delivery, or too much drug toxicity. The objective of this appfication, which is the next step toward attainment of our long-range goal, is to find the best antileukemic, antifungal, and antimycobacterial 2-methoxylated fatty acids. The central hypothesis for the proposed research is that fatty acids with the 2-methoxy substitution will display a stronger antileukemic, antifungal, and antimycobacterial activity than presently available fatty acids due to the presence of the 2-methoxy functionality. In order to achieve our goals we are pursuing four specific aims: (1) identifying the most active iso and/or anteiso 2-methoxylated fatty acids against the leukemia K-562 cell line, (2) synthesizing both enantiomers of (Z)-2-methoxy-5-tetradecenoic acid for their potential to be good antifungal myristic acid analogs against C. albicans and other pathogenic fungi such as A. niger, (3) identifying the most active 2-methoxylated fatty acids against Mycobacterium tuberculosis H3zRv, and (4) synthesizing novel antileukemic and/or antimycobacterial 1-O-(2-methoxyalkyl)glycerols containing the iso/anteiso 2-methoxy functionality. At the conclusion of this project we are expected to provide new probes that will be made available to biochemists, cell biologists, and pharmacologists to be used with problematic drugs into which these lipids could be covalently attached. In addition, the lipids could be used synergistically with the drugs against antibiotic-resistant pathogens without being synthetically attached. The new lipids could also conceivably help reduce the side effects of a selected group of drug candidates.