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:
- 金额:$ 25.66万
- 依托单位:
- 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:
- 关键词:AcylationAntineoplastic AgentsAreaArminAwardBiochemistryBiologicalBiological FactorsBreastCellsChemicalsChemistryChemotherapy-Oncologic ProcedureCollaborationsColonCyclizationCyclopentadienesDevelopmentDoctor of PhilosophyEducational process of instructingElectronicsEngineeringEnrollmentExhibitsFamilyFundingFutureGermanyGoalsGrantImmunologyInstitutesInstitutionJournalsKidneyKnowledgeLaboratoriesLeadLeftLigandsLungMalignant neoplasm of cervix uteriMalignant neoplasm of gastrointestinal tractMalignant neoplasm of lungMalignant neoplasm of ovaryMalignant neoplasm of pancreasMalignant neoplasm of prostateMethodologyMethodsMinorityNational Cancer InstituteNatureOrganometallic ChemistryOvarianOxidesPaclitaxelPaperParentsPathway interactionsPatientsPeroxidesPharmaceutical PreparationsPhasePhase II Clinical TrialsPhysical condensationPlantsPlatinumPostdoctoral FellowPrincipal InvestigatorPrintingProductivityPropertyPublicationsPublishingReactionReagentReportingResearchResearch ActivityRouteSan FranciscoSchemeScienceSeriesSesquiterpenesSinglet OxygenSolid NeoplasmSourceStructureStudentsSystemTherapeuticTherapeutic IndexTimeTrainingUnited States National Institutes of HealthUniversitiesUrsidae FamilyVariantWomanWorkacylfulveneanalogantitumor agentbasecancer typecarbonyl groupcareer developmentcycloadditioncytotoxiccytotoxicitydesigndrug developmentexperiencefallsflexibilityfulvenegraduate studentilludin Mimprovedindexinginstrumentationinterestirofulvenmeetingsmembermicroorganismnovelnucleophilic substitutionphase 2 studyprofessorprogramspropadienepublic health relevanceresearch studyscreeningtoxic mushroomtumorundergraduate studentylide
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(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。
项目成果
期刊论文数量(13)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Imidazolidin-4-ones via (3+2) cycloadditions of aza-oxyallyl cations onto (E)-Narylideneanilines.
咪唑烷-4-酮通过氮杂-氧烯丙基阳离子 (E)-亚芳基苯胺 (Narylideneanilines) 的 (3 2) 环加成反应。
- DOI:10.1016/j.tetlet.2018.08.056
- 发表时间:2018-09-05
- 期刊:
- 影响因子:1.8
- 作者:Oznur Eyilcim;S. Issever;N. Ocal;S. Gronert;I. Erden
- 通讯作者:I. Erden
An expedient synthesis of 6-vinylfulvene.
6-乙烯基富烯的便捷合成。
- DOI:
- 发表时间:2013-08-13
- 期刊:
- 影响因子:1.4
- 作者:Erden, Ihsan;Sabol, Jenny;Gubeladze, Ana;Ruiz, Andrea
- 通讯作者:Ruiz, Andrea
Singlet oxygenation of triquinacene, barrelene, and homobarrelene.
三喹苯、桶烯和高桶烯的单线态氧化。
- DOI:
- 发表时间:2020-04-16
- 期刊:
- 影响因子:1.8
- 作者:Ortega, Teresa;Ozer, Galip;Gronert, Scott;Erden, Ihsan
- 通讯作者:Erden, Ihsan
Temperature-dependent, competitive 1,3-acyl shift versus decarbonylation of a cyclopropanone intermediate.
环丙酮中间体的温度依赖性、竞争性 1,3-酰基转移与脱羰基化。
- DOI:
- 发表时间:2013-06-17
- 期刊:
- 影响因子:2.1
- 作者:Erden, Ihsan;Ma, Jingxiang;Gärtner, Christian;Azimi, Saeed;Gronert, Scott
- 通讯作者:Gronert, Scott
First ketene cycloaddition approach to (±)-junionone.
第一种乙烯酮环加成方法生成 (±)-junionone。
- DOI:
- 发表时间:2016-01-13
- 期刊:
- 影响因子:1.8
- 作者:Erden, Ihsan;Watson, Samuel E
- 通讯作者:Watson, Samuel E
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Ihsan Erden其他文献
Ihsan Erden的其他文献
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{{ truncateString('Ihsan Erden', 18)}}的其他基金
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 - 财政年份:2010
- 资助金额:
$ 25.66万 - 项目类别:
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 - 财政年份:2010
- 资助金额:
$ 25.66万 - 项目类别:
The Fulvene Approach to the Syntheses of Antitumor Agents
富烯合成抗肿瘤药物的方法
- 批准号:
8038327 - 财政年份:2010
- 资助金额:
$ 25.66万 - 项目类别:
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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
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