Design, synthesis, and binding affinities of pyrrolinone-based somatostatin mimetics.
[structure: see text] Tetrapyrrolinone somatostatin (SRIF) mimetics (cf. 1), based on a heterochiral (D,L-mixed) pyrrolinone scaffold, were designed, synthesized, and evaluated for biological activity. The iterative synthetic sequence, incorporating the requisite functionalized coded and noncoded amino acid side chains, comprised a longest linear synthetic sequence of 23 steps. Binding affinities at two somatostatin receptor subtypes (hsst 4 and 5) reveal micromolar activity, demonstrating that the d,l-mixed pyrrolinone scaffold can be employed to generate functional mimetics of peptide beta-turns.
Smith
Amos B
AB
Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA.
Charnley
Adam K
AK
Mesaros
Eugen F
EF
Kikuchi
Osamu
O
Wang
Wenyong
W
Benowitz
Andrew
A
Chu
Chi-Lien
CL
Feng
Jin-Jye
JJ
Chen
Kuo-Hsin
KH
Lin
Atsui
A
Cheng
Fong-Chi
FC
Taylor
Laurie
L
Hirschmann
Ralph
R
D000596:Amino Acids / Q000737:chemistry; D015195:Drug Design; D006727:Hormone Antagonists / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007202:Indicators and Reagents; D008024:Ligands; D008958:Models, Molecular; D018716:Molecular Mimicry; D011487:Protein Conformation; D011758:Pyrroles / Q000138:chemical synthesis* / Q000378:metabolism* / Q000494:pharmacology; D017481:Receptors, Somatostatin / Q000378:metabolism; D013004:Somatostatin / Q000737:chemistry* / Q000378:metabolism*
D000596:Amino Acids; D006727:Hormone Antagonists; D007202:Indicators and Reagents; D008024:Ligands; D011758:Pyrroles; D017481:Receptors, Somatostatin; D013004:Somatostatin