Structural variations of piritrexim, a lipophilic inhibitor of human dihydrofolate reductase: synthesis, antitumor activity and molecular modeling investigations.
Piritrexim (PTX) (1), a lipophilic inhibitor of the human dihydrofolate reductase, has been evaluated as an anticancer agent. The synthesis of four structural variations (2-5) of PTX is reported. The PTX analogues 2-5 were obtained by reaction of suitable C3-building blocks with pyrimidine-2,4,6-triamine (14) or with cyanacetamide (7) and guanidine (10). The evaluation of 2-4 for antitumor activity against a panel of 60 human cancer cell lines showed inhibitory effects on the growth of the cell lines. These data are supported by molecular modeling and docking studies, which show that compounds 2-4 share the same binding mode within the DHFR active site. Moreover, the estimated ligand binding energies are in good agreement with the experimental activity data.
Zink
Mario
M
Department of Medicinal Chemistry, Institut für Pharmazie und Lebensmittelchemie im Emil Fischer Center, Friedrich-Alexander Universität, Schuhstrasse 19, 91052 Erlangen, Germany.
Lanig
Harald
H
Troschütz
Reinhard
R
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D011487:Protein Conformation; D011725:Pyridines / Q000138:chemical synthesis / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry
C496331:6-(2,5-dimethoxybenzyl)-5,6,7,8-tetrahydropyrido(2,3-d)pyrimidine-2,4-diamine; C496329:6-(2,5-dimethoxybenzyl)-5,7-dimethylpyrido(2,3-d)pyrimidine-2,4-diamine; C496330:6-(2,5-dimethoxybenzyl)pyrido(2,3-d)pyrimidine-2,4-diamine; D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; D011725:Pyridines; D011743:Pyrimidines; D013762:Tetrahydrofolate Dehydrogenase; C024530:piritrexim