Based on the structure of Octreotide (SMS 201-995) some modified at positions 5 with Dap (diaminopropanoic acid), Dab (diaminobutanoic acid) and Orn new C-amide analogs were synthesized. The Thr6 was replaced by unnatural amino acids Tle (t-leucine). The cytotoxic effects of the novel compounds were tested in vitro against a panel of human tumor cell lines. All investigated compounds exhibited different concentration-dependent antiproliferative effects against the HT-29, MDA-MB-231, HepG2 and HeLa cell lines after 24 h treatment. The compound 2 (D-Phe-c(Cys-Phe-D-Trp- Dap-Tle-Cys)-Thr-NH2) had antiproliferative effects on MDA-MB-231 cells with the IC50 0.03 mM. The HeLa and HepG-2 cells were most sensitive towards tested compounds at various concentrations. Results demonstrated that the peptide analogs 3 (D-Phe-c(Cys-Phe-D-Trp-Lys-Tle-Cys)-Thr-NH2), 4 (D-Phe-c(Cys-Phe-D-Trp-Orn-Tle-Cys)-Thr-NH2) and 5 (RC-102) exert the most pronounced inhibition of the cell vitality up to 77% at higher concentrations and were not toxic to the normal Lep-3 cells.
Keywords: Cytotoxic, octreotide, somatostatin analogs, SPPS, unnatural amino acids, carcinoid syndrome, neuroendocrine tumors, growth hormone, peptide receptor, G-protein-coupled receptors.