Novel method for the synthesis of urea backbone cyclic peptides using new Alloc-protected glycine building units.
Cyclization of bioactive peptides, utilizing functional groups serving as natural pharmacophors, is often accompanied with loss of activity. The backbone cyclization approach was developed to overcome this limitation and enhance pharmacological properties. Backbone cyclic peptides are prepared by the incorporation of special building units, capable of forming amide, disulfide and coordinative bonds. Urea bridge is often used for the preparation of cyclic peptides by connecting two amine functionalized side chains. Here we present urea backbone cyclization as an additional method for the preparation of backbone cyclic peptide libraries. A straightforward method for the synthesis of crystalline Fmoc-N(alpha) [omega-amino(Alloc)-alkyl] glycine building units is presented. A set of urea backbone cyclic Glycogen Synthase Kinase 3 analogs was prepared and assessed for protein kinase B inhibition as anticancer leads.
Hurevich
Mattan
M
Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem, Israel.
Tal-Gan
Yftah
Y
Klein
Shoshana
S
Barda
Yaniv
Y
Levitzki
Alexander
A
Gilon
Chaim
C
D002851:Chromatography, High Pressure Liquid; D003500:Cyclization; D005998:Glycine / Q000737:chemistry*; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry; D021241:Spectrometry, Mass, Electrospray Ionization; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014508:Urea / Q000737:chemistry*
D010456:Peptides, Cyclic; D014508:Urea; D005998:Glycine