Several alkylating agents, for example alkyl halides and dimethyl sulfate, were employed in aprotic Solvents Under a variety of conditions for the alkylation of mono- and disubstituted 1H- or 3H-[1,2,3]triazolo[4,5-d]pyrimidine-5,7(4H,6H)-diones, which were prepared by cyclization of the appropriate 5,6-diaminouracils with nitrous acid. The alkylation on the triazole ring in the presence of anhydrous potassium carbonate took place simultaneously at the 1- and 2-positions, with alkylation at the 2-position taking priority. Similar alkylation on the pyrimidine ring with an equivalent alkylating reagent took place only at the 4-position. The alkylation of 3,6-disubstituted derivatives at room temperature led to 5-O-alkylation accompanied by 4-N-alkylation, but at high temperature only 4-N-alkylation took place. Reaction of 3,4,6-trisubstituted derivatives with excess alkylating agent at high temperature leads to the formation of 1,4,6-trisubstituted derivatives with elimination of the 3-substituent.
en-copyright= kn-copyright= en-aut-name=IslamRafiqul en-aut-sei=Islam en-aut-mei=Rafiqul kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=NagamatsuTomohisa en-aut-sei=Nagamatsu en-aut-mei=Tomohisa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= affil-num=1 en-affil= kn-affil=Department of Drug Discovery and Development, Division of Pharmaceutical Sciences, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University affil-num=2 en-affil= kn-affil=Department of Drug Discovery and Development, Division of Pharmaceutical Sciences, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University en-keyword=8-azaxanthines kn-keyword=8-azaxanthines en-keyword=triazolopyrimidines kn-keyword=triazolopyrimidines en-keyword=regioselectivity kn-keyword=regioselectivity en-keyword=alkylations kn-keyword=alkylations en-keyword=heterocycles kn-keyword=heterocycles END start-ver=1.4 cd-journal=joma no-vol=16 cd-vols= no-issue=2 article-no= start-page=922 end-page=940 dt-received= dt-revised= dt-accepted= dt-pub-year=2008 dt-pub=20080115 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=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 en-subtitle= kn-subtitle= en-abstract= kn-abstract=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. en-copyright= kn-copyright= en-aut-name=AliHamed I. en-aut-sei=Ali en-aut-mei=Hamed I. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=AshidaNoriyuki en-aut-sei=Ashida en-aut-mei=Noriyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=NagamatsuTomohisa en-aut-sei=Nagamatsu en-aut-mei=Tomohisa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= affil-num=1 en-affil= kn-affil=Department of Drug Discovery and Development, Division of Pharmaceutical Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University affil-num=2 en-affil= kn-affil=Biology Laboratory, Research and Development Division, Yamasa Shoyu Co. affil-num=3 en-affil= kn-affil=Department of Drug Discovery and Development, Division of Pharmaceutical Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University en-keyword=antitumor activity kn-keyword=antitumor activity en-keyword=flavin-5-oxide kn-keyword=flavin-5-oxide en-keyword=alloxazine-5-oxide kn-keyword=alloxazine-5-oxide en-keyword=AutoDock kn-keyword=AutoDock END start-ver=1.4 cd-journal=joma no-vol=15 cd-vols= no-issue=1 article-no= start-page=242 end-page=256 dt-received= dt-revised= dt-accepted= dt-pub-year=2007 dt-pub=20070101 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Antitumor studies. Part 1: Design, synthesis, antitumor activity, and AutoDock study of 2-deoxo-2-phenyl-5-deazaflavins and 2-deoxo-2-phenylflavin-5-oxides as a new class of antitumor agents en-subtitle= kn-subtitle= en-abstract= kn-abstract=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, and KB 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 IC50 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. en-copyright= kn-copyright= en-aut-name=AliHamed I.. en-aut-sei=Ali en-aut-mei=Hamed I.. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=TomitaKeiichiro en-aut-sei=Tomita en-aut-mei=Keiichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=AkahoEiichi en-aut-sei=Akaho en-aut-mei=Eiichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KambaraHiroto en-aut-sei=Kambara en-aut-mei=Hiroto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=MiuraShinji en-aut-sei=Miura en-aut-mei=Shinji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=HayakawaHiroyuki en-aut-sei=Hayakawa en-aut-mei=Hiroyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=AshidaNoriyuki en-aut-sei=Ashida en-aut-mei=Noriyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=KawashimaYutaka en-aut-sei=Kawashima en-aut-mei=Yutaka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=YamagishiTakehiro en-aut-sei=Yamagishi en-aut-mei=Takehiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=IkeyaHisao en-aut-sei=Ikeya en-aut-mei=Hisao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=YonedaFumio en-aut-sei=Yoneda en-aut-mei=Fumio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=NagamatsuTomohisa en-aut-sei=Nagamatsu en-aut-mei=Tomohisa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= affil-num=1 en-affil= kn-affil=Division of Pharmaceutical Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University affil-num=2 en-affil= kn-affil=Division of Pharmaceutical Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University affil-num=3 en-affil= kn-affil=Faculty of Pharmaceutical Sciences, High Technology Research Center (Life Science Center), and Center for Area Research and Development, Kobe Gakuin University affil-num=4 en-affil= kn-affil=Faculty of Pharmaceutical Sciences, High Technology Research Center (Life Science Center), and Center for Area Research and Development, Kobe Gakuin University affil-num=5 en-affil= kn-affil=Biology Laboratory, Research and Development Division, Yamasa Shoyu Co. affil-num=6 en-affil= kn-affil=Biology Laboratory, Research and Development Division, Yamasa Shoyu Co. affil-num=7 en-affil= kn-affil=Biology Laboratory, Research and Development Division, Yamasa Shoyu Co. affil-num=8 en-affil= kn-affil=Medicinal Research Laboratories, Taisho Pharmaceutical Co. affil-num=9 en-affil= kn-affil=Medicinal Research Laboratories, Taisho Pharmaceutical Co. affil-num=10 en-affil= kn-affil=Medicinal Research Laboratories, Taisho Pharmaceutical Co. affil-num=11 en-affil= kn-affil=Faculty of Pharmaceutical Sciences, Kyoto University affil-num=12 en-affil= kn-affil=Division of Pharmaceutical Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University en-keyword=antitumor activity kn-keyword=antitumor activity en-keyword=Flavin analog kn-keyword=Flavin analog en-keyword=AutoDock kn-keyword=AutoDock en-keyword=protein tyrosine kinase kn-keyword=protein tyrosine kinase END start-ver=1.4 cd-journal=joma no-vol=64 cd-vols= no-issue=42 article-no= start-page=9885 end-page=9894 dt-received= dt-revised= dt-accepted= dt-pub-year=2008 dt-pub=20081013 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Synthesis and regioselective N- and O-alkylation of 3-alkyl-5-phenyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-ones and 2-phenyl-9-propyl-9H-purin-6(1H)-one with evaluation of antiviral and antitumor activities en-subtitle= kn-subtitle= en-abstract= kn-abstract=3-Alkyl-5-phenyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-ones were prepared by nitrosative cyclization of the appropriate 5,6-diamino-2-phenylpyrimidin-4(3H)-ones with nitrous acid and were subjected to regioselective alkylation with several alkylating agents in aprotic solvent at different temperature. Simultaneous 6-N- and 7-O-alkylation were observed and the regioselectivity varied remarkably with size and shape of the alkylating agents as well as with the reaction temperature. Similarly, N- and O-alkylation as well as selectivity was also observed in the case of 2-phenyl-9-propyl-9H-purin-6(1H)-one. Some of the synthesized compounds showed moderate antiviral and antitumor activities.
en-copyright= kn-copyright= en-aut-name=RafiqulIslam en-aut-sei=Rafiqul en-aut-mei=Islam kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=AshidaNoriyuki en-aut-sei=Ashida en-aut-mei=Noriyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=NagamatsuTomohisa en-aut-sei=Nagamatsu en-aut-mei=Tomohisa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= affil-num=1 en-affil= kn-affil=Department of Drug Discovery and Development, Division of Pharmaceutical Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University affil-num=2 en-affil= kn-affil=Biology Laboratory, Research and Development Division, Yamasa Shoyu Co. affil-num=3 en-affil= kn-affil=Department of Drug Discovery and Development, Division of Pharmaceutical Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University en-keyword=synthesis kn-keyword=synthesis en-keyword=regioselective alkylation kn-keyword=regioselective alkylation en-keyword=triazolopyrimidinone kn-keyword=triazolopyrimidinone en-keyword=antiviral activity kn-keyword=antiviral activity en-keyword=antitumor activity kn-keyword=antitumor activity END start-ver=1.4 cd-journal=joma no-vol=15 cd-vols= no-issue=19 article-no= start-page=6336 end-page=6352 dt-received= dt-revised= dt-accepted= dt-pub-year=2007 dt-pub=20071001 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Antitumor studies. Part 3: Design, synthesis, antitumor activity, and molecular docking study of novel 2-methylthio-, 2-amino-, and 2-(N-substituted amino)-10-alkyl-2-deoxo-5-deazaflavins en-subtitle= kn-subtitle= en-abstract= kn-abstract=Various novel 10-alkyl-2-deoxo-2-methylthio-5-deazaflavins have been synthesized by reaction of 6-(N-alkylanilino)-2-methylthiopyrimidin-4(3H)-ones with Vilsmeier reagent. The similar 2-(N-substituted amino) derivatives were prepared by nucleophilic replacement reaction of the 2-methylthio moiety by appropriate amines. The 2-oxo derivatives (i.e., 5-deazaflavins) were obtained by acidic hydrolysis of the 2-methylthio derivatives. The antitumor activities against CCRF-HSB-2 and KB cells and the antiviral activities against HSV-1 and HSV-2 have been investigated in vitro, and many compounds showed promising antitumor activities. Furthermore, AutoDock molecular docking into PTK has been done for lead optimization of these compounds as potential PTK inhibitors. Whereas, the designed 2-deoxo-5-deazaflavins connected with amino acids at the 2-position exhibited the good binding affinities into PTK with more hydrogen bonds. en-copyright= kn-copyright= en-aut-name=AliHamed I. en-aut-sei=Ali en-aut-mei=Hamed I. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=AshidaNoriyuki en-aut-sei=Ashida en-aut-mei=Noriyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=NagamatsuTomohisa en-aut-sei=Nagamatsu en-aut-mei=Tomohisa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= affil-num=1 en-affil= kn-affil=Department of Drug Discovery and Development, Division of Pharmaceutical Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University affil-num=2 en-affil= kn-affil=Biology Laboratory, Research and Development Division, Yamasa Shoyu Co. affil-num=3 en-affil= kn-affil=aDepartment of Drug Discovery and Development, Division of Pharmaceutical Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University en-keyword=antitumor activity kn-keyword=antitumor activity en-keyword=5-deazaflavin kn-keyword=5-deazaflavin en-keyword=AutoDock kn-keyword=AutoDock en-keyword=protein tyrosine kn-keyword=protein tyrosine en-keyword=kinase kn-keyword=kinase END