Development of Ribonucleotide Reductase Inhibitor: A Review on Structure Activity Relationships

• Type: Another Publication in an International Scientific Journal
• Date: 2013

Authors

Narayana S H N Moorthy (Author) Other; Nuno M F S A Cerqueira (Author) Other; Maria J Ramos (Author) FCUP; Pedro A Fernandes (Author) FCUP

Journal

Title: Mini-Reviews in Medicinal Chemistry

Vol. 13

Pages: 1862-1872

ISSN: 1389-5575

Publisher: Bentham Science

Indexing

ISI Web of Knowledge - 23 Citations

Scopus - 23 Citations

Scientific classification

FOS: Medical and Health sciences > Basic medicine

Other information

Authenticus ID: P-008-H9D

DOI: 10.2174/13895575113136660090

Abstract (EN): 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 11