Development of General Methodologies for the Synthesis of Solution Phase Libraries of HUN 7293 Analogues

Erwin Schrödinger Fellowship J 1911 Solution Phase Combinatorial Libraries of HUN-7293 Analogs Melitta BILBIAN 08.05.2000 Development of General Methodologies for the Synthesis of Solution Phase Libraries of HUN 7293 Analogs: The cyclic heptadepsipeptide HUN-7293 is a natural product isolated as a fungal metabolite. It represents a unique lead compound for a novel class of anti-inflammatory agents due to its potent inhibition of the expression of cell adhesion molecules VCAM-1, ICAM-1 and E-Selectin. This should prove especially effective in the therapy of the chronic disorders psoriasis, atopic dermatitis, allergic and irritant dermatitis or multiple sclerosis, which are characterised by cell adhesion molecule overexpression. In this project, the parallel solution phase synthesis of an initial library of HUN-7293 analogs containing single point substituent changes at each site of the structure is planned. This is essential in defining the role of each subunit and substituent to optimise the biological activity and to eliminate the recently discovered side effects of HUN-7293. Furthermore, an efficient model for the structure activity relationship will be based on these results. Notably, these analogs are not available through modification of the natural product itself. The route for the convergent, parallel assembly will include the key steps of the recently completed first total synthesis of HUN- 7293. Using simple liquid/liquid or liquid/solid extraction techniques, a general method for the parallel convergent synthesis of a library in solution will be developed. Each amide bond coupling intermediate and final product of the family of the HUN-7293 analogs may be isolated yielding an initial library of >50 compounds (typically >90 % purity, 25 mg scale). This library will be subjected to an initial round of biological screening, which will provide insights into the structural requirements for active compounds and perform the basis for subsequent libraries.