title: Tumor-cell-targeted methionine-enkephalin analogues containing unnatural amino acids: design, synthesis, and in vitro antitumor activity.
abstract: A series of new peptides (8-25) containing different unnatural amino acids of the adamantane type (1-6), was synthesized. Possible cytotoxic activity on human cervical adenocarcinoma (HeLa), larynx carcinoma (HEp-2), colon carcinomas (HT-29, Caco-2), poorly differentiated cells from lymph node metastasis of colon carcinoma (SW-620), mammary gland adenocarcinoma (MCF-7), and melanoma (HBL) cells were tested by the MTT assay. The results were compared with the effect of methionine-enkephalin (Tyr-Gly-Gly-Phe-Met, or opioid growth factor, OGF), and its shorter N-terminal fragments. Peptide analogues containing C(alpha alpha)-dialkylated glycine (Aaa1, 1) or C(alpha)-alkylated glycine (Aaa2, 2) amino acid residues showed antitumor activity against melanoma, larynx carcinoma, colon carcinomas, and colon metastasis cell lines in vitro. The pentapeptide Tyr-(R,S)-Aaa2-Gly-Phe-Met (18) was the most effective analogue especially against the most antitumor drug-resistant cell lines HEp-2 and SW-620. Apoptosis as a mode of cell death was confirmed in these tumor cells after exposure to pentapeptide 18.
authors.affiliation: Division of Organic Chemistry and Biochemistry, Ruder Bosković Institute, POB 180, 10002 Zagreb, Croatia. shorvat@irb.hr
authors.forename: Stefica
authors.initials: S
authors.lastname: Horvat
authors.forename: Kata
authors.initials: K
authors.lastname: Mlinarić-Majerski
authors.forename: Ljubica
authors.initials: L
authors.lastname: Glavas-Obrovac
authors.forename: Andreja
authors.initials: A
authors.lastname: Jakas
authors.forename: Jelena
authors.initials: J
authors.lastname: Veljković
authors.forename: Saska
authors.initials: S
authors.lastname: Marczi
authors.forename: Goran
authors.initials: G
authors.lastname: Kragol
authors.forename: Maja
authors.initials: M
authors.lastname: Roscić
authors.forename: Marija
authors.initials: M
authors.lastname: Matković
authors.forename: Andrea
authors.initials: A
authors.lastname: Milostić-Srb
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000596:Amino Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004744:Enkephalin, Methionine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D000970:Antineoplastic Agents; D009842:Oligopeptides; C511632:tyrosyl-(1-adamantyl)glycyl-glycyl-phenylalanyl-methionine; D004744:Enkephalin, Methionine; D000218:Adamantane