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：
8038327
负责人：
Ihsan Erden
金额：
$ 26.59万
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 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8038327
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 Screening procedure 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 toxic mushroom tumor 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. PUBLIC HEALTH RELEVANCE: The target molecules in this proposal are related to the naturally occurring sesquiterpenes illudin M and S that have been isolated from the toxic mushroom Omphalotus illudens. These compounds have been shown by the National Cancer Institute to possess antitumor activity, albeit with poor index. The semisynthetic illudin analog, hydroxymethylfulvene (HMAF) and some of its analogs are currently being used in Phase II clinical trials supported by the NCI and MGI Pharma. The series of Phase II trials include studies in breast, colon, renal, ovarian, non-small cell lung, and cervical cancer. MGI Pharma, Inc has also started to enroll patients in a Phase II study in prostate, pancreatic and ovarian cancers. The ovarian cancer study involves women with tumors who are no longer responding to a chemotherapy regimen that includes Taxol and platinum-based reagents.

描述（由申请人提供）：本申请中提出的研究旨在针对一类重要的天然抗肿瘤剂及其合成类似物开发新的合成策略。感兴趣的化合物是Illudin倍半萜家族的成员，就细胞毒性而言，其中最突出的成员是Illudin S和Illudin M。尽管它们有望成为有效的抗癌剂，但天然产物也具有高细胞毒性和低治疗指数，特别是在实体瘤系统中。尤其是隐聚素 S 的一种半合成衍生物，称为羟甲基酰基富烯 (HMAF)，引起了极大的关注，因为它的治疗指数远高于其天然同类物，目前正在进行针对多种癌症类型的 II 期临床试验，包括卵巢癌、前列腺癌、胃肠道癌和肺癌。此类化合物的合成方法屈指可数，目前最重要的成员 HMAF 仅有三种概念上不同的合成路线。一种方法采用 Padwa 碳叶立德环加成方法（至少三个不同的研究组使用），另一种方法采用分子内联烯 Pauson-Khand 环化方法，最近的合成以闭环易位反应为关键步骤。持续需要改进合成这一类非常重要的化合物的方法。这里提出的方法是新颖的，因为它们代表了基于通过环戊二烯单元和羰基之间的缩合的经典富烯合成的酰基富烯的唯一途径。该合成策略是实用的，允许起始材料的结构变化，并且不仅应该提供所需的酰基富烯，而且还应该提供许多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。每个合成方案中呈现的化学成分都有可能揭示富烯的一个新方面，富烯是一类已知已有 100 多年的化合物。此外，所有以前未知的衍生物在提交给 NCI 药物开发项目之前，都将与我们在德国哈勒大学的同事合作进行初步的生物筛选。公共健康相关性：本提案中的目标分子与从有毒蘑菇 Omphalotus illudens 中分离出来的天然倍半萜 Illudin M 和 S 相关。美国国家癌症研究所已证明这些化合物具有抗肿瘤活性，尽管指数较差。半合成的灯伞素类似物羟甲基富烯（HMAF）及其一些类似物目前正在 NCI 和 MGI Pharma 支持的 II 期临床试验中使用。该系列 II 期试验包括乳腺癌、结肠癌、肾癌、卵巢癌、非小细胞肺癌和宫颈癌的研究。 MGI Pharma, Inc 还开始招募患者参加前列腺癌、胰腺癌和卵巢癌的 II 期研究。卵巢癌研究涉及患有肿瘤的女性，她们对包含紫杉醇和铂类试剂的化疗方案不再有反应。