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

Small cell lung cancer (SCLC) cell lines produce and secrete various peptid e hormones, e.g. bombesin (BN)/gastrin releasing peptide (GRP) like peptide s that are proposed to function as their autocrine growth factors. To inhib it the proliferative effect of these hormones we have synthesized short cha in 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 se veral substance P (SP) analogues were found to inhibit the growth of SCLC c ells, some short chain SP-analogues have been synthesized. (Pseudo)octapept ides were synthesized in solution, by fragment condensation using the DCC/H OPfp method. Fragments and SP-analogues were synthesized stepwise using pen tafluorophenyl esters. The resistance to hydrolysis of the reduced peptide bond made permitted exact quantification of the Leu psi(CH2NH)Leu pseudopep tide in hydrolysates, The binding ability of both types of peptides to BN-r eceptors on Swiss 3T3 mouse fibroblast cells and their antiproliferative ef fect on NCI-H69 human SCLC cell line have been tested and compared with a s hort 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 s howed weak activity in inhibition of proliferation of SCLC cells, SP-analog ues 6: D-MePhe-D-Trp-Phe-D-Trp-Leu psi(CH2NH)-Leu and 7: D-MePhe-D-Trp-Phe- D-Trp-Leu-MPA, in spite of greatly diminished affinity towards the BN-recep tor, inhibited SCLC proliferation more effectively than R (6: IC50=2 mu M, 7: IC50=5 mu M and R: IC50=10 mu M). Moreover, 6 inhibited the respiratory activity of SK-MES 1 epithelial type of lung carcinoma cells in proliferati ng but not in the quiescent state, suggesting that the antiproliferative ef fect of these compounds is not due to simple cytotoxicity. These short chai n analogues of SP might be promising candidates as therapeutic agents in th e treatment of SCLC. (C) 1998 European Peptide Society and John Wiley & Son s, Ltd.