Novel sst5-selective somatostatin dicarba-analogues: synthesis and conformation-affinity relationships

D'Addona, Debora; Carotenuto, Alfonso; Novellino, Ettore; Piccand, Véronique; Reubi, Jean Claude; Di Cianni, Alessandra; Gori, Francesca; Papini, Anna Maria; Ginanneschi, Mauro (2008). Novel sst5-selective somatostatin dicarba-analogues: synthesis and conformation-affinity relationships. Journal of medicinal chemistry, 51(3), pp. 512-20. Easton, Pa.: American Chemical Society 10.1021/jm070886i

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We describe synthesis, conformational studies, and binding to the five somatostatin receptors (sst 1-5) of a few analogues of the cyclic octapeptide octreotide (1), where the disulfide bridge was replaced by a dicarba group. These analogues were prepared by on-resin RCM of linear hepta-peptides containing two allylglycine residues; first- and second-generation Grubbs catalyst efficiencies were compared. The C=C bridge was hydrogenated via two different methods. Binding experiments showed that two analogues had good affinity and high selectivity for the sst5 receptor. Three-dimensional structures of the active analogues were determined by (1)H NMR spectroscopy. Conformation-affinity relationships confirmed the importance of D-Phe(2) orientation for sst2 affinity. Moreover, helical propensities well correlates with the peptide sst5 affinity. The presence of the bulky aromatic side chain of Tyr(Bzl)(10) favored the formation of a 3(10)-helix and enhanced the sst5 selectivity suppressing the sst2 affinity. Finally, a new pharmacophore model for the sst5 was developed.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute of Pathology
04 Faculty of Medicine > Service Sector > Institute of Pathology > Tumour Pathology

UniBE Contributor:

Piccand, Véronique and Reubi-Kattenbusch, Jean-Claude

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

0022-2623

ISBN:

18210999

Publisher:

American Chemical Society

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 15:02

Last Modified:

15 Oct 2019 12:44

Publisher DOI:

10.1021/jm070886i

PubMed ID:

18210999

Web of Science ID:

000252968700020

URI:

https://boris.unibe.ch/id/eprint/27069 (FactScience: 101635)

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