The Fulvene Approach to the Syntheses of Antitumor Agents

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。 公共卫生相关性：本提案中的目标分子与从有毒蘑菇中分离出的天然倍半萜类化合物伊鲁丁M和S有关。这些化合物已经被国家癌症研究所证明具有抗肿瘤活性，尽管指数很低。半合成的伊鲁丁类似物羟甲基富烯(HMAF)及其一些类似物目前正在NCI和MGI Pharma支持的第二阶段临床试验中使用。该系列第二阶段试验包括对乳腺癌、结肠癌、肾癌、卵巢癌、非小细胞肺癌和宫颈癌的研究。MGI Pharma，Inc.还开始招募前列腺癌、胰腺癌和卵巢癌患者参加第二阶段研究。卵巢癌研究涉及患有肿瘤的妇女，她们对包括紫杉醇和铂类试剂在内的化疗方案不再有效。

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.