ABSTRACT
Various analogs of flavins, 5-deazaflavins, and flavin-5-oxides were docked into the binding site of protein tyrosine kinase pp60(c-src), and some of them were assayed for their potential antitumor and PKC (protein kinase C) inhibitory activities in vitro. The results considering SAR (structure-activity relationship) revealed that the higher binding affinities obtained include compounds with the structure modifications on the flavin or 5-deazaflavin skeleton, namely, NH(2) or Ph (phenyl-) group at the C-2 position and so on. Computationally designed compounds 4a, 6a, b, 7, 11b, c, 12, 15, and 22c exhibited good docking results suggesting that they are potentially active antitumor agents. These compounds have 1-3 phenyl moieties, which are thought to be responsible for the planar aromatic fitting or electrostatic attraction onto the groove of the binding pocket.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Flavins/chemistry , Flavins/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , In Vitro Techniques , Models, Molecular , Structure-Activity RelationshipABSTRACT
Novel 2-deoxo-2-phenyl-5-deazaflavins and 2-deoxo-2-phenylflavin-5-oxides were prepared as a new class of antitumor agents and showed significant antitumor activities against NCI-H 460, HCT 116, A 431, CCRF-HSB-2, andKB cell lines. In vivo investigation, 2-deoxo-10-methyl-2-phenyl-5-deazaflavin exhibited the effective antitumor activity against A 431 human adenocarcinoma cells transplanted subcutaneously into nude mouse. Furthermore, AutoDock study has been done by binding of the flavin analogs into PTK pp60(c-src), where a good correlation between their IC(50) and AutoDock binding free energy was exhibited. In particular, 2-deoxo-2-phenylflavin-5-oxides exhibited the highest potential binding affinity within the binding pocket of PTK.
