Tetrahydroisoquinoline Antitumor Drugs: Synthesis and Biosynthesis

四氢异喹啉抗肿瘤药物：合成与生物合成

基本信息

批准号：
8300197
负责人：
Robert Michael Williams
金额：
$ 30.62万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-04-10 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8300197
关键词：
Affinity Affinity Labels Alkaloids Amino Acid Sequence Anabolism Antineoplastic Agents Binding Biochemical Bioinformatics Biological Biological Factors Biotin Carbohydrates Carrier Proteins Cell Separation Cells Chemicals Chemistry Clinical Complex DNA DNA Alkylation DNA Sequence DNA crosslink DNA-Binding Proteins Databases Development Early identification Ecteinascidin 743 Engineering Enzymes Evaluation Family Florida Fourier transform ion cyclotron resonance Gene Cluster Genetic Engineering Goals Grant Health Investigation Label Laboratories Ligation Link Marines Metagenomics Methodology Methods Molecular Molecular Structure Nature Nucleic Acids Oxidation-Reduction Pathway interactions Peptide Sequence Determination Pharmaceutical Preparations Physical condensation Population Production Proteins Sequence Analysis Series Staging Streptavidin Sulfides Superoxides Synthesis Chemistry System Technology Tetrahydroisoquinolines Transferase Tyrosine Urochordata adduct affinity labeling analog antineoplastic antibiotics antitumor drug base chemical addition chemical synthesis clinically relevant crosslink cyanonaphthyridinomycin design drug synthesis genome sequencing human ZNF9 protein lemonomycin member metagenomic sequencing microbial microbial community microbial host microorganism new technology oxidation oxidative damage peptide synthase positional cloning programs rRNA Genes tetrazomine tool

项目摘要

DESCRIPTION (provided by applicant): The primary focus of this application is to study the total synthesis and biosynthesis of complex, biomedically significant natural products constituted of tetrahydroisoquinolines. The synthetic chemistry that will be developed shall be utilized to prepare analogues of the natural substances as biological, biosynthetic and mechanistic probes. This proposal is primarily hypothesis-driven, and extensively employs new synthetic methodologies developed in this laboratory for the construction of such agents. The specific aims of this program are to study the interaction of the natural antitumor antibiotics and mechanistically inspired synthetic analogs, including ecteinascidin 743 (Et-743), saframycin, jorumycin, tetrazomine, lemonomycin and the bioxalomycins with cellular nucleic acids. The DNA-alkylating capacity of these drugs compared with their ability to cause oxidative damage to nucleic acids will be explored. The synthesis of members of this class of antitumor drugs will continue to be developed with the objective of harnessing the synthetic methodology developed to make new, less toxic, more selective and more potent antitumor drugs. In addition, the tools of synthesis will be exploited to synthesize mechanistic probes for the interaction of these substances with cellular nucleic acids and proteins that bind to cellular nucleic acids. We have recently discovered that bioxalomycin 12 specifically cross-links duplex DNA at 54dCpG34 steps. We propose to elucidate the exact molecular structure of the covalent adduct. This finding has inspired new design concepts for simpler analogs based on the tetrahydroisoquinoline core that may be capable of alkylating and cross-linking DNA as well as potentially cross-linking DNA to DNA-binding proteins. The antiproliferative activity of this family of alkaloids is intimately associated with the capacity of these agents to bind to and covalently modify DNA. This is particularly evident in the case of Et-743. Plans are presented to mechanistically separate the DNA alkylation and cross-linking chemistry of these agents from their capacity to inflict oxidative damage on cells. The investigation of the biosynthesis of Et-743 with a particular focus on the late-stage assembly of the macrocyclic sulfide-bridged spiro-tetrahydroisoquinoline ring system will be pursued. We plan to apply high throughput genome sequencing methods using 454 technology to identify the Et-743 biosynthetic gene cluster from Ecteinascidia turbinata. The ultimate goals of the biosynthesis studies are to genetically engineer a fermentable microorganism to produce Et-743 for clinical use. PUBLIC HEALTH RELEVANCE: The purpose of this application is to utilize the tools of chemical synthesis to study the molecular details of how Nature biosynthesizes anti-cancer drugs. In particular, this program will deploy new technologies to produce the clinically relevant anticancer drug ecteinascidin 743 (Et-743) on industrially practical scale through genetic engineering of a microbial host. In addition, the chemical technologies being developed will be applied to the design and synthesis of new anti-cancer drugs.

描述（由申请人提供）：本申请的主要重点是研究复杂的，生物医学上重要的天然产物的总合成和生物合成。将要开发的合成化学应用于制备天然物质的类似物作为生物学，生物合成和机械探针。该提案主要是由假设驱动的，并且广泛采用该实验室中开发的新合成方法来构建此类药物。该程序的具体目的是研究天然抗肿瘤抗生素和机械启发的合成类似物的相互作用，包括雌激素743（ET-743），saframycin，少霉素，肉豆制霉素，四唑胺，柠檬酸霉素，柠檬霉素，柠檬霉素和生物霉素与细胞构酸酸性。这些药物与对核酸造成氧化损伤的能力相比，将探索这些药物的DNA烷基化能力。该类别的抗肿瘤药物的合成将继续开发，目的是利用开发的合成方法，以使新的，毒性更少，更有选择性，更有效的抗肿瘤药物。另外，将利用合成工具来合成机械探针，以使这些物质与细胞核酸和与细胞核酸结合的蛋白质的相互作用相互作用。我们最近发现，生化霉素12在54DCPG34步骤中特异性交叉链接双链DNA。我们建议阐明共价加合物的确切分子结构。这一发现激发了基于四氢异喹啉核的简单类似物的新设计概念，该核心可能能够烷基化和交联的DNA以及潜在的交联DNA与DNA结合蛋白。这种生物碱家族的抗增殖活性与这些药物结合并共价修改DNA的能力密切相关。在ET-743的情况下，这尤其明显。提出了计划将这些药物的DNA烷基化和交联化学分开的计划与对细胞造成氧化损伤的能力。将研究ET-743的生物合成，特别关注大环硫化物桥桥的晚期组装，将追求四氢异喹啉环系统。我们计划使用454技术应用高吞吐量基因组测序方法，以识别来自Ecteinascidia turbinata的ET-743生物合成基因簇。生物合成研究的最终目标是在遗传上培养一种可发酵的微生物，以产生ET-743用于临床使用。公共卫生相关性：本应用的目的是利用化学合成的工具来研究自然生物合成抗癌药物的分子细节。特别是，该计划将通过微生物宿主的基因工程来生产新技术，以生产临床相关的抗癌药物雌激素743（ET-743）。此外，开发的化学技术将应用于新的抗癌药物的设计和合成。