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.
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