ABSTRACT
The combined use of two-dimensional NMR correlation experiments and gauge including atomic orbital density functional theory in (13)C NMR chemical shift (CS) calculations allowed reliable and simple structural determination of regioisomeric heterocyclic systems that originate from the reactions of acylquinolinones with substituted hydrazines. Moreover, the results of differential analysis between the calculated (15)N NMR CSs for hypothetical structures and the experimental data of the title azaheterocyclic systems were even more advantageous with respect to (13)C because there was no need for correlational analysis: structures of the regioisomeric compounds could be determined just by direct comparison.
Subject(s)
Pyrazoles/chemistry , Carbon Isotopes , Computer Simulation , Magnetic Resonance Spectroscopy/standards , Molecular Structure , Nitrogen Isotopes , Reference Standards , StereoisomerismABSTRACT
The synthesis of N-protected glycosyl amino acids from amines has been investigated and it was found that, under microwave conditions, glycosylamines could be hydrolyzed leading to new products containing a glycosyl ester linkage. The efficiency of the microwave-induced glycosylation of aspartic acid was studied comparing the microwave activity between amide and ester bond formation. Different sugar moieties have been employed to demonstrate the simple and reproducible coupling methodology. New glycosyl ester compounds were further characterized by NMR spectroscopy.
Subject(s)
Amines/chemistry , Aspartic Acid/radiation effects , Microwaves , Amines/radiation effects , Glucosamine/analogs & derivatives , Glucosamine/chemistry , Glucosamine/radiation effects , Glycosylation , Nuclear Magnetic Resonance, BiomolecularABSTRACT
New geiparvarin derivatives modified at the unsaturated alkenyloxy bridge, where a hydrogen atom replaces the 3'-methyl group, were synthesized and evaluated against a panel of human tumor cell lines in vitro. These compounds demonstrated an increase in growth inhibitory activity relative to the parent compound, geiparvarin. The activity increased even further in the series of demethylated compounds, with the introduction of a methyl group at the 1'-position of the alkenyloxy chain. In contrast, a remarkable decrease in activity was observed with the introduction of a methyl group at the 2'-position. Interestingly, the new derivatives fully inhibited the growth of drug-resistant cell lines, suggesting that they are not subject to pump-mediated drug efflux. On the basis of their cytotoxic profiles, the most active compounds (R)-4 and (R)-5 were selected for further biological evaluation in comparison with the lead compound. The new derivatives strongly induce apoptosis in a promyelocytic leukemia cell line (HL-60) mediated by depolarization of mitochondrial transmembrane potential and mitochondrial production of reactive oxygen species (ROS).
Subject(s)
4-Butyrolactone/analogs & derivatives , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/toxicity , Coumarins/chemistry , Coumarins/chemical synthesis , Coumarins/toxicity , 4-Butyrolactone/chemical synthesis , 4-Butyrolactone/chemistry , 4-Butyrolactone/toxicity , Antineoplastic Agents/chemistry , Cell Line, Tumor , Coumarins/pharmacology , Drug Resistance, Neoplasm/drug effects , Drug Screening Assays, Antitumor , Humans , Reactive Oxygen Species/metabolismABSTRACT
Reaction of 6-acetyl-7-(2-dimethylaminovinyl)pyrazolo[1,5-a]pyrimidine 1 with 1,3- and 1,4-bisnucleophiles has been investigated; obtainment of new polycyclic heterocyclic derivatives is reported. A convenient procedure leading to new pyrazolo[1,5-a]quinazolines is described; a modest bioactivity of these compounds against two human tumor cell lines was also ascertained.
Subject(s)
Pyrimidines/chemistry , Pyrimidines/chemical synthesis , Cell Proliferation/drug effects , Electrons , Humans , Jurkat Cells , Polycyclic Compounds/chemical synthesis , Pyrimidines/pharmacology , Structure-Activity RelationshipABSTRACT
Dehydrocholic acid (DHCA), an unnatural bile acid, is manufactured by oxidation of cholic acid. Its biotransformation by two basidiomycetes (Trametes hirsuta and Collybia velutipes) is reported. These mycelia showed different affinities for the substrate and selectivities of attack: T. hirsuta in particular regio- and stereoselectively reduced the 3-keto group to yield 3 alpha-hydroxy-7,12-diketo-5 beta-cholan-24-oic acid (7,12-diketolithocolic acid) as the main product. A number of different chemical reductions were carried out on DHCA; among them hydrogenation with Raney Nickel in water under high-intensity ultrasound proved highly regio- and stereoselective, yielding 7,12-diketolithocolic acid exclusively. (1)H and (13)C resonances were assigned in details thanks to a series of 1D and 2D NMR runs including DEPT, NOESY, H-H COSY, gHSQC and gHMBC.
Subject(s)
Basidiomycota/metabolism , Dehydrocholic Acid/metabolism , Biotransformation , Hydrogenation , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Oxidation-Reduction , Species Specificity , Substrate Specificity , Ultrasonics , Water/chemistryABSTRACT
A few naturally occurring prenyl- and prenyloxycoumarins and several new related synthetic derivatives were evaluated as inhibitors of squalene-hopene cyclase (SHC), a useful model enzyme, to predict their interactions with oxidosqualene cyclase (OSC). Umbelliprenin-10',11'-monoepoxide (IC(50) 2.5 microM) and the corresponding 6',7'-10',11' diepoxide (IC(50) 1.5 microM) were the most active enzyme inhibitors.
Subject(s)
Coumarins/classification , Coumarins/pharmacology , Enzyme Inhibitors/classification , Enzyme Inhibitors/pharmacology , Intramolecular Transferases/antagonists & inhibitors , Bacillaceae/enzymology , Coumarins/chemical synthesis , Enzyme Activation/drug effects , Enzyme Inhibitors/chemical synthesis , Humans , Molecular Structure , Structure-Activity RelationshipABSTRACT
A series of geiparvarin analogues modified on the unsaturated alkenyloxy bridge, where a H-atom replaced the 3'-Me group, were synthesized and evaluated against a panel of human tumor cell lines in vitro. These compounds demonstrated a stronger increase in growth inhibitory activity when compared to the parent compound geiparvarin (8). In particular, the activity increased even further in the series of demethylated compounds when a Me substituent in the coumarin moiety is introduced. On the contrary, the same modifications exerted on the parent compound led to an activity reduction. Interestingly, the new derivatives proved to be fully inhibitory to drug-resistant cell lines, thus suggesting that they are not subject to the pump-mediating efflux of antitumor drugs. On the basis of their cytotoxic profiles, the most-active compounds were selected for further biological evaluation. The extracellular acidification rate by the new geiparvarin analogues was measured with the Cytosensor microphysiometer. The new derivatives significantly increased the acidification rate during the 24-48 h of incubation in a concentration-dependent manner. Cell-cycle analysis, evaluated by flow cytometry, revealed a strong apoptotic induction by these compounds confirmed by DNA laddering and observation by electron microscopy. Interestingly, the apoptotic pathway did not appear to be mediated by the activation of caspase-3.
Subject(s)
Apoptosis/drug effects , Coumarins/chemical synthesis , Coumarins/toxicity , Apoptosis/physiology , Cell Line, Tumor , Cell Survival/drug effects , Cell Survival/physiology , Drug Screening Assays, Antitumor/methods , HL-60 Cells , HumansABSTRACT
Natural geiparvarin 1 and a number of its analogues were prepared and tested as inhibitors of both monoamine oxidase isoforms, MAO-B and MAO-A. The desmethyl congener 6 of geiparvarin, proved potent and selective MAO-B inhibitor (pIC(50)=7.55 vs 4.62). X-ray crystallography and molecular modelling studies helped the understanding of the observed structure-activity relationships.
