Concise Syntheses of the Meroterpenoids: Facilitating the Discovery of New Classes of Pharmaceuticals

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Cancer and infectious disease are the cause of very considerable morbidity and mortality in the UK and globally. Resistance with both diseases is of particular concern since, when a patient does not respond to available therapies, the prognosis is often grim. For example, the most common cancer in the UK and USA is breast cancer. The National Cancer Institute has published statistics for cancer in the USA numbers of new cases on breast cancer there in 2015 has been estimated to be 234,190 with 40,700 deaths [http://www.cancer.org/acs/groups/content/@editorial/documents/document/acspc-044552.pdf]. Cancer Research UK also publishes statistics for the UK with 331,487 new diagnoses of cancer in 2011 with cancers of the breast, prostate, lung and bowel accounting for over half that number. In the same article, the authors reported 50,285 new cases of breast cancer and 11,716 deaths from breast cancer in 2011 [http://www.cancerresearchuk.org/health-professional/cancer-statistics#heading-Zero]. Patients with many cancers including breast cancer develop resistance to the medicines used during treatment. For example, Tamoxifen resistance occurs in about 25% of patients undergoing treatment. Tamoxifen is an antagonist of the estrogen receptor in breast tissue and is a drug of considerable importance in breast cancer therapy. In the area of infectious disease, bacterial resistance to common antibiotics is widely reported in the general press with harrowing accounts of Vancomycin Resistant Enterococci or Methicillin-resistant Staphylococcus aureus infections with clinical manifestations such as Necrotizing fasciitis (flesh eating disease). The emergence of resistance amongst cohorts of patients is a major driver for the discovery and development of new medicines to treat cancer and bacterial infections amongst other diseases.In 2014, scientists in the Vertex company [http://pubs.acs.org/doi/abs/10.1021/jm500941m] reported that natural products are again very appropriate to study and derivatise by chemical transformations in order to prepare new bioactive compounds for assay and optimization as the anti-cancer agents and antibiotics of tomorrow. In this article, they reported that from January 1981 to December 2010, 540 out of 1073 of the new drugs introduced were either natural products, derivatives of natural products or were structurally related to natural products (bioinspired) but made by chemical synthesis. By way of examples, the authors described the importance of natural product leads for Docetaxel, which is a derivative of paclitaxel used to treat diverse cancers, and Ixabepilone, which is an analogue of epothilone B used to treat taxol-resistant cancers, amongst many other examples. The focus of this research proposal is the design and development of four new chemical transformations, which have been invented at Imperial College, for the synthesis of a class of natural products, the meroterpenoids. The meroterpenoids are a structurally diverse series noted for diverse bioactivities as antibiotics and as anti-cancer agents, etc. In general, these compounds are active but insufficiently active to be drugs in their own right. In pharmaceutical terminology they are hits not leads. In order for the synthesis of a complex natural product such as a meroterpenoids to be practical, it is necessary that the synthetic route is short and amenable to parallel synthesis directed by bioassay results and computer assisted drug design to produce pharmaceutical leads. The Imperial team now has the necessary synthetic tools to make structure activity studies and bring new drug discovery based on the meroterpenoids within reach. In the research, the new Imperial chemical reactions will be employed with other transformations including selective oxidation and cyclisation reactions (forming additional rings) to open up the area of the meroterpenoids to rational medicinal chemistry and drug discovery.