Aminoadamantanes containing monoterpene-derived fragments as potent tyrosyl-DNA phosphodiesterase 1 inhibitors

• Published in: Bioorganic chemistry Vol. 76; pp. 392 - 399
• Main Authors: Ponomarev, Konstantin Yu, Suslov, Evgeniy V., Zakharenko, Alexandra L., Zakharova, Olga D., Rogachev, Artem D., Korchagina, Dina V., Zafar, Ayesha, Reynisson, Jóhannes, Nefedov, Andrey A., Volcho, Konstantin P., Salakhutdinov, Nariman F., Lavrik, Olga I.
• Format: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier Inc 01.02.2018; Elsevier
• Subjects: Adamantane - analogs & derivatives; Adamantane - chemical synthesis; Adamantane - chemistry; Adamantane - pharmacology; Adamantanes; Amine; Amines - chemical synthesis; Amines - chemistry; Amines - pharmacology; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Binding Sites; Biochemistry & Molecular Biology; Chemical space; Chemistry; Chemistry, Organic; Cytotoxicity; Drug Screening Assays, Antitumor; Drug Synergism; Fluorescent assay; HCT116 Cells; Humans; Life Sciences & Biomedicine; Molecular Docking Simulation; Monoterpenes - chemical synthesis; Monoterpenes - chemistry; Monoterpenes - pharmacology; Natural products; Phosphodiesterase Inhibitors - chemical synthesis; Phosphodiesterase Inhibitors - chemistry; Phosphodiesterase Inhibitors - pharmacology; Phosphoric Diester Hydrolases - chemistry; Phosphoric Diester Hydrolases - metabolism; Physical Sciences; Science & Technology; Stereoisomerism; Tdp1, molecular modelling; Topotecan - pharmacology; CXTYQHBRDVJROL-UHEPKEFZSA-N; Chemical space; Adamantanes; Amine; XNQOUINXDUSWSQ-UHFFFAOYSA-N; Natural products; Tdp1, molecular modelling; Cytotoxicity; Fluorescent assay; 2-AMINOADAMANTANE DERIVATIVES; EMPIRICAL SCORING FUNCTIONS; CAMPTOTHECINS; TOPOISOMERASE-I; CANCER; PROTEIN-LIGAND DOCKING; DATA-BANK; BIOLOGICAL EVALUATION; ADAMANTANE DERIVATIVES; TDP1 INHIBITORS
• ISSN: 0045-2068; 1090-2120; 1090-2120
• DOI: 10.1016/j.bioorg.2017.12.005

[Display omitted] •Aminoadamantane and monoterpene hybrids are good inhibitors of Tdp1.•The most promising inhibitor was synthesized from 1-aminoadamantane and citronellal.•The inhibitor enhanced cytotoxicity of topotecan against colon carcinoma HCT-116.•The inhibitor proved to have low own cytotoxicity. 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.