Fatty Acid Analogs to treat Cancer/Infectious Diseases

用于治疗癌症/传染病的脂肪酸类似物

• 批准号: 6766332
• 负责人: Nestor Manuel Carballeira
• 金额: $ 9.23万
• 依托单位: UNIVERSITY OF PUERTO RICO RIO PIEDRAS
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6766332
• 关键词: Aspergillus; Candida albicans; DNA topoisomerases; Mycobacterium; antibacterial agents; antifungal agents; antileukemic agent; bioassay; cell line; chemical conjugate; chemical stability; chemical structure function; chemical synthesis; communicable disease control; drug design /synthesis /production; fatty acid analog; inhibitor /antagonist; intermolecular interaction; lipid structure; neoplastic cell; stereoisomer; tuberculosis

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.

传染病是一个严重的问题，寻找新的药物来对抗这些疾病仍然是药物化学家的主要目标。例如，结核病是世界范围内由传染源导致的主要死亡原因，并且由于新的耐多药结核分枝杆菌分离株，其根除每天变得更加复杂。另一方面，白色念珠菌是人类中重要的机会致病菌，感染皮肤和粘膜，但它对免疫功能低下患者的威胁越来越大。然而，C.白色念珠菌也获得了抗药性。因此，我们的长期目标是找到新的脂肪酸，其可以用作前药的脂质组分，也称为药物-脂质缀合物，具有克服一些主要药理学限制的潜力 目前许多候选药物都遇到了诸如多药耐药性、不完全吸收或递送、或太多药物毒性等问题。本申请的目的是找到最好的抗白血病、抗真菌和抗分枝杆菌的2-甲氧基化脂肪酸，这是实现我们长期目标的下一步。拟议研究的中心假设是，由于2-甲氧基官能团的存在，具有2-甲氧基取代的脂肪酸将显示出比目前可用的脂肪酸更强的抗白血病、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目标：（1）鉴定对白血病K-562细胞系最具活性的异和/或反异2-甲氧基化脂肪酸，（2）合成（Z）-2-甲氧基-5-十四碳烯酸的两种对映体 肉豆蔻酸是一种具有良好抗真菌活性的肉豆蔻酸类似物。白色念珠菌等病原真菌。尼日尔，（3）鉴定对结核分枝杆菌H3 zRv最具活性的2-甲氧基化脂肪酸，和（4）合成含有异/反异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。在这个项目的结论，我们预计将提供新的探针，将提供给生物化学家，细胞生物学家和药理学家，用于与这些脂质可以共价连接到有问题的药物。此外，脂质可以与药物协同使用，对抗抗药性病原体， 被合成地连接。新的脂质也可以想象有助于减少一组选定的候选药物的副作用。