SYNTHESIS OF SPONGISTATIN ANTITUMOR AGENTS
海绵抑素抗肿瘤药的合成
基本信息
- 批准号:6342006
- 负责人:
- 金额:$ 31.48万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1996
- 资助国家:美国
- 起止时间:1996-09-01 至 2003-12-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
The principal goal of this research program is to develop a practical synthetic approach to spongipyran 1 (1), the most potent member of a new family of architecturally unique bisspiroketal macrolides which possess extraordinary antitumor activities. Three research groups have isolated members of the spongipyran family which they designated the spongistatins 1-9, cinachyrolide A, and the altohyrtins A, B and C, respectively. The spongistatins appear to be the most potent inhibitors of cancer cell growth discovered to date. The specific aims for the next four year period are: (A) to compete our first-generation synthesis of spongistatin 2 (2); (B) to devise a highly efficient second-generation synthetic strategy capable of delivering a minimum of one gram of spongistatin 1(1), exploiting where appropriate new methodology developed in our laboratory; and (C) to prepare a carefully designed library of spongistatin analogs to elucidate the pharmacophore of this important class of antitumor agents. Towards the latter end, we have a long standing collaboration with Professor Pettit, Director of the Cancer Research Institute, Arizona State University, who has agreed not only to assay our designed analogs and advanced synthetic intermediates, but also to explore the mode of action of the most promising antitumor candidates, for possible further development. Apart from the anticipated pharmaceutical impact, success in this venture would constitute a major achievement for complex molecule synthesis in general. In addition, this program will serve as excellent training for graduate and postdoctoral students for careers in both academia and the pharmaceutical industry. In conjunction with the proposed synthesis of spongistatin 1 (1), we will (D) investigate our multicomponent linchpin coupling of silyl dithianes with aziridines and other potential electrophiles. This builds upon our extensive experience with dithiane coupling in the assembly of complex structures. Finally, we will (E) develop a new bifunctional reagent for accessing a variety of homoallylic building blocks taking advantage of the Brown asymmetric allylboration. This method holds promise as a valuable protocol for efficient assembly of complex polyol fragments, as well as substituted pyran rings, both of which play an important role in natural product synthesis. A central theme of this and related programs in our laboratory is (and will continue to be) the development of effective synthetic strategies that are not single-target oriented, but instead will permit construction of entire classes of natural products. We believe that this philosophy of "unified" synthetic strategies" will be amply demonstrated in this proposal.
本研究计划的主要目标是开发一种实用的合成方法来合成海绵吡喃1(1),海绵吡喃1(1)是结构独特的双螺旋酮大环内酯新家族中最有效的成员,具有非凡的抗肿瘤活性。三个研究小组已经分离出了海绵虫家族的成员,他们分别将其命名为海绵抑制素1-9、cinachyrolide A和altohyrtin A、B和C。海绵抑素似乎是迄今为止发现的最有效的癌细胞生长抑制剂。未来四年的具体目标是:(A)与我们的第一代合成海绵抑素2(2)竞争;(B)设计一种高效的第二代合成策略,能够提供至少一克海绵抑素1(1),在适当的情况下利用我们实验室开发的新方法;(C)准备一个精心设计的海绵抑素类似物文库,以阐明这类重要抗肿瘤药物的药效团。对于后者,我们与亚利桑那州立大学癌症研究所所长Pettit教授有长期的合作,他不仅同意分析我们设计的类似物和先进的合成中间体,而且还同意探索最有希望的抗肿瘤候选药物的作用模式,以进行可能的进一步开发。除了预期的药物影响外,这项冒险的成功将构成复杂分子合成的一项重大成就。此外,该项目将为研究生和博士后在学术界和制药行业的职业生涯提供良好的培训。结合海绵抑素1(1)的合成,我们将(D)研究硅基二硫烷与氮嘧啶和其他潜在亲电试剂的多组分关键偶联。这建立在我们在复杂结构组装中二硫烷偶联的丰富经验之上。最后,我们将(E)开发一种新的双功能试剂,利用布朗不对称烯丙基硼化反应获得各种同丙基基。该方法有望成为高效组装复杂多元醇片段以及取代吡喃环的有价值的协议,这两者在天然产物合成中都起着重要作用。本项目和我们实验室相关项目的一个中心主题是(并将继续是)开发有效的合成策略,这种策略不是以单一目标为导向,而是允许构建整个类别的天然产物。我们认为,这一“统一的”综合战略的哲学将在这一建议中得到充分体现。
项目成果
期刊论文数量(0)
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{{ truncateString('Amos B Smith', 18)}}的其他基金
Dictyostatin and related prodrugs as candidates for tauopathy treatment
Dictyostatin 和相关前药作为 tau 蛋白病治疗的候选药物
- 批准号:
8821175 - 财政年份:2014
- 资助金额:
$ 31.48万 - 项目类别:
Pilot-Scale Libraries for High-throughput Screening
用于高通量筛选的中试规模文库
- 批准号:
7291136 - 财政年份:2007
- 资助金额:
$ 31.48万 - 项目类别:
Pilot-Scale Libraries for High-throughput Screening
用于高通量筛选的中试规模文库
- 批准号:
7684229 - 财政年份:2007
- 资助金额:
$ 31.48万 - 项目类别: