Structure-activity relationship studies optimizing the antiproliferative activity of novel cyclic somatostatin analogues containing a restrained cyclic β-amino acid

Martin Sukopp, Richard Schwab, Luciana Marinelli, Eric Biron, Markus Heller, Edit Várkondi, Ákos Pap, Ettore Novellino, György Kéri, Horst Kessler

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

The cyclic somatostatin analogue cyclo[Pro1-Phe 2-D-Trp3-Lys4-Thr5-Phe6] (L-363,301) displays high biological activity in inhibiting the release of growth hormone, insulin, and glucagon. According to the sequence of L-363,301, we synthesized a number of cyclic hexa- and pentapeptides containing nonnatural α- and β-amino acids. The N-fluorenylmethoxycarbonyl protected cyclic β-amino acid [1S, 2S, 5R]-2-amino-3,5-dimethyl-2-cyclohex-3-enecarboxylic acid (cβAA), for the replacement of the Phe6-Pro1 moiety of L-363,301, was synthesized in two steps by an enantioselective multicomponent reaction using (-)-8-phenylmenthol as a chiral auxiliary. The resulting peptide cyclo[cβAA1-Tyr2-D-Trp 3-Nle4-Thr(Trt)5] (Trt = triphenylmethyl) shows high antiproliferative effects in an in vitro assay with A431 cancer cells. The same peptide without the Trt group does not reveal any biological activity, whereas L-363,301 and closely related hexapeptides show only minor activity. By comparison of the solution structure of cyclo[cβAA1-Tyr 2-D-Trp3-Nle4-Thr(Trt)5] with the structure of L-363,301, a nearly perfect match of the βII′-turn region with D-Trp in the i + 1 position was observed. The cyclic β-amino acid cβAA is likely needed for the bioactive conformation of the peptide.

Original languageEnglish
Pages (from-to)2916-2926
Number of pages11
JournalJournal of Medicinal Chemistry
Volume48
Issue number8
DOIs
Publication statusPublished - Apr 21 2005

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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