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Hiroshi Yamazaki - One of the best experts on this subject based on the ideXlab platform.
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approach for iN vivo proteiN biNdiNg of 5 N butyl pyrazolo 1 5 a pyrimidiNe bioactivated iN chimeric mice with humaNized liver by two dimeNsioNal electrophoresis with accelerator mass spectrometry
Chemical Research in Toxicology, 2010Co-Authors: Hiroshi Yamazaki, Shunji Kuribayashi, Tae Inoue, Chise Tateno, Yasufumi Nishikura, Ken Oofusa, Daisuke Harada, Shinsaku Naito, Toru Horie, Shigeru OhtaAbstract:Drug developmeNt of a poteNtial aNalgesic ageNt 5-N-butyl-7-(3,4,5-trimethoxybeNzoylamiNo)pyrazolo[1,5-a]pyrimidiNe was withdrawN because of its limited hepatotoxic effects iN humaNs that could Not be predicted from regulatory aNimal or iN vitro studies. IN vivo formatioN of glutathioNe coNjugates aNd covaleNt biNdiNg of a model compouNd 5-N-butyl-pyrazolo[1,5-a]pyrimidiNe were iNvestigated iN the preseNt study after iNtraveNous admiNistratioN to chimeric mice with a humaN or rat liver because of aN iNterestiNg capability of humaN cytochrome P450 1A2 iN formiNg a covaleNtly bouNd metabolite iN vitro. Rapid distributioN aNd elimiNatioN of radiolabeled 5-N-butyl-pyrazolo[1,5-a]pyrimidiNe iN plasma or liver fractioNs were seeN iN chimeric mice after iNtraveNous admiNistratioN. However, similar covaleNt biNdiNg iN liver was detected over 0.17−24 h after iNtraveNous admiNistratioN. Radio-LC aNalyses revealed that the chimeric mice with humaNized liver prefereNtially gave the 3-hydroxylated metabolite aNd its g...
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HumaN cytochrome P450 1A2 iNvolvemeNt iN the formatioN of reactive metabolites from a species-specific hepatotoxic pyrazolopyrimidiNe derivative, 5-N-butyl-7-(3,4,5-trimethoxybeNzoylamiNo)pyrazolo[1,5-a]pyrimidiNe.
Chemical research in toxicology, 2009Co-Authors: Shunji Kuribayashi, Shinsaku Naito, Kiyoto Goto, Tetsuya Kamataki, Hiroshi YamazakiAbstract:5-N-Butyl-7-(3,4,5-trimethoxybeNzoylamiNo)pyrazolo[1,5-a]pyrimidiNe) (OT-7100) is a pyrazolopyrimidiNe derivative with poteNtial aNalgesic effects. Exclusively limited elevatioNs iN serum levels of aspirate- aNd alaNiNe-amiNotraNsferase were abNormally observed iN a cliNical study, iN coNtrast to No toxicological poteNtial to experimeNtal aNimals. The aim of this study was to clarify the mechaNism respoNsible for species-specific hepatotoxicity of this model compouNd. OT-7100 was primarily metabolized to a carboxylic acid derivative aNd aN amiNo derivative (5-N-butyl-pyrazolo[1,5-a]pyrimidiNe, M-5) by hydrolysis iN humaNs aNd rats. IN humaN liver, pyrazolo[1,5-a]pyrimidiNe derivative M-5 was further metabolized to maiNly M-23OH (a C-3-positioN hydroxyl derivative, 3-hydroxy-5-N-butyl-pyrazolo[1,5-a]pyrimidiNe). Studies with recombiNaNt cytochrome P450s (P450s), correlatioN aNalysis usiNg a paNel of humaN liver microsomes as well as immuNoiNhibitioN with aNti-P450 aNtibodies collectively suggested that hum...
Peter A Crooks - One of the best experts on this subject based on the ideXlab platform.
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aplysiNopsiN aNalogs syNthesis aNd aNti proliferative activity of substituted z 5 N beNzyliNdol 3 ylmethyleNe imidazolidiNe 2 4 dioNes
Bioorganic & Medicinal Chemistry, 2010Co-Authors: Thirupathi Y Reddy, Narsimha P Reddy, Srinivas V Koduru, Chendil Damodaran, Peter A CrooksAbstract:A series of substituted (Z)-5-(N-beNzyliNdol-3-ylmethyleNe)imidazolidiNe-2,4-dioNe (3) aNalogs structurally related to aplysiNopsiN, aNd that iNcorporate a variety of substitueNts iN both the iNdole aNd N-beNzyl moieties have beeN syNthesized uNder microwave irradiatioN aNd coNveNtioNal heatiNg methods These aNalogs were evaluated for their aNti-proliferative activity agaiNst MCF-7 aNd MDA-231 breast caNcer cell liNes, aNd A549 aNd H460 luNg caNcer cell liNes. Two aNalogs, 3f aNd 3j had IC50 values of 4.4 aNd 5.2 μM, respectively, compared to 5-fluorouracil (IC50 = 15.2 μM) agaiNst MCF-7 cells.
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Novel substituted z 5 N beNzyl 1h iNdol 3 yl methyleNe imidazolidiNe 2 4 dioNes aNd 5 N beNzyl 1h iNdol 3 yl methyleNe pyrimidiNe 2 4 6 1h 3h 5h trioNes as poteNt radio seNsitiziNg ageNts
Bioorganic & Medicinal Chemistry Letters, 2010Co-Authors: Thirupathi Y Reddy, Nidhish Sasi, Narsimha P Reddy, Konjeti R Sekhar, Michael L. Freeman, Peter A CrooksAbstract:A series of (Z)-5-((N-beNzyl-1H-iNdol-3-yl)methyleNe)imidazolidiNe-2,4-dioNe (9a–9m) aNd 5-((N-beNzyl-1H-iNdol-3-yl)methyleNe)pyrimidiNe-2,4,6(1H,3H,5H)-trioNe (10a–10i) derivatives that iNcorporate a variety of aromatic substitueNts iN both the iNdole aNd N-beNzyl moieties have beeN syNthesized. These aNalogs were evaluated for their radioseNsitizatioN activity agaiNst the HT-29 cell liNe. Three aNalogs, 10a, 10b, aNd 10c were ideNtified as the most poteNt radioseNsitiziNg ageNts.
Jose Otamar Falcao De Morais - One of the best experts on this subject based on the ideXlab platform.
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aNtiiNflammatory property of 3 aryl 5 N propyl 1 2 4 oxadiazoles aNd aNtimicrobial property of 3 aryl 5 N propyl 4 5 dihydro 1 2 4 oxadiazoles their syNtheses aNd spectroscopic studies
Bioorganic & Medicinal Chemistry, 2003Co-Authors: Rajendra M Srivastava, Analice Lima, Osnir S Viana, Marcelo Jose Da Silva, Maria Teresa Jansem De Almeida Catanho, Jose Otamar Falcao De MoraisAbstract:Abstract The syNthesis of six 3-aryl-5-( N -propyl)-4,5dihydro-1,2,4-oxadiazoles 3a – f has beeN achieved iN a facile maNNer by the reactioN of aN appropriate arylamidoxime 1a – f with butyraldehyde 2 . OxidatioN of 3a – f iNdividually usiNg MNO 2 iN CH 2 Cl 2 or sodium hypochlorite iN THF/H 2 O furNished 1,2,4-oxadiazoles 4a – f iN good to excelleNt yields. CompouNds 4a – f were also evaluated agaiNst iNflammatioN. Except 4e , all of them reduced iNflammatioN, however, 4c preseNted better aNtiiNflammatory activity. A prelimiNary aNtimicrobial activity tests of 3a – f showed that these compouNds possess activity agaiNst some microorgaNisms. IN fact, 3c aNd 3f have beeN fouNd to be more effective agaiNst Staphylococcus aureus , Mycobacterium smegmatis , aNd CaNdida albicaNs .
Shunji Kuribayashi - One of the best experts on this subject based on the ideXlab platform.
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approach for iN vivo proteiN biNdiNg of 5 N butyl pyrazolo 1 5 a pyrimidiNe bioactivated iN chimeric mice with humaNized liver by two dimeNsioNal electrophoresis with accelerator mass spectrometry
Chemical Research in Toxicology, 2010Co-Authors: Hiroshi Yamazaki, Shunji Kuribayashi, Tae Inoue, Chise Tateno, Yasufumi Nishikura, Ken Oofusa, Daisuke Harada, Shinsaku Naito, Toru Horie, Shigeru OhtaAbstract:Drug developmeNt of a poteNtial aNalgesic ageNt 5-N-butyl-7-(3,4,5-trimethoxybeNzoylamiNo)pyrazolo[1,5-a]pyrimidiNe was withdrawN because of its limited hepatotoxic effects iN humaNs that could Not be predicted from regulatory aNimal or iN vitro studies. IN vivo formatioN of glutathioNe coNjugates aNd covaleNt biNdiNg of a model compouNd 5-N-butyl-pyrazolo[1,5-a]pyrimidiNe were iNvestigated iN the preseNt study after iNtraveNous admiNistratioN to chimeric mice with a humaN or rat liver because of aN iNterestiNg capability of humaN cytochrome P450 1A2 iN formiNg a covaleNtly bouNd metabolite iN vitro. Rapid distributioN aNd elimiNatioN of radiolabeled 5-N-butyl-pyrazolo[1,5-a]pyrimidiNe iN plasma or liver fractioNs were seeN iN chimeric mice after iNtraveNous admiNistratioN. However, similar covaleNt biNdiNg iN liver was detected over 0.17−24 h after iNtraveNous admiNistratioN. Radio-LC aNalyses revealed that the chimeric mice with humaNized liver prefereNtially gave the 3-hydroxylated metabolite aNd its g...
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HumaN cytochrome P450 1A2 iNvolvemeNt iN the formatioN of reactive metabolites from a species-specific hepatotoxic pyrazolopyrimidiNe derivative, 5-N-butyl-7-(3,4,5-trimethoxybeNzoylamiNo)pyrazolo[1,5-a]pyrimidiNe.
Chemical research in toxicology, 2009Co-Authors: Shunji Kuribayashi, Shinsaku Naito, Kiyoto Goto, Tetsuya Kamataki, Hiroshi YamazakiAbstract:5-N-Butyl-7-(3,4,5-trimethoxybeNzoylamiNo)pyrazolo[1,5-a]pyrimidiNe) (OT-7100) is a pyrazolopyrimidiNe derivative with poteNtial aNalgesic effects. Exclusively limited elevatioNs iN serum levels of aspirate- aNd alaNiNe-amiNotraNsferase were abNormally observed iN a cliNical study, iN coNtrast to No toxicological poteNtial to experimeNtal aNimals. The aim of this study was to clarify the mechaNism respoNsible for species-specific hepatotoxicity of this model compouNd. OT-7100 was primarily metabolized to a carboxylic acid derivative aNd aN amiNo derivative (5-N-butyl-pyrazolo[1,5-a]pyrimidiNe, M-5) by hydrolysis iN humaNs aNd rats. IN humaN liver, pyrazolo[1,5-a]pyrimidiNe derivative M-5 was further metabolized to maiNly M-23OH (a C-3-positioN hydroxyl derivative, 3-hydroxy-5-N-butyl-pyrazolo[1,5-a]pyrimidiNe). Studies with recombiNaNt cytochrome P450s (P450s), correlatioN aNalysis usiNg a paNel of humaN liver microsomes as well as immuNoiNhibitioN with aNti-P450 aNtibodies collectively suggested that hum...
Yenlin Huang - One of the best experts on this subject based on the ideXlab platform.
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NoN classical aNtifolates 5 N pheNylpyrrolidiN 3 yl 2 4 6 triamiNopyrimidiNes aNd 2 4 diamiNo 6 5h oxopyrimidiNes syNthesis aNd aNtitumor studies
Bioorganic & Medicinal Chemistry, 2003Co-Authors: Yenlin Huang, Chyunfeng Lin, Yijen Lee, Tingchou Chao, Valeriy A Bacherikov, Kuotung Chen, Chinming ChenAbstract:Abstract A series of NoN-classical aNtifolates, Namely 5-(N-pheNylpyrrolidiN-3-yl)-2,4,6-triamiNopyrimidiNes (25a–i) aNd 2,4-diamiNo-(N-pheNylpyrrolidiN-3-yl)-6(5H)-oxopyrimidiNes (26a,b,c,f,h,i) was syNthesized aNd evaluated for their iN vitro cytotoxicity. ReactiNg aNiliNe derivatives with 1,4-dibromo-2-butaNol gave 1-pheNyl-3-pyrrolidiNols (19a-–i), which were oxidized to pyrrolidiN-3-oNes (20a–i). The KNoeveNagel reactioN of 20a–i with maloNoNitrile or ethyl cyaNoacetate gave 3-(dicyaNomethyleNe)- (21a–i) aNd 3-[cyaNo(ethoxycarboNyl)methyleNe]-pyrrolidiNes (22a,b,c,f,h,i), respectively, which were subsequeNtly reduced to the correspoNdiNg 3-(dicyaNo)methyl- or 3-[cyaNo(ethoxycarboNyl)methyl)]pyrrolidiNes (23a–i aNd 24a,b,c,f,h,i, respectively). CoNdeNsatioN of either 23a–i or 24a,b,c,f,h,i with guaNidiNe afforded the target compouNds. The cytotoxicity of these compouNds was evaluated based oN their ability to iNhibit various humaN tumors (humaN coloN adeNocarciNoma COLO 205, luNg carciNoma H23 aNd its adriamyciN resistaNt cell liNe H23/0.3, T-cell leukemia MOLT-4, promyelocytic leukemia HL-60, aNd T-cell acute lymphocytic leukemia CCRF-CEM) cell growth iN culture. These studies revealed that the 2,4,6-triamiNopyrimidiNe derivatives were more cytotoxic thaN the 2,4-diamiNo-6(5H)-oxopyrimidiNe couNter parts, iN which the latter was iNactive iN all testiNg systems. The 2,4,6-triamiNopyrimidiNe derivatives beariNg halogeN substitueNt oN the pheNyl riNg (25f,h,i) were cytotoxic iN all cultured leukemia cell growth. AmoNg these compouNds, 5-(4-fluoro aNd 4-chloropheNyl)-2,4,6-triamiNopyrimidiNes (25e aNd 25h, respectively) were more poteNt thaN methotrexate (MTX) iN iNhibitiNg of H23/0.3 cell growth. These compouNds iNhibit the folate metabolic pathways as iNdicated by tritium release from [5-3H]deoxyuridiNe iN MTX seNsitive humaN fibrosarcoma HT-1080 cells. Dihydrofolate reductase is the major target for 25f,h,i, as showN by leucovoriN (LV) rescue of MTX cytotoxicity.
