A Photochemical Approach to Dimeric Diazoparaquinones Inspired Through Biosynthetic Speculation

受生物合成启发的二聚重氮对醌的光化学方法

• 批准号: EP/I028951/1
• 负责人: John Moses
• 金额: $ 43.51万
• 依托单位: University of Nottingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FI028951%2F1
• 关键词: Photochemical; Approach; Dimeric; Diazoparaquinones; Inspired

For decades, natural products have been a wellspring of drugs and drug leads. According to a recent survey by the National Cancer Institute, 61% of the 877 small-molecule new chemical entities introduced as drugs worldwide during 1981/2002 can be traced to or were inspired by natural products [J. Nat. Prod., 66, 1022 (2003)]. These include natural products (6%), natural product derivatives (27%), synthetic compounds with natural-product-derived pharmacophores (5%), and synthetic compounds designed on the basis of knowledge gained from a natural product (that is, a natural product mimic; 23%).In certain therapeutic areas, the productivity is higher: 78% of antibacterials and 74% of anticancer compounds are natural products or have been derived from, or inspired by, a natural product. These numbers are not surprising if it is assumed that natural products evolved for self-defence. But the influence of natural products is significant even in therapeutic areas for which they might not seem relevant, such as cholesterol management, diabetes, arthritis, and depression.Unfortunately, there are disadvantages when using natural product extracts for drug discovery. Firstly, nature does not make these molecules in pure form; therefore, complex mixtures are often screened for activity, leaving the problem of purifying and identifying the active constituent(s). Secondly, the extract may come from a limited source, leaving a supply problem. Thirdly, the structural complexity of the active natural product(s) may be so synthetically challenging that compounds are essentially rendered inaccessible and commercially invalid. In this project, we propose to develop novel methodology towards the synthesis of two complex, and extremely potent anticancer-antibiotic natural products, the lomaiviticins (A& B). In contrast to conventional natural product syntheses, we propose to employ a biomimetic approach towards these compounds, which we hope will aid the synthesis by embracing Nature's own biosynthetic strategy.Biomimetic- from the Greek word bios , meaning life, and mimetic-the adjective for mimesis -- imitation or mimicry, is the application of methods and systems found in nature to the study and design of synthetic systems. This technology transfer is desirable because evolutionary pressure typically forces natural systems to become highly optimised and efficient. When applied to natural product syntheses, biomimetic approaches can often facilitate rapid access to complex structures that may otherwise require inconceivable conventional synthetic pathways. In general, biomimetic approaches mimic a key step in the proposed (or known) biosynthetic pathway, and are mostly applicable to those systems that are not under strict enzymatic control. Instead the structure itself is pre-disposed to the biomimetic chemical change. Nevertheless, biomimetic synthesis, by their nature, are often elegant and efficient processes, providing novel pathways very complex structures. We propose the lomaiviticins are produced in Nature, through a dimerisation process of two monomeric units. Once an efficient synthesis of these monomers is achieved using conventional chemistry, we will develop a biomimetic dimerisation photochemical reaction that will facilitate the desired coupling of the monomers, through a pre-disposed chemical pathway. Thus, by mimicking Nature's own strategy towards the lomaiviticins, we will gain access to these valuable natural products in relatively few steps.

几十年来，天然产品一直是药物和药物先导的源泉。根据国家癌症研究所最近的调查，在1981/2002年期间全世界作为药物引入的877种小分子新化学实体中的61%可以追溯到天然产物或受天然产物的启发[J. Nat. Prod.，66，1022（2003）]。其中包括天然产物（6%）、天然产物衍生物（27%）、具有天然产物衍生药效团的合成化合物（5%）以及基于从天然产物获得的知识设计的合成化合物（即天然产物模拟物; 23%）。在某些治疗领域，生产率更高：78%的抗菌药物和74%的抗癌化合物是天然产物，或来源于天然产物或受其启发。如果假设天然产物是为了自卫而进化的，那么这些数字就不足为奇了。但是，即使在胆固醇管理、糖尿病、关节炎和抑郁症等看似不相关的治疗领域，天然产物的影响也是显著的。不幸的是，使用天然产物提取物进行药物发现时存在缺点。首先，自然界不会使这些分子处于纯形式;因此，复杂的混合物通常被筛选活性，留下纯化和鉴定活性成分的问题。第二，提取物可能来自有限的来源，留下供应问题。第三，活性天然产物的结构复杂性在合成上可能是如此具有挑战性，以至于化合物基本上无法获得并且在商业上无效。在这个项目中，我们建议开发新的方法来合成两个复杂的，非常有效的抗癌抗生素天然产物，洛麦维他星（A和B）。与传统的天然产物合成相比，我们建议采用仿生方法来合成这些化合物，我们希望通过拥抱自然界自己的生物合成策略来帮助合成。仿生-来自希腊词bios，意思是生命，和mimetic-模仿的形容词-模仿或模仿，是应用自然界中发现的方法和系统来研究和设计合成系统。这种技术转让是可取的，因为进化的压力通常迫使自然系统变得高度优化和高效。当应用于天然产物合成时，仿生方法通常可以促进快速获得复杂结构，否则可能需要不可思议的常规合成途径。一般来说，仿生方法模拟了所提出的（或已知的）生物合成途径中的关键步骤，并且大多适用于那些不受严格酶控制的系统。相反，结构本身倾向于仿生化学变化。然而，仿生合成，就其性质而言，往往是优雅和有效的过程，提供了新的途径非常复杂的结构。我们提出洛麦替星是在自然界中通过两个单体单元的二聚化过程产生的。一旦使用常规化学实现了这些单体的有效合成，我们将开发一种仿生二聚化光化学反应，该反应将通过预先设置的化学途径促进单体的所需偶联。因此，通过模仿大自然对洛麦维汀的策略，我们将以相对较少的步骤获得这些有价值的天然产品。

项目成果

tter Catalytic Reduction of ortho- and para-Azidonitrobenzenes via tert-Butoxide Ion Mediated Electron Transfer

通过叔丁醇离子介导的电子转移催化还原邻和对叠氮硝基苯

• 期刊: SYNLETT
• 影响因子: 2
• 作者: John Moses (Author)