Benzylamines ; Cardiomyopathy, Hypertrophic/drug therapy* ; Humans ; Pharmaceutical Preparations ; Uracil/analogs & derivatives*

OBJECTIVETo investigate the chemical constituents of marine alga Chaetomorpha basiretorsa.

METHODCompounds were isolated by normal phase silica gel and Sephadex LH-20 gel colum chromatography, reverse phase MPLC, reverse phase HPLC and recrystallization. Their structures were elucidated by spectroscopic methods including MS, IR, NMR, and X-ray crystalography. Cytotoxicity of the compounds were screened by using standard MTT method.

RESULTNine compounds were isolated from C. basiretorsa and their structures were identified as N-phenyl-2-naphthalenamine( I ), dibutyl phthalate( II ), diisobutyl phthalate( III ), 1-phenyl-ethane-1, 2-diol( IV ), 2-hydrox-gamma-benzaldehyde( V ), diethyleneglycol monobenzoate( VI ), uracil( VII ), thymine( VIII ) and thymidine( IX ).

CONCLUSIONAll these compounds were obtained from this genus for the first time, N-phenyl-2-naphthalenamine and diethyleneglycol monobenzoate were first reported from the marine organisms. Compound I and VII showed moderate activity against KB cell(IC50 10.15 microg x mL(-1) for I and 3.79 microg x mL(-1) for VII ) and MCF-7 cell(IC50 3.24 microg x mL(-1) for VII).

1-Naphthylamine ; analogs & derivatives ; chemistry ; isolation & purification ; Chlorophyta ; chemistry ; Crystallization ; Humans ; KB Cells ; drug effects ; Uracil ; chemistry ; isolation & purification ; pharmacology

OBJECTIVETo explore the feasibility of single photon emission computed tomography (SPECT) detection of heart reporter gene expression and observed the optimal transfecting titer and imaging time by using herpes simplex virus 1-thymidine kinase (HSV1-tk) as reporter gene and 131I-2'-fluoro-2'-deoxy-1-beta-D-arabinofuranosyl-5-iodouracil (131I-FIAU) as reporter probe in rabbit myocardium.

METHODSThe recombinant Ad-tk carrying HSV1-tk gene and adenovirus (Ad) as vector was constructed and intramyocardially injected to rabbits at various concentrations (1 x 10(9) pfu, 5 x 10(8) pfu, 1 x 10(8) pfu, 5 x 10(7) pfu, 1 x 10(7) pfu). Two days later, rabbits were injected with 600 microCi 131I-FIAU in ear-margin vein and then underwent SPECT myocardium imaging for detection of HSV1-tk expression at 6 h, 24 h, 48 h and 72 h after injection, rabbits with 1 x 10(9) pfu Ad-tk injection were imaged at 96 h and 120 h. Rabbits were sacrificed after imaging and the total myocardial 131I-FIAU accumulation was quantified in percent of injected dose per gram myocardium (% ID/g). The myocardial Ad-tk expression was determined with RT-PCR.

RESULTSReporter gene was detected by SPECT imaging in the injection site while not detected in the control myocardium and site remote from injection. RT-PCR results also evidenced HSV1-tk express in the injection site. The SPECT target/nontarget ratio was correlated with ex vivo gamma-counting (r2 = 0.933, P<0.01) and expression of HSV1-tk (r2 = 0.877, P<0.01). Myocardial accumulation could be identified at viral titers as low as 1 x 10(7) pfu by SPECT imaging.

CONCLUSIONThe cardiac SPECT reporter gene imaging with HSV1-tk as reporter gene and 131I-FIAU as reporter probe is feasible.

Animals ; Female ; Gene Expression ; Gene Transfer Techniques ; Genes, Reporter ; Heart ; diagnostic imaging ; Male ; Myocardium ; metabolism ; Rabbits ; Thymidine Kinase ; genetics ; Tomography, Emission-Computed, Single-Photon ; Transfection ; Uracil ; analogs & derivatives

OBJECTIVETo investigate the chemical constituents of Hemistepta lyrata.

METHODThe constituents of the EtOAc-soluble portions of the 95% ethanol extract were isolated and purified by means of chromatography. Compounds were identified by their physical characteristics and spectral features.

RESULTFive compounds were isolated and identified as caffeic acid (1), tracheloside (2), uracil (3), 8-carboxymethyl-p-hydroxycinnamic acid (4), and 3-O-p-coumaroylquinic acid (5).

CONCLUSIONCompounds 1-5 were isolated from this genus for the first time.

4-Butyrolactone ; analogs & derivatives ; chemistry ; isolation & purification ; Asteraceae ; chemistry ; Caffeic Acids ; chemistry ; isolation & purification ; Glucosides ; chemistry ; isolation & purification ; Plants, Medicinal ; chemistry ; Uracil ; chemistry ; isolation & purification

The primary objective of this study was to compare thepharmacokinetics of a new anti-human immunodeficiencyvirus agent 1-(2-amino-pyridin-4-ylmethyl)-6-(3,5-dimethyl-benzoyl)-5-isopropyl-1H-pyrimidine-2,4-dione (VP-0502)with its amino acid prodrug alanine amide of VP-0502(VP-0502AL), following intravenous and oral administrationsto rats. The plasma concentrations of both analytes wereanalyzed via high-performance liquid chromatographycoupled with photodiode-array detection (HPLC-DAD).When VP-0502 was intravenously administered at 20mg/kg, the analyte appeared in low levels with an AUC of 0.3microg.h/ml, and C0 of 0.2microg/ml in plasma. However, boththe prodrug VP-0502AL and its metabolite VP-0502 appearedat comparatively higher levels following intravenousinjection of VP-0502AL at the same dose. VP-0502AL'spharmacokinetic parameters were Vd: 4.6 l/kg; AUC:3microg.h/ml; t1/2: 0.5h; C0: 6microg/ml; CLtot: 7l/h/kg; andMRT: 0.6h. Following oral administration of VP-0502(100mg/kg), it was not detectable in plasma (<50ng/ml),while after the oral administration of VP-0502AL, VP-0502 was quantitatively detected as an active metabolite forthe first 7h, with a maximum plasma concentration(Cmax) of 0.8microg/ml, and an area under the concentration-time curve (AUC) of 2microg.h/ml. The oral pharmacokineticparameters of VP-0502AL were calculated to be: maximumconcentration time (tmax) 2.7h; Cmax 0.2microg/ml; eliminationhalf-life (t1/2): 0.8h; and AUC 0.5microg.h/ml. Overall thefindings indicate that VP-0502AL has a favorable pharmaco-kinetic profile as a prodrug with rapid transformationinto the active metabolite, and that the attachment of theamino acid alanine to VP-0502 is an effective approach toimprove its oral bioavailability. VP-0502AL is predictedto become a new highly bioavailable anti-AIDS drugcandidate and/or lead compound.
Administration, Oral ; Alanine/*analogs & derivatives/pharmacokinetics ; Aminopyridines/*pharmacokinetics ; Animals ; Anti-HIV Agents/administration & dosage/blood/*pharmacokinetics ; Area Under Curve ; Biological Availability ; Half-Life ; Injections, Intravenous ; Male ; Prodrugs/administration & dosage/*pharmacokinetics ; Rats ; Rats, Sprague-Dawley ; Uracil/*analogs & derivatives/pharmacokinetics

AIMTo establish a HPLC method for determining five major metabolites of caffeine in the urine, 5-acetylamino-6-formylamino-3-methyluracil (AFMU), 1-methylxanthine (1X), 1-methyluric acid (1U), 1,7-dimethyluric acid (17U) and 1,7-dimethylxanthine (17X) and assess the activity of cytochrome P-450 CYP2A6.

METHODSThe contents of five major metabolites of caffeine in the urine were determined by RP-HPLC method. Frequency distribution histogram was drawn by calculating the 17U/(AFMU + 1X + 1U + 17X + 17U) and then evaluated the activity of CYP2A6.

RESULTSThe frequency distribution histograms of CYP2A6 approximately indicated three distinct groups, the cut of point is 0.23 between fast metabolizer and intermediate type. And the cut of point is 0.15 between slow metabolizer and intermediate type.

CONCLUSIONThe method is simple and rapid, suitable for the determination of metabolites of caffeine in urine. The method can be used to assay the activity of CYP2A6.

Adult ; Aryl Hydrocarbon Hydroxylases ; metabolism ; Caffeine ; metabolism ; urine ; Chromatography, High Pressure Liquid ; methods ; Cytochrome P-450 CYP2A6 ; Female ; Humans ; Male ; Mixed Function Oxygenases ; metabolism ; Theophylline ; urine ; Uracil ; analogs & derivatives ; urine ; Uric Acid ; analogs & derivatives ; urine ; Xanthines ; urine

Benzylacyclouridines were developed as specific and potent competitive inhibitors of uridine phosphorylase with Ki values in the nanomolar range. These compounds have no activity against thymidine phosphorylase, uridine kinase, thymidine kinase and orotate phosphoribosyltransferase. Benzylacyclouridines potentiate the chemotherapeutic effect of FdUrd. Coadministration of uridine phosphorylase inhibitor with FdUrd caused selective toxicity against tumors with low or no thymidine phosphorylase, but not against the host tissues which have thymidine phosphorylase, and thus retain the capacity to cleave FdUrd, and hence overcome its toxicity. There are distinct differences between uridine phosphorylase and thymidine phosphorylase. Benzylacyclouridines competitively inhibit the nucleoside transport of mammalian cells. The structure-activity relationship of inhibitors of uridine phosphorylase showed that a large hydrophobic pocket exists where C-5 of uracil binds, and that it is necessary to have the 3'-hydroxyl group and syn-configuration around the N-glycosidic bond for the nucleosides or their analogs to bind. Dihydrouracil dehydrogenase was found to be widely distributed among mammalian cells, where it was previously believed to be present only in the liver and the kidney. The structure-activity relationship of its inhibitors revealed benzyloxybenzyluracil and 2,6-pyridinediol as most potent. Also identified for orotate phosphoribosyltransferase was 2,4-pyridinediol.
Human ; Neoplasms/drug therapy ; Pentosyltransferases/*antagonists and inhibitors ; Pyrimidines/*metabolism ; Structure-Activity Relationship ; Support, Non-U.S. Gov't ; Support, U.S. Gov't, P.H.S. ; Thymidine Phosphorylase/antagonists and inhibitors ; Uracil/*analogs and derivatives/chemical synthesis/metabolism ; Uridine Phosphorylase/*antagonists and inhibitors

Benzylacyclouridines were developed as specific and potent competitive inhibitors of uridine phosphorylase with Ki values in the nanomolar range. These compounds have no activity against thymidine phosphorylase, uridine kinase, thymidine kinase and orotate phosphoribosyltransferase. Benzylacyclouridines potentiate the chemotherapeutic effect of FdUrd. Coadministration of uridine phosphorylase inhibitor with FdUrd caused selective toxicity against tumors with low or no thymidine phosphorylase, but not against the host tissues which have thymidine phosphorylase, and thus retain the capacity to cleave FdUrd, and hence overcome its toxicity. There are distinct differences between uridine phosphorylase and thymidine phosphorylase. Benzylacyclouridines competitively inhibit the nucleoside transport of mammalian cells. The structure-activity relationship of inhibitors of uridine phosphorylase showed that a large hydrophobic pocket exists where C-5 of uracil binds, and that it is necessary to have the 3'-hydroxyl group and syn-configuration around the N-glycosidic bond for the nucleosides or their analogs to bind. Dihydrouracil dehydrogenase was found to be widely distributed among mammalian cells, where it was previously believed to be present only in the liver and the kidney. The structure-activity relationship of its inhibitors revealed benzyloxybenzyluracil and 2,6-pyridinediol as most potent. Also identified for orotate phosphoribosyltransferase was 2,4-pyridinediol.
Human ; Neoplasms/drug therapy ; Pentosyltransferases/*antagonists and inhibitors ; Pyrimidines/*metabolism ; Structure-Activity Relationship ; Support, Non-U.S. Gov't ; Support, U.S. Gov't, P.H.S. ; Thymidine Phosphorylase/antagonists and inhibitors ; Uracil/*analogs and derivatives/chemical synthesis/metabolism ; Uridine Phosphorylase/*antagonists and inhibitors

OBJECTIVETo study the chemical constituents from the seeds of Notopterygium franchetii.

METHODEthanol extracts of seeds N. franchetii were separated and purified by such methods as normal and reversed phase column chromatographies and thin-layer chromatography and structurally elucidated by MS and NMR evidences.

RESULTTwenty nine compounds were separated, they were isoimperatorin (1), [3-sitosterol (2), phellopterin (3), bergapten (4), N-tetra, hexa, octacosanoylanthranilic acid (5-7), daucosterol (8), oxypeucedanin hydrate (9), umbelliferone (10), demethylfuropinnarin (11), (2S, 3S, 4R, 8E)-2-[(2'R)- 2'-hydroxydoco, trico, tetraco, entaco, hexaco sanosylamino] -octadecene-1, 3, 4-triol (12-16), (-)-oxypeucedanin (17), diosmetin (18), bergaptol-O-beta-D-glucopyranoside (19), nodakenin (20), 1'-O-beta-D-glucopyranosyl-(2R, 3S)-3-hydroxynodakenetin (21), uracil (22), decuroside V (23), 8-O-beta-D-glucopyranosyl-5-hydroxypsoralen (24), 8-O-beta-D-glucopyranosyl-5-methoxylpsoralen (25), diosmin (26), alaschanioside C (27), kynurenic acid (28) and mannitol (29).

CONCLUSIONAll of these compounds were separated from the seeds of N. franchetii for the first time. Of them, 18, 22, 26 and 29 were firstly obtained from genus Notopterygium.

Apiaceae ; chemistry ; Chromatography, Thin Layer ; Coumarins ; chemistry ; Diosmin ; chemistry ; Flavonoids ; chemistry ; Furocoumarins ; chemistry ; Glucosides ; chemistry ; Kynurenic Acid ; chemistry ; Magnetic Resonance Spectroscopy ; Mannitol ; chemistry ; Methoxsalen ; analogs & derivatives ; chemistry ; Seeds ; chemistry ; Sitosterols ; chemistry ; Uracil ; chemistry

Though all the marketed drugs of dipeptidyl peptidase IV inhibitors are structurally different, their inherent correlation is worthy of further investigation. Herein we rapidly discovered a novel DPP-IV inhibitor 8g (IC50 = 4.9 nmol.L-1) which exhibits as good activity and selectivity as the market drugs through scaffold hopping and drug splicing strategies based on alogliptin and linagliptin. This study demonstrated that the employment of classic medicinal chemistry strategy to the marketed drugs with specific target is an efficient approach to discover novel bioactive molecules.
Dipeptidyl-Peptidase IV Inhibitors ; chemical synthesis ; chemistry ; Drug Design ; Drug Discovery ; methods ; Humans ; Hypoglycemic Agents ; chemical synthesis ; chemistry ; Linagliptin ; chemical synthesis ; chemistry ; Molecular Structure ; Piperidines ; chemical synthesis ; chemistry ; Structure-Activity Relationship ; Uracil ; analogs & derivatives ; chemical synthesis ; chemistry