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Int J Mol Sci ; 21(19)2020 Sep 28.
Article in English | MEDLINE | ID: mdl-32998385

ABSTRACT

A series of berberine and tetrahydroberberine sulfonate derivatives were prepared and tested against the tyrosyl-DNA phosphodiesterase 1 (Tdp1) DNA-repair enzyme. The berberine derivatives inhibit the Tdp1 enzyme in the low micromolar range; this is the first reported berberine based Tdp1 inhibitor. A structure-activity relationship analysis revealed the importance of bromine substitution in the 12-position on the tetrahydroberberine scaffold. Furthermore, it was shown that the addition of a sulfonate group containing a polyfluoroaromatic moiety at position 9 leads to increased potency, while most of the derivatives containing an alkyl fragment at the same position were not active. According to the molecular modeling, the bromine atom in position 12 forms a hydrogen bond to histidine 493, a key catalytic residue. The cytotoxic effect of topotecan, a clinically important topoisomerase 1 inhibitor, was doubled in the cervical cancer HeLa cell line by derivatives 11g and 12g; both displayed low toxicity without topotecan. Derivatives 11g and 12g can therefore be used for further development to sensitize the action of clinically relevant Topo1 inhibitors.


Subject(s)
Antineoplastic Agents, Phytogenic/chemical synthesis , Berberine/analogs & derivatives , Phosphodiesterase Inhibitors/chemical synthesis , Phosphoric Diester Hydrolases/chemistry , Topoisomerase I Inhibitors/pharmacology , Topotecan/pharmacology , Antineoplastic Agents, Phytogenic/metabolism , Antineoplastic Agents, Phytogenic/pharmacology , Berberine/chemistry , Berberine/pharmacology , Binding Sites , DNA Repair/drug effects , Drug Combinations , Drug Design , Drug Synergism , HeLa Cells , Humans , Inhibitory Concentration 50 , Molecular Docking Simulation , Phosphodiesterase Inhibitors/metabolism , Phosphodiesterase Inhibitors/pharmacology , Phosphoric Diester Hydrolases/genetics , Phosphoric Diester Hydrolases/metabolism , Protein Binding , Protein Conformation , Structure-Activity Relationship , Topoisomerase I Inhibitors/chemistry , Topotecan/chemistry
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