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Biomimetic Late Stage Aromatisation Reactions: from Cancer Chemotherapy to Novel Polymers

Final Report Summary - KETENCYCLS (Biomimetic Late Stage Aromatisation Reactions: from Cancer Chemotherapy to Novel Polymers)

Medicinal chemistry is a discipline of paramount importance to biomedical research and pharmaceutical innovation. It impacts directly on all stages of the discovery and development process for new medicines. It is self evident that the discovery of new hits and their optimisation to produce lead structures depends on drug design, iterative chemical synthesis and biological evaluation. What may be less apparent in 2016 is the vital importance of natural product (NP) chemistry including their isolation, derivatisation and synthesis for the discovery of the commercially successful drugs of the future. Natural products have proved highly significant in pharmaceutical discovery in treating infectious diseases and cancer and in many other areas. For example, would the important medicines the cephalosporin antibiotics, the anti-cancer Taxotere, the immunosuppressant mycophenolic acid, or morphine been introduced into medicine without the guidance provide by the natural product lead structures? The answer is absolutely not. Very recent publications show that natural products still play a major role in marketed medicines and in fact natural products are now regaining their former importance in drug discovery and development. For example in 2014, Vertex scientists wrote “Despite the prevalence of combinatorially derived compound libraries in the pharmaceutical industry, half of all new chemical entities introduced as drugs (540 out of 1073) were NPs, modified NPs, or synthetic compounds with a NP pharmacophore over a 30 year period from January 1981 to December 2010” ( It is clear that the derivatisation of natural products or the total synthesis of novel patentable analogues depends critically on the availability of concise, flexible and reliable synthetic routes to explore structure activity relationships (SARs) and to identify optimum lead compounds for development, clinical trials and ultimate marketing as the medicines of tomorrow.
Resorcylates and the more complicated meroterpenoids, which are compounds structurally related to aspirin, occur widely in numerous bioactive natural products. These show activities against bacteria, fungal pathogens, cancer cells, viruses, etc. and are highly relevant to future drug discovery and development. The Barrett group at Imperial College has designed new synthetic methodology that greatly simplifies the total synthesis of structurally different classes of resorcylates and meroterpenoids starting from very simple carboxylic acid building blocks. By short sequences of linking reactions that involve highly reactive but controlled intermediates named ketenes, the group has succeeded in the total synthesis of structurally different members of these classes of natural products including antibiotics, the insulin adjuvant amorfrutin A, the immunosuppressant mycophenolic acid and many other compounds noted for antiviral, fungicidal, immunomodulatory, mycotoxic, anticancer, anti-psoriasis, anticonvulsive, insecticidal and insect antifeeding activities as well as being modulators of proteases, endothelin receptors, FPTase, myoinositol monophosphatase, and plasminogen activation and fibrinolysis. The enabling Barrett group methodology is now available for the discovery of some of the medicines of the future.