Functional Optimization of Natural Products

Synthetic chemistry allows us to produce modified natural products for specific applications such as chemical probes or surface linkers. The synthesis of natural product analogues for SAR studies can give important information about their mechanism of action and role in a biological system. This information ca be used to design compounds that retain the activity of the parent compound in a simplified and thus synthetically more accessible structure. 

Promoters of neurite growth offer a potential treatment method for neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. We have synthesised several natural products (Withanolide A, Cyrneine A, Militarinone D, Farinosone C) that show neurite outgrowth promoting activity and evaluated their biological activity. As part of this programme we discovered that Militarinone D could be modified to exclude the unsaturated side chain whilst still retaining (and in some cases improving) the neuritogenic activity. Synthesis of this much-simplified structure required 12 fewer steps than Militarinone D and we were able to rapidly produce a library of pyridone analogues for biological evaluation.

We have investigated structural simplification and functional optimisation on several other classes of compound, most successfully on the Anginomycins where the compound SB640 retained most of the anticancer activity of the parent natural product despite the removal of more than half of the structure!

In order to study natural products in the environment we developed a method for the direct modification of arginine residues in native peptides. Using this method we were able to prepare a series of fluorescent derivatives of the cyanobacterial toxin microcystin. These probes were used to investigate the uptake and distribution of the toxin in marine crustaceans.