Synthesis of peptide and pseudopeptide amides inhibiting the proliferation of small cell and epithelial types of lung carcinoma cells

• Published in: Journal of peptide science Vol. 4; no. 8; pp. 486 - 495
• Main Authors: Nyéki, Olga, Rill, Attila, Schőn, István, Orosz, Antal, Schrett, János, Bartha, László, Nagy, József
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.12.1998
• Subjects: 1-amino-1-cyclopentane-carbonyl; 2-amino-3-methylpentane; 3T3 Cells; 4-dinitrophenyl; 4-hydroxyphenyl-acetyl; Amides; Amino Acid Sequence; Animals; BN, bombesin; bombesin; Bombesin - analogs & derivatives; Bombesin - antagonists & inhibitors; Bombesin - chemistry; Bombesin - pharmacology; Carcinoma, Small Cell - pathology; Cell Division - drug effects; cycloLeu; cycloLeu, 1‐amino‐1‐cyclopentane‐carbonyl; d-MePhe; d-N-methyl-phenylalanyl; DCC; DCC, dicyclohexylcarbodiimide; DCU; DCU, dicyclohexylurea; dicyclohexylcarbodiimide; dicyclohexylurea; Dnp; Dnp, 2,4‐dinitrophenyl; d‐MePhe, d‐N‐methyl‐phenylalanyl; gastrin releasing peptide; GRP; GRP, gastrin releasing peptide; HOPfp; HOPfp, pentafluorophenol; Humans; Hydrolysis; inhibition of proliferation; LAH; LAH, lithium aluminium hydride; lithium aluminium hydride; Lung Neoplasms - pathology; mercaptoethanesulfonic acid; MES; MES, mercaptoethanesulfonic acid; Mice; Molecular Sequence Data; MPA; MPA, 2‐amino‐3‐methylpentane; pentafluorophenol; Peptides - chemical synthesis; pHOPA; pHOPA, 4‐hydroxyphenyl‐acetyl; SCLC; SCLC, small cell lung cancer; small cell lung cancer; SP, substance P; substance P; Substance P - analogs & derivatives; Substance P - chemistry; Substance P - pharmacology; substance P analogues; synthesis of pseudopeptide amides; Tumor Cells, Cultured
• ISSN: 1075-2617; 1099-1387
• DOI: 10.1002/(SICI)1099-1387(199812)4:8<486::AID-PSC168>3.0.CO;2-N

Small cell lung cancer (SCLC) cell lines produce and secrete various peptide hormones, e.g. bombesin (BN)/gastrin releasing peptide (GRP) like peptides that are proposed to function as their autocrine growth factors. To inhibit the proliferative effect of these hormones we have synthesized short chain BN[7‐14]‐analogues replacing the C‐terminal peptide bond by a methylene‐amino (‐CH2NH‐) unit and introducing d‐Phe or d‐Ser into position 12. As several substance P (SP) analogues were found to inhibit the growth of SCLC cells, some short chain SP‐analogues have been synthesized. (Pseudo)octapeptides were synthesized in solution, by fragment condensation using the DCC/HOPfp method. Fragments and SP‐analogues were synthesized stepwise using pentafluorophenyl esters. The resistance to hydrolysis of the reduced peptide bond made permitted exact quantification of the Leuψ(CH2NH)Leu pseudopeptide in hydrolysates. The binding ability of both types of peptides to BN‐receptors on Swiss 3T3 mouse fibroblast cells and their antiproliferative effect on NCI‐H69 human SCLC cell line have been tested and compared with a short chain SP‐antagonist pHOPA‐d‐Trp‐Phe‐d‐Trp‐Leu‐Leu‐NH2 (R) previously described as a potent inhibitor of SCLC proliferation. While BN‐analogues showed weak activity in inhibition of proliferation of SCLC cells, SP‐analogues 6: d‐MePhe‐d‐Trp‐Phe‐d‐Trp‐Leuψ(CH2NH)‐Leu‐NH2 and 7: d‐MePhe‐d‐Trp‐Phe‐d‐Trp‐Leu‐MPA, in spite of greatly diminished affinity towards the BN‐receptor, inhibited SCLC proliferation more effectively than R (6: IC50=2 μm, 7: IC50=5 μm and R: IC50=10 μm). Moreover, 6 inhibited the respiratory activity of SK‐MES 1 epithelial type of lung carcinoma cells in proliferating but not in the quiescent state, suggesting that the antiproliferative effect of these compounds is not due to simple cytotoxicity. These short chain analogues of SP might be promising candidates as therapeutic agents in the treatment of SCLC. © 1998 European Peptide Society and John Wiley & Sons, Ltd.