Synthetic approaches to medicinally relevant Euphorbia diterpenes

This project falls within the EPSRC Synthetic Organic Chemistry research area.
The prevalence of natural products (and analogues and derivatives thereof) as therapeutic agents has been extensively documented by Newman et al. in a comprehensive series of reviews over the last two decades. Their analyses reveal that these molecules remain dominant players on the clinical stage, despite the rise of combinatorial medicinal chemistry. In both the anti-infective and anti-cancer categories, natural products and their descendants constitute over 50% of our small molecule therapeutic arsenal. However, due to high degrees of molecular complexity, syntheses can be considered to be too lengthy and inefficient to be considered as an effective branch of medicinal chemistry. Modern natural product synthesis is moving towards a paradigm wherein a strategy to reach an intermediate or series of closely related intermediates is achieved, and then diversification to various natural products and analogues thereof follows.
The members of the Euphorbia genus of plants produce an array of complex terpenoid natural products, which feature a vast diversity of structural motifs and biological activities. The complexity and therapeutic potential of these molecules, and non-natural analogues thereof, make them alluring synthetic targets. Euphorbia diterpenes within the jatrophane class are differentiated from one another by various oxidation, unsaturation, and esterification states at key positions. Such modular structural diversity renders this class of natural product well-suited to a divergent synthetic approach, wherein a robust strategy for reaching complex intermediates is developed which allows for subsequent selective derivatisation to various natural products and non-natural analogues.
Pepluanin A and euphodendroidin D, isolated from E. peplus and E. dendroides respectively, are members of the jatrophane class and show potent inhibition of the P-glycoprotein (P-gp) efflux of daunomycin in cancer cells; each is approximately twice as effective as the current clinical gold-standard, cyclosporin. This potent activity, along with the broad P-gp efflux pump inhibition found throughout the jatrophane class, suggests that these natural products and their derivatives might be powerful tools with which to combat multidrug resistance. The derivatisation effort would be guided by the structure-activity relationship studies of the jatrophane diterpenes undertaken by Corea et al. in 2003.
As such, we have previously developed functional routes to late-stage intermediates in our proposed syntheses of pepluanin A and euphodendroidin D. The aim of this project is to consolidate prior work by refining and completing these proposed syntheses, and then to strike out for other targets within the Euphorbia diterpene class.