Antitumor studies. Part 4: Design, synthesis, antitumor activity, and molecular docking study of novel 2-substituted 2-deoxoflavin-5-oxides, 2-deoxoalloxazine-5-oxides, and their 5-deaza analogs.
Various novel 10-alkyl-2-deoxo-2-methylthioflavin-5-oxides and their 2-alkylamino derivatives were prepared by facile nitrosative cyclization of 6-(N-alkylanilino)-2-methylthiopyrimidin-4(3H)-ones followed by nucleophilic replacement of the 2-methylthio moiety by different amines, and acidic hydrolysis of the 2-methylthio moiety afforded the corresponding flavin derivatives. 2-Deoxo-2-methylthio-5-deazaalloxazines and 2-deoxo-2-methylthioalloxazine-5-oxides were also prepared by Vilsmeier reaction and by nitrosation of 6-anilino-2-methylthiopyrimidin-4(3H)-ones, respectively. Then, they were subjected to nucleophilic replacement with appropriate amines to produce the corresponding 2-alkylamino derivatives. Regiospecific N(3)-alkylation of 2-deoxo-2-methylthioalloxazine-5-oxides was carried out with various alkylating agents in the usual way. The antitumor activities against CCRF-HSB-2 and KB tumor cells have been investigated in vitro, and many compounds showed promising antitumor activities. Furthermore, AutoDock molecular docking into PTK (PDB: 1t46) has been done for lead optimization of the aforementioned compounds as potential PTK inhibitors.
Ali
Hamed I
HI
Department of Drug Discovery and Development, Division of Pharmaceutical Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University 1-1-1, Tsushima-Naka, Okayama 700-8530, Japan.
Ashida
Noriyuki
N
Nagamatsu
Tomohisa
T
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor / Q000187:drug effects; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005415:Flavins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007624:KB Cells; D015394:Molecular Structure; D010078:Oxazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010087:Oxides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D005415:Flavins; D010078:Oxazines; D010087:Oxides; D011505:Protein-Tyrosine Kinases