From Total Synthesis-Inspired Methodology to Anti-HIV therapy

从全合成启发的方法到抗 HIV 治疗

• 批准号: EP/E055273/1
• 负责人: Edward Anderson
• 金额: $ 84.94万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2007
• 资助国家: 英国
• 起止时间: 2007 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FE055273%2F1
• 关键词: Total; Synthesis; Inspired; Methodology; Anti

Organic chemistry provides a bridge between the physical world of atoms, molecules and their reactions, and the biological sciences, with one area of particular importance being the development of new medicines. Many drugs are originally inspired by 'natural products' / molecules refined by Nature over millions of years, which can have potent, specific biological activity against human diseases. As such, natural products represent highly advanced starting points for pharmaceutical research; however, their development as drug leads can be hampered by low natural abundance. One solution (which avoids decimation of the natural habitat) is the artificial preparation, or 'total synthesis' of the natural product. Historically, this process can take many years, a timescale which cannot satisfy the requirements of automated pharmaceutical screening. However, the application of improved, efficient chemical methods which enable rapid and scalable syntheses of these natural medicines (and non-natural 'analogues' with improved efficacy), is now an aim that is within the grasp of the organic chemist. Natural products chemistry thus stands on the brink of being re-embraced by the pharmaceutical community; this proposal aims to show that the natural product target itself is just the beginning of what an organic chemist can deliver.Traditionally, organic chemistry can be divided into two schools of research. The development of new reactions, which is fundamental to improving the efficiency of chemical synthesis, investigates new ways to form bonds between atoms. Often there is no specific target, and researchers can resort to scouring a vast array of natural products for one which will showcase their methodology. By contrast, in the field of total synthesis of structurally challenging molecules (which provides the ultimate testing ground for methodology), chemists tend to use known methods to forge the most efficient path they are able to a given target. The challenge of synthesis itself usually dictates that the choice of reaction is one with precedent and reliability.This proposal seeks to reverse this accepted order of reaction development: Natural products are seen as the inspiration for new reactions, rather than an arbitrary setting. Biologically important targets will be selected, and provide the impetus for the invention of an efficient and appealing synthetic transformation. Following development in a general setting, this method will then be applied in the context it was intended / a total synthesis of the natural product and analogues. Two projects which demonstrate the potential for natural products to initiate the development of useful, general reactions with broad applicability are proposed: Cepacin A, a potent antibiotic which contains an intriguing unsaturation motif, is the inspiration for a novel synthesis of chiral allenes. Lancifodilactone G and rubriflordilactone A, which possess anti-HIV properties, are the basis for an innovative route to bi- or tricyclic molecules.My proposal also details a collaborative project towards new methods for HIV inhibition. A currently uninvestigated area of the HIV life cycle is the 'packaging' of viral RNA into new virus particles. Packaging is initiated by binding of the viral protein Gag to a region of the viral RNA called psi. It is known that psi, and a truncated analogue, are bound specifically by a region of Gag that contains amino acids with nucleophilic sidechains. We intend to design psi analogues containing an electrophilic site, which will bind to Gag and place this site in proximity to the nucleophilic sidechain amino acids, leading to the formation of a covalent bond, irreversible binding of Gag, and inhibition of packaging. This is an exciting and unexplored area of chemical biology which harnesses the expertise of both the organic chemist and the virologist, and could have implications for the design of inhibitors for other virus specific RNA-protein interactions.

有机化学提供了原子，分子及其反应的物理世界与生物科学之间的桥梁，其中一个特别重要的领域是开发新药物。许多药物最初是受自然精炼的“天然产物” /分子的启发，数百万年来可以对人类疾病具有有效的特定生物学活性。因此，天然产品代表了药物研究的高级起点。但是，它们作为药物铅的发展可能会因低自然丰度而受到阻碍。一种解决方案（避免了自然栖息地的破裂）是人工制备或自然产物的“完全合成”。从历史上看，这个过程可能需要很多年，一个时间表无法满足自动化药物筛查的要求。但是，改进，有效的化学方法的应用可以使这些天然药物的快速和可扩展合成（以及具有提高疗效的非天然“类似物”）的应用，现在是有机化学家所掌握的目的。因此，天然产品化学依赖于药物群落重新构想的边缘。该建议旨在表明自然产品目标本身只是有机化学家可以提供的开始的开始。在传统上，有机化学可以分为两种研究流派。新反应的发展，这是提高化学合成效率的基础，它研究了原子之间形成键的新方法。通常没有具体的目标，研究人员可以求助于将大量天然产品搜索将展示其方法论的天然产品。相比之下，在结构上具有挑战性的分子（为方法论提供了最终的测试地面）的总合成领域中，化学家倾向于使用已知的方法来伪造它们能够实现给定靶标的最有效的路径。合成本身的挑战通常表明，反应的选择是具有先例和可靠性的。该提案试图扭转这种公认的反应发展顺序：天然产物被视为新反应的灵感，而不是任意环境。将选择具有生物学上重要的目标，并为有效且具有吸引力的合成转化提供动力。在一般环境中开发后，此方法将在其意图 /天然产品和类似物的全部合成中应用。提出了两个项目，这些项目证明了天然产物启动有用的，具有广泛适用性的一般反应的潜力：cepacin a是一种有效的抗生素，其中包含一个有趣的不饱和基序，是杂种胆小鬼的新型启发。具有抗HIV特性的Lancifodilactone g和Rubriflordilactone A是进行双轮或三环类分子的创新途径的基础。我的建议还详细介绍了针对HIV抑制新方法的协作项目。 HIV生命周期的当前未投入的区域是病毒RNA的“包装”到新的病毒颗粒中。包装是通过病毒蛋白GAG与称为psi的病毒RNA区域的结合来开始的。众所周知，PSI和一个截短的类似物是由含有含有亲核侧技术的氨基酸的GAG区域特别结合的。我们打算设计包含亲电位点的PSI类似物，该类似物将结合到GAG，并将该部位与亲核侧chain氨基酸接近，从而导致形成共价键，无可逆的GAG结合，并抑制包装。这是一个令人兴奋且未开发的化学生物学领域，它可以利用有机化学家和病毒学家的专业知识，并且可能对抑制剂的设计对其他特定病毒特异性RNA蛋白质相互作用有影响。

项目成果

Selectivity in Transition Metal-catalyzed Cyclizations: Insights from Experiment and Theory.

过渡金属催化环化的选择性：实验和理论的见解。

• DOI: 10.2533/chimia.2018.614
• 发表时间: 2018
• 期刊: Chimia
• 影响因子: 1.2
• 作者: Anderson EA

Carbopalladation of bromoene-alkynylsilanes: mechanistic insights and synthesis of fused-ring bicyclic silanes and phenols

• DOI: 10.1039/c4qo00123k
• 发表时间: 2014-01-01
• 期刊: ORGANIC CHEMISTRY FRONTIERS
• 影响因子: 5.4
• 作者: Cordonnier, Marie-Caroline A.;Kan, S. B. Jennifer;Anderson, Edward A.
• 通讯作者: Anderson, Edward A.