|
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.
|