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New Deoxycholic Acid Derived Tyrosyl-DNA Phosphodiesterase 1 Inhibitors Also Inhibit Tyrosyl-DNA Phosphodiesterase 2.
- Source :
-
Molecules (Basel, Switzerland) [Molecules] 2021 Dec 23; Vol. 27 (1). Date of Electronic Publication: 2021 Dec 23. - Publication Year :
- 2021
-
Abstract
- A series of deoxycholic acid (DCA) amides containing benzyl ether groups on the steroid core were tested against the tyrosyl-DNA phosphodiesterase 1 (TDP1) and 2 (TDP2) enzymes. In addition, 1,2,4- and 1,3,4-oxadiazole derivatives were synthesized to study the linker influence between a para -bromophenyl moiety and the steroid scaffold. The DCA derivatives demonstrated promising inhibitory activity against TDP1 with IC <subscript>50</subscript> in the submicromolar range. Furthermore, the amides and the 1,3,4-oxadiazole derivatives inhibited the TDP2 enzyme but at substantially higher concentration. Tryptamide 5 and para -bromoanilide 8 derivatives containing benzyloxy substituent at the C-3 position and non-substituted hydroxy group at C-12 on the DCA scaffold inhibited both TDP1 and TDP2 as well as enhanced the cytotoxicity of topotecan in non-toxic concentration in vitro. According to molecular modeling, ligand 5 is anchored into the catalytic pocket of TDP1 by one hydrogen bond to the backbone of Gly458 as well as by π-π stacking between the indolyl rings of the ligand and Tyr590, resulting in excellent activity. It can therefore be concluded that these derivatives contribute to the development of specific TDP1 and TDP2 inhibitors for adjuvant therapy against cancer in combination with topoisomerase poisons.
- Subjects :
- Binding Sites
Cell Line
Chemical Phenomena
Chemistry Techniques, Synthetic
Deoxycholic Acid pharmacology
Enzyme Activation drug effects
Humans
Models, Molecular
Molecular Conformation
Molecular Structure
Phosphodiesterase Inhibitors chemical synthesis
Phosphodiesterase Inhibitors pharmacology
Phosphoric Diester Hydrolases metabolism
Protein Binding
Recombinant Proteins chemistry
Structure-Activity Relationship
Deoxycholic Acid analogs & derivatives
Deoxycholic Acid chemistry
Phosphodiesterase Inhibitors chemistry
Phosphoric Diester Hydrolases chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1420-3049
- Volume :
- 27
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Molecules (Basel, Switzerland)
- Publication Type :
- Academic Journal
- Accession number :
- 35011303
- Full Text :
- https://doi.org/10.3390/molecules27010072