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.

Advantages This technology has the advantage of preparing macrocyclic molecules in high yield without requiring functional group protection or carrying out reactions in organic solvents. Furthermore, the linker-bound resin enables peptide synthesis using standard FMOC protected techniques (compatible with robotic automation), simple product purification, and the ability to recycle the solid-phase resin. These advantages culminate in the parallel or combinatorial synthesis of large libraries of macrocyclic compounds.

Market The broad therapeutic applications for macrocyclic compounds suggest growing, as well as very large, market opportunities. Collectively, it is estimated that over 25% of FDA-approved compounds between 1981 and 2002 were either natural products, including polyketides and non-ribosomal peptides, or were compounds derived from natural products. Lead compounds may be targeted at anti-cancer therapies, anti-bacterials, statins, immunosuppressants, and anti-fungals.

Patent Status A series of US and PCT applications have been filed by Harvard University covering methods for the high-yield synthesis of macrocyclic compounds. For Further Information Please Contact the Director of Business Development Michal Preminger Email: [email protected] Telephone: (617) 432-0920

Inventor(s): Walsh, Christopher T.

Type of Offer: Licensing



Next Patent »
« More Pharmaceutical Patents

Share on      


CrowdSell Your Patent