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The Fulvene Approach to the Syntheses of Antitumor Agents

富烯合成抗肿瘤药物的方法

基本信息

批准号：
8432448
负责人：
Ihsan Erden
金额：
$ 25.66万
依托单位：
SAN FRANCISCO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-04 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8432448
关键词：
Acylation Antineoplastic Agents Area Armin Award Biochemistry Biological Biological Factors Breast Cells Chemicals Chemistry Chemotherapy-Oncologic Procedure Collaborations Colon Cyclization Cyclopentadienes Development Doctor of Philosophy Educational process of instructing Electronics Engineering Enrollment Exhibits Family Funding Future Germany Goals Grant Immunology Institutes Institution Journals Kidney Knowledge Laboratories Lead Left Ligands Lung Malignant neoplasm of cervix uteri Malignant neoplasm of gastrointestinal tract Malignant neoplasm of lung Malignant neoplasm of ovary Malignant neoplasm of pancreas Malignant neoplasm of prostate Methodology Methods Minority National Cancer Institute Nature Organometallic Chemistry Ovarian Oxides Paclitaxel Paper Parents Pathway interactions Patients Peroxides Pharmaceutical Preparations Phase Phase II Clinical Trials Physical condensation Plants Platinum Postdoctoral Fellow Principal Investigator Printing Productivity Property Publications Publishing Reaction Reagent Reporting Research Research Activity Route San Francisco Scheme Science Series Sesquiterpenes Singlet Oxygen Solid Neoplasm Source Structure Students System Therapeutic Therapeutic Index Time Training United States National Institutes of Health Universities Ursidae Family Variant Woman Work acylfulvene analog antitumor agent base cancer type carbonyl group career development cycloaddition cytotoxic cytotoxicity design drug development experience falls flexibility fulvene graduate student illudin M improved indexing instrumentation interest irofulven meetings member microorganism novel nucleophilic substitution phase 2 study professor programs propadiene public health relevance research study screening toxic mushroom tumor undergraduate student ylide

项目摘要

DESCRIPTION (provided by applicant): The proposed studies in this application are aimed at developing new synthetic strategies toward an important class of naturally occurring antitumor agents, as well as their synthetic analogs. The compounds of interest are members of the Illudin family of sesquiterpenes, the most prominent members of which, in terms of cytotoxicity are Illudin S and Illudin M. Despite their promise as potent anticancer agents, the natural products are also highly cytotoxic with low therapeutic index, especially in solid tumor systems. One semisynthetic derivative of Illudin S in particular, known as hydroxymethylacylfulvene (HMAF) has generated a great deal of excitement, since it has a much higher therapeutic index than its natural counterparts and is currently in phase II clinical trials against a wide spectrum of cancer types, including ovarian, prostate, gastrointestinal and lung cancers. There are only a handful of syntheses of this class of compounds, and currently only three conceptually different routes to the most prominent member, HMAF. One approach employs the Padwa carbonly ylide cycloaddition methodology (used by at least three different groups), the other utilizes an intramolecular allenic Pauson-Khand cyclization method, and a very recent synthesis features a ring-closing methatesis reaction as the key step. There is a continuing need for improved methods for the synthesis of this very important class of compounds. The methodologies proposed here are novel in that they represent the only routes to acylfulvenes that are based on classical fulvene syntheses via condensation between a cyclopentadiene unit and a carbonyl group. The synthetic strategies are practical, allow for structural variations in the starting materials and should not only deliver the desired acylfulvenes but also a number of analogs that might possess more favorable therapeutic properties. The intramolecular tandem acylation-condensation pathway figures prominently in several of the strategies. The chemistry presented in each of the synthetic scheme has the potential to uncover a new facet of fulvenes, a class of compounds that has been known for over 100 years. Moreover, all previously unknown derivatives will be subjected to preliminary biological screening in collaboration with our colleagues at the University of Halle, Germany, before they are submitted to the NCI Drug Development program.

描述(申请人提供)：本申请中建议的研究旨在针对一类重要的自然产生的抗肿瘤药物及其合成类似物开发新的合成策略。令人感兴趣的化合物是伊利鲁丁倍半萜家族的成员，其中最突出的细胞毒性成员是伊利鲁丁S和伊利鲁丁M，尽管它们有望成为有效的抗癌药物，但天然产物也具有高度的细胞毒性和低的治疗指数，特别是在实体肿瘤系统中。尤其是伊鲁丁S的一种半合成衍生物，即羟甲基酰富烯，引起了极大的兴奋，因为它的治疗指数比天然同类药物高得多，目前正处于治疗多种癌症类型的第二阶段临床试验，包括卵巢癌、前列腺癌、胃肠道癌和肺癌。这类化合物的合成为数不多，目前只有三条概念上不同的路线可以到达最突出的成员HMAF。一种方法使用Padwa碳素叶立德环加成方法(至少有三个不同的基团使用)，另一种方法使用分子内联烯Pauson-Khandd环化方法，而最近的一种合成方法以闭环甲酸反应为关键步骤。一直需要改进合成这类非常重要的化合物的方法。这里提出的方法是新颖的，因为它们代表了合成酰基富烯的唯一路线，这些路线是基于经典的环戊二烯单元和羰基之间的缩合合成富烯。合成策略是实用的，允许起始材料的结构变化，不仅应该提供所需的酰基富烯，还应该提供一些可能具有更有利的治疗特性的类似物。分子内串联酰化-缩合途径在几种策略中占有重要地位。每一种合成方案中呈现的化学都有可能揭示富烯的一个新方面，富烯是一类已知了100多年的化合物。此外，所有以前未知的衍生物将在提交给NCI药物开发计划之前，与我们在德国哈勒大学的同事合作进行初步的生物筛选。