ABSTRACT
On our joint bioprospecting research on Indonesian marine invertebrates, we found moderate cytotoxicity on an extract of the sponge Dysidea sp. collected at Biak, West Papua. Separation of the extract provided two new compounds, biaketide (1) and debromoantazirine (2), along with four known molecules 3-6. The new structures were elucidated by spectroscopic analyses and by comparison with those reported. Compounds 1 and 2 showed moderate cytotoxicity against NBT-T2 cells with IC50 values of 8.3 and 4.7 µg ml(- 1), respectively.
Subject(s)
Antineoplastic Agents/isolation & purification , Azirines/isolation & purification , Dysidea/chemistry , Furans/isolation & purification , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Azirines/chemistry , Azirines/pharmacology , Drug Screening Assays, Antitumor , Furans/chemistry , Furans/pharmacology , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , RatsABSTRACT
A photostability study of Valsartan (VAL) is reported. Exposure of the drug to UV-vis radiation (λ > 320 nm) yielded two previously unknown compounds, which were detected by HPLC. Preparative amounts of the new potential degradation products (DP-1 and DP-2) were obtained by submitting VAL bulk drug to extensive photodegradation. The impurities were isolated by preparative normal phase column chromatography. Analytical information from the infrared, nuclear magnetic resonance and mass spectral data of the degradation products revealed their structures as N-[2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-N-isobutylpentanamide (DP-1) and N-(diazirino[1,3-f]phenanthridin-4-ylmethyl)-N-isobutylpentanamide (DP-2). DP-1 arose from decarboxylation of VAL, while DP-2 results from further loss of nitrogen from the tetrazole motif of DP-1, with concomitant cyclization to yield a tetracyclic diazacyclopropene derivative.
Subject(s)
Angiotensin II Type 1 Receptor Blockers/chemistry , Azirines/isolation & purification , Drug Contamination , Phenanthridines/isolation & purification , Photolysis , Tetrazoles/chemistry , Tetrazoles/isolation & purification , Valine/analogs & derivatives , Angiotensin II Type 1 Receptor Blockers/radiation effects , Angiotensin II Type 1 Receptor Blockers/standards , Chromatography, High Pressure Liquid/instrumentation , Chromatography, High Pressure Liquid/methods , Drug Stability , Magnetic Resonance Spectroscopy/instrumentation , Magnetic Resonance Spectroscopy/methods , Molecular Structure , Spectroscopy, Fourier Transform Infrared/instrumentation , Spectroscopy, Fourier Transform Infrared/methods , Tetrazoles/radiation effects , Tetrazoles/standards , Valine/chemistry , Valine/radiation effects , Valine/standards , ValsartanABSTRACT
Three new omega-halogenated long-chain 2H-azirines were isolated from the sponge Dysidea fragilis. Their structures revealed heterogeneity in both the composition of the terminal 1,1-dihalo-vinyl group and enantiomeric ratios at C2 of the azirine-2-carboxylate ester terminus. Azirine-2-carboxylate esters were shown to racemize spontaneously. A hypothesis is proposed for the biosynthesis of the azirinecarboxylate family of natural products that involves enzyme-catalyzed free radical halogenation followed by elimination of hydrohalic acid.
Subject(s)
Azirines/chemistry , Biological Factors/chemistry , Dysidea/chemistry , Animals , Apoptosis/drug effects , Azirines/isolation & purification , Azirines/pharmacology , Biological Factors/isolation & purification , Biological Factors/pharmacology , Cell Line, Tumor , Drug Screening Assays, Antitumor , Halogenation , Humans , Microbial Sensitivity Tests , Molecular Structure , StereoisomerismABSTRACT
Interleukin 1 is the prototype of an inflammatory cytokine, and evidence suggests that it uses the sphingomyelin pathway and ceramide production to trigger mitogen-activated protein kinase (MAPK) activation and subsequent gene expression required for acute inflammatory processes. To identify downstream signaling targets of ceramide, a radioiodinated photoaffinity labeling analog of ceramide ([125I] 3-trifluoromethyl-3-(m-iodophenyl)diazirine-ceramide) was employed. It is observed that ceramide specifically binds to and activates protein kinase c-Raf, leading to a subsequent activation of the MAPK cascade. Ceramide does not bind to any other member of the MAPK module nor does it bind to protein kinase C-zeta. These data identify protein kinase c-Raf as a specific molecular target for interleukin 1 beta-stimulated ceramide formation and demonstrate that ceramide is a lipid cofactor participating in regulation of c-Raf activity.
Subject(s)
Azirines/metabolism , Ceramides/metabolism , Ceramides/pharmacology , Glomerular Mesangium/metabolism , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins/metabolism , Affinity Labels , Animals , Azirines/isolation & purification , Binding Sites , Calcium-Calmodulin-Dependent Protein Kinases/metabolism , Cells, Cultured , Ceramides/isolation & purification , Enzyme Activation , Interleukin-1/pharmacology , Kinetics , Protein Serine-Threonine Kinases/isolation & purification , Proto-Oncogene Proteins/isolation & purification , Proto-Oncogene Proteins c-raf , RatsABSTRACT
The sponge Dysidea fragilis from Pohnpei contained four azacyclopropene derivatives, (4E)-S-dysidazirine [2], which is the optical enantiomer of the known compound dysidazirine [1], (4Z)-dysidazirine [3], (4E)-S-antazirine [4], and (4Z)-antazirine [5]. The structures of the new compounds were elucidated by interpretation of spectral data.