Syntheses and activities of new C10 beta-turn peptidomimetics.
A program to identify small molecules that mimic or disrupt protein-protein interactions led us to design the peptidomimetics 1-3. Solid-phase syntheses of 1-3 were developed. The purities of the crude materials isolated from the resin tend to be highest for the S- and N-compounds 2 and 3 and better than in the corresponding syntheses of peptidomimetics A. The particular dipeptide units incorporated were chosen to correspond with the turn regions of the neurotrophins (e.g., nerve growth factor [NGF] and the neurotrophin factor-3 [NT-3]). Preliminary studies were performed to access the binding of these analogues to Trk receptors and their ability to induce cell survival (just as NGF and NT-3 do). Several active compounds were identified. However, poor water solubilities of some of the other compounds preclude reliable testing. Consequently, solid-phase modifications to the synthetic procedures were investigated to provide access to the derivatives 12-14 in which the aromatic nitro group is replaced by amine, guanidine, or sulfonamide functionalities. The latter are more acceptable pharmacophores than nitro groups and also tend to increase the water solubilities of the peptidomimetics.
Lee
Hong Boon
HB
Chemistry Department, Texas A & M University, P.O. Box 30012, College Station, Texas 77843-3012, USA.
Zaccaro
Maria Clara
MC
Pattarawarapan
Mookda
M
Roy
Sudipta
S
Saragovi
H Uri
HU
Burgess
Kevin
K
D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D001667:Binding, Competitive; D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D051379:Mice; D008958:Models, Molecular; D041681:NIH 3T3 Cells; D020932:Nerve Growth Factor / Q000031:analogs & derivatives / Q000378:metabolism; D020933:Neurotrophin 3 / Q000031:analogs & derivatives / Q000378:metabolism; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D020917:Receptor, trkA / Q000378:metabolism; D020812:Receptor, trkC / Q000378:metabolism
D000596:Amino Acids; D020933:Neurotrophin 3; D010456:Peptides, Cyclic; D020932:Nerve Growth Factor; D020917:Receptor, trkA; D020812:Receptor, trkC