非常简洁的路线到epothilones:epothilone 490的总合成和评估
Kaustav Biswas1, Hong Lin, Jon T Njardarson
1Bioorganic Chemistry, Preclinical Pharmacology Core Facility and Analytical Pharmacology Core Facility, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, New York 10021, USA.
Journal of the American Chemical Society
|August 15, 2002
概括
这项研究介绍了一种新的立体特异性合成epothilones使用环闭olefin转化解 (RCM). 新的RCM-reduction协议有效地产生了用于抗瘤药物开发和模拟合成的epothilone框架.
科学领域:
- 有机化学 有机化学
- 药用化学 医学化学
- 化学生物学 化学生物学
背景情况:
- 埃波提隆是一种有前途的抗瘤药物.
- 以往使用环闭性油甲解酶 (RCM) 合成的epotilones缺乏立体控制.
- 埃波提隆490 (3) 促使对RCM进行重新评估,以对埃波提隆合成.
研究的目的:
- 开发一个简洁,模块化和立体选择性的实验室合成epothilones.
- 建立一个新的RCM-减少协议,以有效地生成epothilone框架.
- 探索用于结构-活性关系 (SAR) 研究的新型epotilone类型的合成.
主要方法:
- 立体特异环闭式烯基基基转化 (RCM) 形成宏环.
- 在C3-(S) - 酒精的晚期引入中,基拉尔介导的阿尔多尔条件.
- 选择性二胺降解新形成的烯酸.
- 新烯用于模拟合成的功能化.
主要成果:
- 通过执行RCM作为最后一个合成步骤,实现了64%的所需E-olefin产量.
- 选择性二胺降解产生了12,13-脱氧乙,一种临床候选物.
- 这条新路线促进了用于细胞毒性和微管类亲和性查的新类型的构建.
- 由于不良的药理动力学,Epothilone 490在异种移植中体内表现不佳,但根据药理动力学标准,它对人类的使用具有前景.
结论:
- 一种基于RCM的新型,立体选择性的epotilone合成已经成功开发出来.
- 该RCM-减少协议提供了一个高效的路线,以epothilone类似物和临床候选人12,13-desoxyepothilone B.
- 虽然epothilone 490在临床前模型中体内疗效较差,但其药物动力学特征表明它在人类中具有潜在的治疗价值.
相关概念视频
02:29Ethers from Alcohols: Alcohol Dehydration and Williamson Ether Synthesis
Overview
Ethers can be prepared from organic compounds by various methods. Some of them are discussed below,
Preparation of Ethers by Alcohol Dehydration
In this method, in the presence of protic acids, alcohol dehydrates to produce alkenes and ethers under different conditions. For example, in the presence of sulphuric acid, dehydration of ethanol at 413 K yields ethoxyethane, whereas it yields ethene at 443 K.
Ethers can be prepared from organic compounds by various methods. Some of them are discussed below,
Preparation of Ethers by Alcohol Dehydration
In this method, in the presence of protic acids, alcohol dehydrates to produce alkenes and ethers under different conditions. For example, in the presence of sulphuric acid, dehydration of ethanol at 413 K yields ethoxyethane, whereas it yields ethene at 443 K.
02:43E1 Reaction: Stereochemistry and Regiochemistry
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02:38Structure and Nomenclature of Epoxides
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03:00Preparation of Epoxides
Overview
Epoxides result from alkene oxidation, which can be achieved by a) air, b) peroxy acids, c) hypochlorous acids, and d) halohydrin cyclization.
Epoxidation with Peroxy Acids
Epoxidation of alkenes via oxidation with peroxy acids involves the conversion of a carbon–carbon double bond to an epoxide using the oxidizing agent meta-chloroperoxybenzoic acid, commonly known as MCPBA. Since the O–O bond of peroxy acids is very weak, the addition of electrophilic oxygen of peroxy acids to...
Epoxides result from alkene oxidation, which can be achieved by a) air, b) peroxy acids, c) hypochlorous acids, and d) halohydrin cyclization.
Epoxidation with Peroxy Acids
Epoxidation of alkenes via oxidation with peroxy acids involves the conversion of a carbon–carbon double bond to an epoxide using the oxidizing agent meta-chloroperoxybenzoic acid, commonly known as MCPBA. Since the O–O bond of peroxy acids is very weak, the addition of electrophilic oxygen of peroxy acids to...
02:57Sharpless Epoxidation
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02:24Acid-Catalyzed Ring-Opening of Epoxides
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