Synthesis and in vitro evaluation of a rhenium-cyclized somatostatin derivative series.
The structure-activity relationships of a series of rhenium (Re)-cyclized octreotide derivatives are described. The effects of changes in the peptide sequence, N-terminus, and C-terminus on metal cyclization, as well as binding to the somatostatin receptor, were investigated. Each peptide complex was found to have an integrated Re(V) core with a single metal oxo group, two coordination sites filled by the cysteine sulfhydryls, and another by the amide nitrogen of Phe (3)/Tyr (3). The final coordination site was determined by the peptide N-terminus: the N-terminal amine coordinated for N-NH 2 peptides and the amide nitrogen of Thr (6) for peptides with acetylated N-termini. Re-cyclization of the octreotide derivatives led to structural perturbations of the somatostatin receptor-binding sequence relative to the Re-free disulfide analogues, resulting in reduced binding affinities. The findings presented herein demonstrate the importance of understanding the consequences of structural modifications when designing metal-peptide complexes for somatostatin receptor targeting.
Bigott-Hennkens
Heather M
HM
Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, Missouri 65211, USA.
Junnotula
Sulochana
S
Ma
Lixin
L
Gallazzi
Fabio
F
Lewis
Michael R
MR
Jurisson
Silvia S
SS
D000818:Animals; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry; D003500:Cyclization; D004220:Disulfides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D015282:Octreotide / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017481:Receptors, Somatostatin / Q000378:metabolism; D012211:Rhenium; D013329:Structure-Activity Relationship
D002614:Chelating Agents; D004220:Disulfides; D017481:Receptors, Somatostatin; D012211:Rhenium; C093733:somatostatin receptor 2; D015282:Octreotide