ABSTRACT
It was found that compounds combining diazaadamantane and monoterpenoid fragments are potent inhibitors of new structural type of human recombinant DNA repair enzyme Tyrosyl-DNA phosphodiesterase I (Tdp1). It was demonstrated that the inhibition efficiency depended on the length and flexibility of the aliphatic chain of the substituent.
Subject(s)
Adamantane , Enzyme Inhibitors , Monoterpenes , Nitrogen/chemistry , Phosphoric Diester Hydrolases/chemistry , Adamantane/chemical synthesis , Adamantane/chemistry , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Monoterpenes/chemical synthesis , Monoterpenes/chemistryABSTRACT
Amides with homopiperidinic and piperazinic cycles were synthesized from dihydrobetulonic acid which was obtained by dihydrobetulin oxidation. All substances have shown high antitumor activity (CCID50 3.5-36.2 microM) in vitro in lymphoid (CEM-13, U-937) and monocytic (MT-4) human cell lines. Amides with methyl- and ethyl-piperazinic residues don't influence viability of Lung Lewis Carcinoma cell in culture and haven't any significant effect to its transplantates in C57BL/6 mice. But such amides inhibit efficiently the metastatic elaboration in lung of these mice. The antimetastatic activity increases followed by the change of aliphatic residue length in piperazinic cycle from methyl to ethyl.
Subject(s)
Amides/chemical synthesis , Antineoplastic Agents/chemical synthesis , Cell Survival/drug effects , Oleanolic Acid/analogs & derivatives , Amides/chemistry , Amides/pharmacology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Carcinoma, Lewis Lung/drug therapy , Carcinoma, Lewis Lung/pathology , Cell Line, Tumor , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Lung Neoplasms/secondary , Mice , Oleanolic Acid/chemical synthesis , Oleanolic Acid/chemistry , Oleanolic Acid/pharmacologyABSTRACT
Study of molecular mechanisms of psychotropic drug action is the main aim of molecular psychopharmacology. New synthetic analog of variacin 8-(Trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine (TX-2153) was shown to produce anxiolytic and anticonvulsant effects on mice. Here the effect of chronic administration of TX-2153 on expression of some serotonin-related genes in mouse brain was investigated. The drug (10 mg/kg, per os, 16 days) was administered to adult males of ASC (Antidepressant Sensitive Catalepsy) mouse strain characterizing by alterations in behavior and brain serotonin system. The expression of genes encoding 1) the key enzyme of serotonin synthesis, tryptophan hydroxylase 2 (TPH2), 2) main enzyme of serotonin degradation, monoamine oxydase A (MAOA), 3) 5-HT transporter (SERT) and 4) 5-HT(1A) receptor was studied using quantitative RT-PCR. TX-2153 significantly reduced m-RNA level of 5-HT(1A) receptor and MAOA genes in the midbrain without any effect on expression of these genes in the frontal cortex and hippocampus. The drug failed to affect expression of TPH2 and SERT genes in the midbrain. The result indicates involvement of the brain 5-HT system in the molecular mechanism underlying the effect of TX-2153.
