MEDICINES RESEARCH: CURRENT TRENDS AND CASE HISTORIES HIGHLIGHTS OF THE SOCIETY FOR MEDICINES RESEARCH SYMPOSIUM

This Society for Medicines Research symposium, sponsored by Peakdale Molecular and Pharmidex, was held on December 9, 2008, at the Queen Elizabeth II Conference Centre, Westminister, London, U.K. in association with and as part of Genesis 2008. The meeting, organized by Diane Coe, Richard Armer and Andrew Ratcliffe, focused on current trends and case histories in medicines research. Topics included exploiting the synthetic biology of natural products, the use of fragmentbased NMR in drug discovery, and drug discovery and development programs in the areas of oncology, neurology, antivirals and urology. Despite today’s climate of restructuring and merger and acquisition activity in the pharmaceutical industry, drug discovery research in the U.K. has remained high-class and cutting-edge, bringing new medicines to market. Dr. Ming-Qiang Zhang (Biotica Technology Ltd., Chesterford Research Park, Cambridge, U.K.) discussed synthetic biology as a novel emerging technology to further exploit the unique medicinal properties of macrocyclic natural products, in particular rapamycin (sirolimus) (1). As a general class, macrocyclics represent a rich vein of clinically used immunosuppressants, antiinfectives and anticancer drugs. Although generally non-rule-of-5-compliant, they have the ability to undergo flip-flop conformational changes to promote intestinal permeability (2). In addition, their high level of structural preorganization allows binding to large surface areas without incurring an entropic penalty and loss in potency. They also often represent the smallest biomolecules involved in complex noncovalent molecular assemblies, the architecture of which is driven by the nature of the biological pathway. However, the structural complexity of macrocycles, coupled with a shift towards rule-of-5 drug space, has resulted in limited exploitation by the synthetic medicinal chemistry community. As a testament, the shortest de novo route to rapamycin, recently published by Ley and colleagues (3), comprises 35 steps, with < 1% overall yield. As a consequence, semisynthetic methods represent the mainstay of generating analogues, but the range and diversity of functional group transformations is limited in scope. To address this deficiency, attention has turned to manipulation of biosynthetic routes. The biosynthesis of rapamycin is driven using a mixed type I polyketide synthase (PKS)/nonribosomal peptide synthetase (NRPS) system (4). On loading the system with the starter unit, 4,5-dihydroxycyclohex-1-enecarboxylic acid, PKS directs 14 successive polyketide chain extensions. Catalysis by NRPS then promotes an amidation reaction and insertion of L-pipecolic acid, before cleavage from the enzyme and macrocyclization to generate prerapamycin (1). Finally, through the action of post-PKS genes, which include methyltransferases and cytochrome P450 monooxygenases, prerapamycin is fully functionalized to rapamycin. Transformations include oxidation of C-9 to a C=O, insertion of an OMe at C-27, and O-methylation of C-16 and Drugs of the Future 2009, 34(3): 247-254 Copyright © 2009 Prous Science, S.A. U. or its licensors. All rights reserved. CCC: 0377-8282/2009