The Fulvene Approach to the Syntheses of Antitumor Agents

富烯合成抗肿瘤药物的方法

• 批准号: 7762269
• 负责人: Ihsan Erden
• 金额: $ 26.86万
• 依托单位: SAN FRANCISCO STATE UNIVERSITY
• 依托单位国家: 美国
• 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/7762269
• 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 lung; Malignant neoplasm of ovary; Methodology; Methods; Minority; National Cancer Institute; Nature; Organometallic Chemistry; Ovarian; Oxides; Paclitaxel; Pancreas; Paper; Parents; Pathway interactions; Patients; Peroxides; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Physical condensation; Plants; Platinum; Postdoctoral Fellow; Principal Investigator; Printing; Productivity; Property; Prostate; 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; 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; gastrointestinal; 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

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为一类重要的天然抗肿瘤药物及其合成类似物开发新的合成策略。我们感兴趣的化合物是Illudin倍半萜家族的成员，其中最突出的细胞毒性成员是Illudin S和Illudin 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细胞毒性和低治疗指数，特别是在实体肿瘤系统中。特别是一种名为羟甲基酰基fulvene （HMAF）的Illudin S的半合成衍生物引起了极大的兴奋，因为它比天然衍生物具有更高的治疗指数，目前正在进行II期临床试验，用于治疗多种癌症类型，包括卵巢癌、前列腺癌、胃肠道和肺癌。这类化合物的合成方法屈指可数，目前只有三种概念上不同的途径通往最重要的成员HMAF。一种方法采用Padwa碳基环加成方法（至少有三个不同的基团使用），另一种方法采用分子内异位Pauson-Khand环化方法，最近的合成以环闭合反应为关键步骤。对于这类非常重要的化合物的合成方法的不断改进是有必要的。这里提出的方法是新颖的，因为它们代表了通过环戊二烯单元和羰基之间的缩合来合成经典fulvenes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fulvenes，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突出地位。每一种合成方案中的化学成分都有可能揭示黄烯的新方面，黄烯是一类已知已有100多年的化合物。此外，所有之前未知的衍生物在提交给NCI药物开发项目之前，将与我们在德国哈雷大学的同事合作进行初步的生物学筛选。