ABSTRACT
The ability of a number of nitrogen-containing compounds that simultaneously carry the adamantane and monoterpene moieties to inhibit Tdp1, an important enzyme of the DNA repair system, is studied. Inhibition of this enzyme has the potential to overcome chemotherapeutic resistance of some tumor types. Compound (+)-3c synthesized from 1-aminoadamantane and (+)-myrtenal, and compound 4a produced from 2-aminoadamantane and citronellal were found to be most potent as they inhibited Tdp1 with IC50 values of 6 and 3.5⯵M, respectively. These compounds proved to have low cytotoxicity in colon HCT-116 and lung A-549 human tumor cell lines (CC50â¯>â¯50⯵M). It was demonstrated that compound 4a at 10⯵M enhanced cytotoxicity of topotecan, a topoisomerase 1 poison in clinical use, against HCT-116 more than fivefold and to a lesser extent of 1.5 increase in potency for A-549.
Subject(s)
Adamantane/analogs & derivatives , Adamantane/pharmacology , Antineoplastic Agents/pharmacology , Monoterpenes/pharmacology , Phosphodiesterase Inhibitors/pharmacology , Phosphoric Diester Hydrolases/metabolism , Adamantane/chemical synthesis , Adamantane/chemistry , Amines/chemical synthesis , Amines/chemistry , Amines/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Binding Sites , Drug Screening Assays, Antitumor , Drug Synergism , HCT116 Cells , Humans , Molecular Docking Simulation , Monoterpenes/chemical synthesis , Monoterpenes/chemistry , Phosphodiesterase Inhibitors/chemical synthesis , Phosphodiesterase Inhibitors/chemistry , Phosphoric Diester Hydrolases/chemistry , Stereoisomerism , Topotecan/pharmacologyABSTRACT
A series of secondary amines combining monoterpenoid and aminoadamantane moieties have been synthesized. Their cytotoxic activity against human cancer cells CEM-13, MT-4, and U-937 has been studied for the first time. Most of the obtained compounds exhibited a significant cytotoxic activity with the median cytotoxic dose (CTD50) ranging from 6 to 84 µM. The most promising results were obtained for compound 2b which was synthesized from 1-aminoadamantane and (-)-myrtenal and revealed a high activity against all tumor lines used (CTD50 = 12 ÷ 21 µM) along with low toxicity with respect to MDCK cells (CTD50 = 1500 µM). The synthesized amines do not exert the genotoxic effect on cells of the biosensor strain based on recombinant E. coli cells bearing the pRAC-gfp plasmid.
