Title:Development of Ribonucleotide Reductase Inhibitors: A Review on Structure Activity Relationships
Volume: 13
Issue: 13
Author(s): Narayana S.H.N. Moorthy, Nuno M.F.S.A. Cerqueira, Maria J. Ramos and Pedro A. Fernandes
Affiliation:
Keywords:
Ribonucleotide reductase inhibitors, cancer, thiosemicarbazone, triapine.
Abstract: Ribonucleotide reductase (RNR, E.C. 1.17.4.1), which is composed of two dissimilar proteins (subunits), often
referred as R1 (containing polythiols) and R2 (containing non-heme iron and a free tyrosyl radical), which contribute to
the role played by the enzyme. RNRs are one of the important targets in anticancer and antiviral drug development and
many RNR inhibitors have been discovered at the end of the 20th century; many of them are already in clinical use.
Triapine (3-AP) is one of the important RNR inhibitors belonging to the class of thiosemicarbazone derivatives, used in
the treatment of various cancers. The structure activity relationship (SAR) studies on the investigated RNR inhibitors
showed that the nitrogen atom in the pyridine (or other heterocycles) forms coordination complexes with the metal ions
along with the imine, oxo and thio atoms of the thiosemicarbazone or semicarbazone pharmacophores. The computational
analyses results in the adenine and purine derivatives suggest that the nitrogen atoms in the adenine rings make several
hydrogen bonds with the water molecules present in the active site, as well as Gly249 and Glu288 residues. The OH group
in third position of the sugar moiety interacts with the Ser217 (C=O) and the water molecules through hydrogen bonds.
The aromatic rings in the molecules interact with the tyrosine residues. The thiosemicarbazone or semicarbazone
derivatives explain that the flexibility and polar properties in the thiosemicarbazone or semicarbazone pharmacophoric
regions allow the molecules to coordinate with the metal ion (especially iron) present in the RNR enzymes. This review
concluded that RNR inhibitors composed of different fragments such as aryl, heteroaryl, sugar moiety, polar groups,
flexible bonds, etc which are required for the binding of the molecules to the RNR enzymes. Further, the fragmental
analysis of the RNR inhibitors on different toxicological and metabolic targets can provide significant novel molecules
with acceptable pharmacokinetic properties.
