Inhibitory cyclic analogues and chlorambucil derivatives of bombesin-like peptides.
Analogues of the amphibian neuropeptide, bombesin, and of the mammalian homologue, gastrin-releasing peptide, have been synthesized and their biological activity studied in small cell lung carcinoma and rat pancreatic acinar cells. The compounds are truncated sequences of the active tetradecapeptide BN(1-14) or GRP(20-27). Peptides were cyclized between position 5 or 7 and the carboxyl end of the des-Met14 fragment with D and L Ala11 and Lys5 substitutions, as well as various N-terminal groups attached. The smallest cyclic peptide, BN(7-13), bound to SCLC membranes with microM potency and inhibited BN stimulation of intracellular Ca++ levels. The most potent inhibitor is N-chloroambucil-[His7,D-Ala11]BN(7-13)ethyl ester, which antagonized BN function in SCLC and acinar cells with nM potency and also inhibited clonal growth of carcinoma cell lines.
Knight
M
M
Peptide Technologies Corporation, Gaithersburg, MD 20877, USA.
Takahashi
K
K
Chandrasekhar
B
B
Geblaoui
A Z
AZ
Jensen
R T
RT
Strader
D
D
Moody
T W
TW
D000595:Amino Acid Sequence; D000681:Amylases / Q000378:metabolism; D000818:Animals; D001839:Bombesin / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000737:chemistry; D006801:Humans; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D010179:Pancreas / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D018004:Receptors, Bombesin / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D018004:Receptors, Bombesin; D000681:Amylases; D001839:Bombesin