The Fulvene Approach to the Syntheses of Antitumor Agents

富烯合成抗肿瘤药物的方法

• 批准号: 8234054
• 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
• 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/8234054
• 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; Health; 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; research study; toxic mushroom; tumor; undergraduate student; 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）：本申请中拟定的研究旨在开发针对一类重要的天然抗肿瘤药物及其合成类似物的新合成策略。感兴趣的化合物是倍半萜烯的Illudin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。特别是一种被称为羟甲基酰基富烯（HMAF）的Illudin S的半合成衍生物已经产生了很大的兴奋，因为它具有比其天然对应物高得多的治疗指数，并且目前正在针对广泛的癌症类型（包括卵巢癌、前列腺癌、胃肠道癌和肺癌）进行II期临床试验。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路线，最突出的成员是HMAF。一种方法采用Padwa carbone叶立德环加成方法（至少有三个不同的团体使用），另一种方法利用分子内的丙二烯Pauson-Khand环化方法，最近的合成方法以闭环甲基化反应为关键步骤。对于合成这类非常重要的化合物的改进方法存在持续的需求。这里提出的方法是新颖的，因为它们代表了基于经典富烯合成的酰基富烯的唯一途径，通过环戊二烯单元和羰基之间的缩合。合成策略是实用的，允许起始材料的结构变化，并且不仅应递送所需的酰基富烯，而且还应递送许多可能具有更有利的治疗性质的类似物。分子内串联酰化-缩合途径在几种策略中占有突出地位。每个合成方案中所呈现的化学性质都有可能揭示富烯的一个新方面，富烯是一类已知超过100年的化合物。此外，所有以前未知的衍生物将与我们在德国哈雷大学的同事合作进行初步生物筛选，然后提交给NCI药物开发计划。 公共卫生关系：该提议中的靶分子与天然存在的倍半萜烯illudin M和S相关，它们已从有毒蘑菇Ompestus illudens中分离出来。这些化合物已被国家癌症研究所证明具有抗肿瘤活性，尽管指数很差。半合成伊鲁啶类似物羟甲基富烯（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。这一系列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也开始招募前列腺癌，胰腺癌和卵巢癌II期研究的患者。卵巢癌研究涉及对包括紫杉醇和铂类试剂在内的化疗方案不再有反应的肿瘤妇女。