From octreotide to shorter analogues: Synthesis, radiolabeling, stability.

This study aims at analyzing complexation properties of two new short somatostatin analogues, their synthesis, radiolabeling with 44 Sc, 207 Bi, and 152 Eu and stability in vitro. Short tetrapeptide Phe-d-Trp-Lys-Thr and pentapeptide Thz-Phe-d-Trp-Lys-Thr were first conjugated with the DOTA macrocyclic chelator. These conjugates were radiolabeled with 44 Sc, 207 Bi, and 152 Eu and characterized by thin-layer chromatography (TLC) and HPLC. The radiochemical purity was measured using digital autoradiography and gamma spectrometry. Optimum conditions of DOTA-conjugate labeling were found: 0.1mM, pH 8.0 to 8.4 at 90°C for DOTA-tetrapeptide complexes with 207 Bi and 152 Eu; 0.05mM, pH 4.0 to 5.0 at 90°C for 44 Sc-DOTA-tetrapeptide; 0.2mM, pH 4.0 to 5.0 at 90°C for 44 Sc-DOTA-pentapeptide. Complexes of DOTA-pentapeptide with 207 Bi and 152 Eu of radiochemical purity more than 95% were probably unstable at temperature higher than 37°C and were obtained at 37°C, pH 8.0 to 8.4 within 4 days. Mass spectra of the Eu-DOTA-pentapeptide revealed the presence of small fragments of the pentapeptide conjugate in the complex solution. in vitro stability studies were performed in saline in the presence of serum proteins and biologically relevant metal cations. All complexes demonstrated no cation release in vitro within 1 to 4 hours.

Exogenous GalR2-specific peptide agonist as a tool for treating myocardial ischemia/reperfusion injury.

OBJECTIVES: The aim of this work was to elucidate the role of GalR2 receptor activation in protecting the rat heart in vivo from ischemia/reperfusion (I/R) damage by a pharmacological peptide agonist WTLNSAGYLLGPßAH-OH (G1) and full-length rat galanin GWTLNSAGYLLGPHAIDNHRSFSDKHGLT-NH2 (G2) using M871, a selective inhibitor of GalR2. METHODS: The peptides were prepared by the automatic solid-phase synthesis using the Fmoc-strategy and purified by high-performance liquid chromatography (HPLC). A 40-min left anterior descending (LAD) coronary artery occlusion followed by a 60-min reperfusion was performed. The criteria for damage/protection of the heart were the infarct size (IS) and plasma activity of creatine kinase-MB (CK-MB) at the end of reperfusion. RESULTS: Intravenous injection of G1 or G2 at an optimal dose of 1 mg/kg at the fifth minute of reperfusion significantly reduced the IS (by 35% and 32%, respectively) and activity of CK-MB at the end of reperfusion (by 43% and 38%, respectively) compared with the control. Administration of M871 (8 mg/kg) 5 min before the onset of reperfusion abolished the effects of G1 on IS and CK-MB activity, returning them to control values. Co-administration of M871 (8 mg/kg) with G2 attenuated protective effect of G2 on both IS and plasma СK-MB activity. However, differences in these parameters between the M871+G2 and G2 groups did not reach statistical significance (P = 0.139 and P = 0.121, respectively). CONCLUSION: Thus, GalR2 is the principal receptor subtype that transduces the protective effects of galanin and ligand G1 in myocardial I/R injury. This suggests that GalR2-specific peptide agonists could be used as drug candidates for treating ischemic heart disease.

New Spirocyclic Hydroxamic Acids as Effective Antiproliferative Agents.

AIMS: The main goal of this work is to synthesize new original spirocyclic hydroxamic acids, investigate their cytotoxicity against the panel of tumor cell lines and possible mechanism of action of these active compounds. BACKGROUND: Hydroxamic acids are one of the promising classes of chemical compounds with proven potential anticancer properties. This is manifested in the presence of metal chelating and antioxidant activities, the ability to inhibit histone deacetylase enzymes and a chemosensitizing effect against well known cytostatics. OBJECTIVE: Original spirocyclic hydroxamic acids were synthesized and spectra of their antiproliferative activities were investigated. METHODS: The cytotoxic activities on different tumor lines (SH-SY5Y, HeLa and healthy cells HEK-293) were investigated and determined possible underlying mechanisms of their activity. RESULTS: New original spirocyclic hydroxamic acids were synthesized. These compounds exhibit antiproliferative properties against various tumor cultures cells and also exhibit antioxidant activity, a depolarizing effect on the mitochondrial membrane, inhibit the activity of the histone deacetylase enzyme, and also decrease of basal glycolysis and glycolytic capacity reserve of HeLa and SH-SY5Y tumor cell lines. CONCLUSION: The most promising are compounds 5j-l containing two chlorine atoms as substituents in the quinazoline part of the molecule and hydroxamate function. Therefore, these compounds can be considered as hit compounds for the development on their basis multi-target anticancer agents.