Aminoadamantanes containing monoterpene-derived fragments as potent tyrosyl-DNA phosphodiesterase 1 inhibitors |
| |
Affiliation: | 1. Dipartimento di Chimica “Ugo Schiff”, Università di Firenze, Via della Lastruccia 3, I-50019 Sesto Fiorentino, FI, Italy;2. G.K. Skryabin Institute of Biochemistry and Physiology of Microorganisms, Russian Academy of Sciences, 142290 Pushchino, Nauka Prospect 5, Moscow region, Russia |
| |
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 µM, respectively. These compounds proved to have low cytotoxicity in colon HCT-116 and lung A-549 human tumor cell lines (CC50 > 50 µM). It was demonstrated that compound 4a at 10 µM 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. |
| |
Keywords: | Natural products Fluorescent assay Tdp1, molecular modelling Chemical space Amine Cytotoxicity Adamantanes |
本文献已被 ScienceDirect 等数据库收录! |
|