Techniques for high yield synthesis of macrocyclic compounds

Summary Many useful pharmaceuticals, including natural products, have a macrocyclic structure that can be a challenge when exploring synthesis methods. The Walsh Laboratory has discovered a new process using of a solid-phase resin to synthesize macrocycle compounds, including polyketide synthase (PKS), non-ribosomal peptide synthetase (NRPS) and fatty acid synthase (FAS). The peptidic precursor molecules are connected to the solid-phase resin using a specific linker, and macrocyclization is achieved using a Type I thioesterase domain (TE) excised from a NRPS or PKS. The thioesterase catalyzes cyclization on the deprotected, resin-bound peptidic molecule, while concomitantly cleaving the linear peptide from the resin. The process results in a high yield, high specificity macrocyclic compound.

Applications Non-exhaustively, macrocycles prepared using this method have useful pharmaceutical applications as anti-tumor agents (epithilone, rapamycin), anti-bacterials (vancomycin, erythromycin), statins (lovastatin), immunosuppressants (cyclosporin A), and anti-fungals (soraphen, fengycin) Because many bioactive molecules are macrocycles, the generation of a diverse library of compounds followed by biological screening would be an attractive drug discovery strategy. For Further Information Please Contact the Director of Business Development Michal Preminger Email: michal_preminger@hms.harvard.edu Telephone: (617) 432-0920

Inventor(s): Walsh, Christopher T

Type of Offer: Licensing



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