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.

γ‐Aminoadamantanecarboxylic Acids Through Direct C–H Bond Amidations

“…262°C (ref. [11] 265-266°C [11] 20.66 g (99.2 mmol) of 3,5-dimethyladamantane-1-carboxylic acid (12) was suspended in 60 mL of nitric acid and cooled to 0°C with an ice bath. After the addition of 100 mL sulfuric acid, the mixture was stirred at 0°C for 10 min.…”

“…One particular class of γ-amino acids is represented by γ-aminobutyric acid (GABA) analogues such as Vigabatrin ® (2), Pregabalin ® (3), and Gabapentin ® (4, Scheme 1) that have proven effective, e.g., as potent anticonvulsants. [10] γ-Amino acids based on the adamantane framework are rigid GABA analogues and, although simple representatives have already been prepared decades ago, [11] they have not been utilized as peptide building blocks or pharmaceutically active compounds until very recently, [12] despite the fact that all adamantane derivatives currently used as pharmaceuticals are amino derivatives (Scheme 2). [13][14][15][16][17][18][19] Here, we report the synthesis of a number of representative γ-aminoadamantane-1-carboxylic acids (we use the short-hand designation "…”

Effects of Methionine on the Immune Function in Animals

“…As an animal essential amino acid in the daily diet, methionine possesses high nutritional value and important physiological functions [1] [2] [3], such as growth promotion [4] [5], detoxification [6], antitumor and anticancer [7] [8], resistance for coccidium infection [9], involved in methyl transfer [10] [11] [12] and synthesis of protein [13] [14] [15] [16] and so on. What's more, methionine is closely related to the immune function of livestock and poultry, which is not only has effects on the growth and development of immune organs, but also on the specific and nonspecific immune function of organism [17] [18] [19] [20] [21].…”

Thermodynamic Investigation of Tripeptide Tyr-Aaa-Gly in Gas Phase in Different Solvents

“…To obtain more selective opioid peptides with improved or novel activity profiles toward malignant diseases, modifications using lipophilic moieties may be of particular benefit to passive or active cellular absorption by membrane penetration or attachment. The diastereomeric tripeptides Tyr-(S)-Aaa-Gly and Tyr-(R)-Aaa-Gly [Aaa = (R,S)-(1-adamantyl)glycine] ( Figure 1) showed similar, cell-selective, cytotoxic effects on tumor cell lines irrespective of Aaa chirality 8 . They are methionine-enkephalin analogue.…”