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

该研究项目旨在探索波多黎各海洋生物多样性，以发现新的和改进的抗癌和抗微生物候选药物，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药物，具有管理和治疗癌症以及传染病的能力，并为全球医疗保健做出贡献。长期以来，海洋无脊椎动物一直被认为是新的生物医学物质的可能来源。药理学家、生理学家和生物化学家已经证明，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。这些分子可以作为先导，指导制药和化学工业开发新产品。我们提出的研究专门针对波多黎各海洋无脊椎动物（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品的可能资源。由于已知存在于波多黎各附近的海洋无脊椎动物物种中，只有不到1%的物种进行了次级代谢物成分的化学评估，其中许多已被证明产生具有强效化疗特性的代谢物，因此该地区的生物体有可能含有丰富的新型药物。具体而言，在这项研究的四年中，我们计划仔细审查属于加勒比海四个主要门的350个代表性物种的药理学和化学。用不同极性的溶剂（例如，己烷、二氯甲烷和甲醇）将使用细胞毒性和抗微生物活性测定进行监测。仅对具有强细胞毒性和抗微生物特性的浸提残留物，通过HPLC/ESI-MS和NMR光谱进一步筛选化学结构特征。如果筛选结果有必要，将通过色谱法（柱、GC、LC）进一步纯化并测定分子结构。结构解析将严重依赖于光谱方法（例如，1H和13 C NMR、MS、IR、UV）和X射线衍射技术。候选化合物将安排进行临床试验，以评估其临床潜力。通过确定化学结构，并最终确定产生这些化合物的生物化学途径以及控制其产生的环境或生理触发因素，可以开发增强商业生产的技术。 公共卫生相关性：仅在美国，预计2008年将诊断出140多万新的癌症病例。目前的流行病学证据表明，艾滋病毒/艾滋病、疟疾和结核病每年在全世界造成900多万人死亡。我们的研究计划旨在探索海洋无脊椎动物的生物多样性，以发现新的和改进的抗癌和抗感染候选药物，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药物，并有能力管理和治疗这些疾病，从而为全球医疗保健做出贡献。

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.