New Leads Against Cancer and Infectious Diseases from Puerto Rican Reef Species

描述（由申请人提供）：这项研究项目旨在探索波多黎各的海洋生物多样性，作为发现新的和改进的抗癌和抗微生物候选药物的手段，并进一步寻求将这些候选药物开发成商业上可接受的治疗方法，有能力管理和治疗癌症和传染病，并为全球卫生保健作出贡献。海洋无脊椎动物长期以来一直被认为是新的生物医药物质的可能来源。药理学家、生理学家和生化学家已经证明，许多这些新型海洋产品以生物医学应用的方式改变了基本的生命过程。这些分子可以作为引导制药和化学工业开发新产品的线索。我们提出的研究特别针对波多黎各的海洋无脊椎动物（海绵，柳珊瑚，软体动物和海鞘）作为新的抗癌和抗微生物天然产物的可能资源。由于在波多黎各附近已知存在的海洋无脊椎动物物种中，只有不到1%的物种被化学评估了它们的次级代谢物组成，其中许多已被证明能产生具有强效化疗特性的代谢物，因此来自该地区的生物有可能含有丰富的新药。具体地说，在这项研究的四年期间，我们计划仔细审查属于四个主要加勒比门的350个代表性物种的药理学和化学。不同极性溶剂（如己烷、二氯甲烷和甲醇）的初始提取将使用细胞毒性和抗微生物活性测定进行监测。通过HPLC/ESI-MS和NMR进一步筛选具有强细胞毒性和抗微生物特性的提取物残留物的化学结构特征。如果筛选结果得到保证，将进行进一步的色谱纯化（柱、气相色谱、液相色谱）和分子结构测定。结构解析将主要依赖于光谱方法（例如，1H和13C NMR， MS， IR， UV）和x射线衍射技术。候选化合物将安排临床试验以评估其临床潜力。通过确定化学结构，最终确定这些化合物产生的生化途径以及控制其生产的环境或生理触发因素，可以开发出增强商业生产的技术。

DESCRIPTION (provided by applicant): This research venture aims to explore Puerto Rican marine biodiversity as a means to discover new and improved anti-cancer and anti-microbial drug candidates, and further seeks to develop these drug candidates into commercially acceptable therapeutics, with the capacity to manage and treat cancers as well as infectious diseases, and contribute to global health care. Marine invertebrates have been identified for a long time as likely sources of new biomedicinal substances. Pharmacologists, physiologists and biochemists have demonstrated that many of these novel marine products modify fundamental life processes in ways suggesting biomedical applications. These molecules can serve as leads to guide the pharmaceutical and chemical industries in developing new products. Our proposed research aims specifically at Puerto Rican marine invertebrates (sponges, gorgonian corals, mollusks, and ascidians) as a likely resource for novel anti- cancer and anti-microbial natural products. Since less than 1% of the species of marine invertebrates known to exist near Puerto Rico have been assessed chemically for their secondary metabolite composition, and many of these have been shown to produce metabolites possessing potent chemotherapeutic properties, organisms from this region have the potential to contain a wealth of novel drugs. Specifically, during the four years of this research we plan to carefully scrutinize the pharmacology and chemistry of 350 representative species belonging to four major Caribbean phyla. Initial extraction with solvents of different polarities (e.g., hexane, methylene chloride, and methanol) will be monitored using cytotoxicity and anti-microbial activity assays. Only extract residues possessing strong cytotoxic and anti-microbial properties will be screened further for chemical structural features by HPLC/ESI-MS and NMR spectroscopy. Further purification by chromatography (column, GC, LC) and determination of molecular structure will proceed if warranted by the screening results. Structure elucidation will rely heavily on spectral methods (e.g., 1H and 13C NMR, MS, IR, UV) and X-ray diffraction techniques. Candidate compounds will be scheduled for clinical trial to assess their clinical potential. By determining the chemical structures and, eventually, the biochemical pathways by which these compounds are produced and the environmental or physiological triggers controlling their production, techniques of enhanced commercial production can be developed. PUBLIC HEALTH RELEVANCE: In the USA alone over 1.4 million new cancer cases are expected to be diagnosed in 2008. Current epidemiological evidence suggests that every year HIV/AIDS, malaria, and tuberculosis account for over 9 million deaths worldwide. Our research program aims to explore marine invertebrate biodiversity as a means to discover new and improved anti-cancer and anti-infective drug candidates, and further seeks to develop these drug candidates into commercially acceptable therapeutics, with the capacity to manage and treat these diseases, thus contributing to global health care.