A Photochemical Approach to Dimeric Diazoparaquinones Inspired Through Biosynthetic Speculation

几十年来，天然产物一直是药物和药物先导的源泉。根据美国国家癌症研究所最近的一项调查，1981年至2002年期间，全球引进的877种小分子新化学实体中，有61%可以追溯到天然产物或受到天然产物的启发。Nat Prod. 66, 1022(2003)]。这些包括天然产物（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%）和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%的抗菌药和74%的抗癌化合物是天然产物，或者是从天然产物中提取或受天然产物的启发。如果假设天然产物是为了自卫而进化的，那么这些数字并不令人惊讶。但天然产品的影响是显著的，甚至在治疗领域，他们可能看起来不相关，如胆固醇管理，糖尿病，关节炎和抑郁症。不幸的是，当使用天然产品提取物进行药物发现时，存在缺点。首先，自然界并没有以纯粹的形式制造这些分子；因此，复杂的混合物经常筛选活性，留下了纯化和鉴定活性成分的问题。其次，这种提取物可能来自有限的来源，造成供应问题。第三，活性天然产物的结构复杂性可能在合成上具有挑战性，使得化合物基本上无法获得并且在商业上无效。在这个项目中，我们提出了一种新的方法来合成两种复杂的，非常有效的抗癌抗生素天然产物，洛马维菌素（a和B）。与传统的天然产物合成相比，我们建议对这些化合物采用仿生方法，我们希望通过拥抱大自然自己的生物合成策略来帮助合成。仿生学（Biomimetic）来自希腊语单词bios，意思是生命，而mimic是mimesis的形容词，意思是模仿或模仿，是将自然界中发现的方法和系统应用于研究和设计合成系统。这种技术转移是可取的，因为进化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，否则可能需要难以想象的传统合成途径。一般来说，仿生方法模拟提出的（或已知的）生物合成途径的关键步骤，并且大多适用于那些不受严格酶控制的系统。相反，结构本身是预先处理仿生化学变化的。然而，仿生合成，就其本质而言，往往是优雅而高效的过程，提供了新颖的途径和非常复杂的结构。我们提出，在自然界中，通过两个单体单位的二聚化过程产生了lomaivitticins。一旦使用传统化学方法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，通过预先处理的化学途径促进单体的期望偶联。因此，通过模仿大自然自己对lomaivitticins的策略，我们将在相对较少的步骤中获得这些宝贵的天然产品。

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.