Potent bombesin antagonists with C-terminal Leu-ψ(CH2-N)-Tac-NH2 or its derivatives

R. Z. Cai, H. Reile, P. Armatis, A. V. Schally

Research output: Contribution to journalArticlepeer-review

47 Scopus citations


Various pseudononapeptide bombesin (BN)-(6-14) antagonists with a reduced peptide bond (CH2-NH) between positions 13 and 14 can suppress the mitogenic activity of BN or gastrin-releasing peptide in 3T3 fibroblast cells and small cell lung carcinoma. In the search for more potent BN antagonists, 10 modified nonapeptide BN antagonists containing N-terminal D-Phe, D-Cpa, and D- or L-Tpi and C-terminal Leu-ψ(CH2-N)-Tac-NH2, Leu-ψ(CH2-N)-MeTac- NH2, or Leu-ψ(CH2-N)-Me2Tac-NH2 have been synthesized by incubating [13ψ14,CH2-NH,Cys14]BN-(6-14) or [13ψ14-CH2-NH,Pen14]BN-(6- 14) with formaldehyde or acetaldehyde (Cpa = 4-chlorophenylalanine, Tac = thiazolidine-4-carboxylic acid, Tpi = 2,3,4,9-tetrahydro-1H-pyrido[3,4- b]indol-3-carboxylic acid, and Pen = penicillamine). The biological activities of these compounds were then evaluated. [D-Phe6,13ψ14,CH2- N,Tac14]BN-(6-14) (RC-3950-II) and [D-Phe6,13ψ14,CH2- N,Me2Tac14]BN-(6-14) (RC-3985-II) exhibited greater potency in inhibition of 125I-labeled [Tyr4]BN binding to Swiss 3T3 cells than their parent compounds [D-Phe6,13ψ14,CH2-NH,Cys14]BN-(6-14) (RC-3950-I) and [D- Phe6,13ψ14,CH2-NH,Pen14]BN-(6-14) (RC-3985-I). The order of binding affinities of these compounds was as follows: [13ψ14,CH2-N,Tac14]BN- (6-14) > [13ψ14,CH2-N,Me2Tac14]BN-(6-14) > [13ψ14,CH2- N,MeTac14]BN-(6-14). In most cases, the analogs with C-terminal Leu- ψ(CH2-N)-Tac-NH2 were also more potent growth inhibitors of 3T3 cells than compounds containing C-terminal Leu-ψ(CH2-N)-Me2Tac-NH2 or Leu-ψ(CH2- N)-MeTac-NH2. The best BN antagonists of this series, RC-3950-II and [D- Cpa6,13ψ14,CH2-N,Tac14]BN-(6-14) (RC-3925-II), inhibited gastrin- releasing peptide-stimulated growth of Swiss 3T3 cells with IC50 values of 1 nM and 6 nM, respectively. Since antagonists of this class inhibit growth of various tumors in animal cancer models, some of them may have clinical applications.

Original languageEnglish (US)
Pages (from-to)12664-12668
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number26
StatePublished - Dec 20 1994
Externally publishedYes


  • peptide receptors
  • peptide synthesis
  • pseudononapeptide analogs
  • tumor growth inhibition

ASJC Scopus subject areas

  • Genetics
  • General


Dive into the research topics of 'Potent bombesin antagonists with C-terminal Leu-ψ(CH2-N)-Tac-NH2 or its derivatives'. Together they form a unique fingerprint.

Cite this