Synthesis, cytostatic activity and ADME properties of C-5 substituted and N-acyclic pyrimidine derivatives.

Abstract

The synthesis of the novel 5-alkyl pyrimidine derivatives, 5,6-dihydrofuro[2,3-d]pyrimidines and 5-alkyl N-methoxymethyl pyrimidine derivatives and evaluation of their cytostatic activities are described. The mechanism of antiproliferative effect of 5-(2-chloroethyl)-substituted pyrimidine 3 that exerted the pronounced cytostatic activity was studied in further details on colon carcinoma (HCT116) cells. The cell cycle perturbation analysis demonstrated severe DNA damage (G2/M arrest) pointing to a potential DNA alkylating ability of 3. Preliminary ADME data of 3 and its 6-methylated structural congener (6-Me-3) showed their high permeability and good metabolic stability.

• Authors: Tatjana Gazivoda Kraljević, Mateja Klika, Marijeta Kralj, Irena Martin-Kleiner, Stella Jurmanović, Astrid Milić, Jasna Padovan, Silvana Raić-Malić
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 22 Issue 1 Pg. 308-12 (Jan 01 2012) ISSN: 1464-3405 [Electronic] England
• PMID: 22130132 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• Alkylating Agents
• Cytostatic Agents
• Pyrimidines
• DNA

Topics

• Alkylating Agents (pharmacology)
• Animals
• Cell Division
• Cell Line, Tumor
• Cell Proliferation
• Chemistry, Pharmaceutical (methods)
• Cytostatic Agents (pharmacology)
• DNA (chemistry)
• Dose-Response Relationship, Drug
• Drug Design
• Drug Screening Assays, Antitumor (methods)
• G2 Phase
• Humans
• Inhibitory Concentration 50
• Mice
• Models, Chemical
• Permeability
• Pyrimidines (chemical synthesis, chemistry)
• Rats