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1.
J Org Chem ; 75(15): 5083-91, 2010 Aug 06.
Article in English | MEDLINE | ID: mdl-20604518

ABSTRACT

A method that allows for the reduction of protected hydroperoxides by employing catalytic amounts of phosphine is presented. The combination of a titanium(IV) alkoxide and a siloxane allowed for the chemoselective reduction of phosphine oxides in the presence of alkyl silyl peroxides. Subsequent reduction of the peroxide moiety by phosphine provided the corresponding silylated alcohols in useful yields. Mechanistic experiments, including crossover experiments, support a mechanism in which the peroxide group was reduced and the silyl group was transferred in a concerted step. Labeling studies with (17)O-labeled peroxides demonstrate that the oxygen atom adjacent to the silicon atom is removed from the silyl peroxide.


Subject(s)
Peroxides/chemistry , Phosphines/chemistry , Titanium/chemistry , Catalysis , Electron Spin Resonance Spectroscopy , Indicators and Reagents/chemistry , Magnetic Resonance Spectroscopy , Mass Spectrometry , Oxidation-Reduction , Spectrophotometry, Infrared
2.
Org Lett ; 11(15): 3290-3, 2009 Aug 06.
Article in English | MEDLINE | ID: mdl-19555089

ABSTRACT

The cyclization of gamma,delta-unsaturated tertiary hydroperoxides in the presence of a palladium(II) catalyst afforded 1,2-dioxanes resembling biologically active natural products. A variety of substrates were screened, and synthetic manipulations were accomplished to construct compounds with structural similarity to antimalarial targets.


Subject(s)
Antimalarials/chemical synthesis , Dioxanes/chemical synthesis , Hydrogen Peroxide/chemistry , Palladium/chemistry , Antimalarials/chemistry , Catalysis , Cyclization , Dioxanes/chemistry , Drug Design
3.
Bioorg Med Chem Lett ; 19(13): 3637-41, 2009 Jul 01.
Article in English | MEDLINE | ID: mdl-19447623

ABSTRACT

The importance of internal hydrogen bonding in a series of benzothiadiazine and 1,4-benzothiazine NS5b inhibitors has been explored. Computational analysis has been used to compare the protonated vs. anionic forms of each series and we demonstrate that activity against HCV NS5b polymerase is best explained using the anionic forms. The syntheses and structure-activity relationships for a variety of new analogs are also discussed.


Subject(s)
Antiviral Agents/chemical synthesis , Benzothiadiazines/chemical synthesis , DNA-Directed RNA Polymerases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Hepacivirus/drug effects , Thiazines/chemical synthesis , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Benzothiadiazines/chemistry , Benzothiadiazines/pharmacology , Computational Biology , Computer Simulation , Crystallography, X-Ray , DNA-Directed RNA Polymerases/metabolism , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Protein Binding , Structure-Activity Relationship , Thiazines/chemistry , Thiazines/pharmacology , Viral Nonstructural Proteins/metabolism , Virus Replication/drug effects
5.
J Med Chem ; 47(25): 6124-7, 2004 Dec 02.
Article in English | MEDLINE | ID: mdl-15566283

ABSTRACT

Two distinct synthetic schemes were applied to access heteroatom-containing alpha-chain lactams or lactams terminated as aryl acids. The latter lactams were devised using a pharmacophore for EP(4) receptor activity. gamma-Lactams were characterized for their prostanoid EP receptor affinities and EP(4) activity and found to be selective for the EP(2) and EP(4) receptors or selective for the EP(4) subtype. Benzoic acid 17 displayed enhanced in vivo exposure relative to 3.


Subject(s)
Benzoates/chemical synthesis , Lactams/chemical synthesis , Pyrrolidines/chemical synthesis , Receptors, Prostaglandin E/agonists , Animals , Benzoates/pharmacokinetics , Benzoates/pharmacology , Blood Proteins/metabolism , Half-Life , Humans , Lactams/pharmacokinetics , Lactams/pharmacology , Models, Molecular , Molecular Conformation , Monte Carlo Method , Oxidation-Reduction , Protein Binding , Pyrrolidines/pharmacokinetics , Pyrrolidines/pharmacology , Rats , Receptors, Prostaglandin E/metabolism , Receptors, Prostaglandin E, EP2 Subtype , Receptors, Prostaglandin E, EP4 Subtype , Structure-Activity Relationship
6.
J Vasc Interv Radiol ; 14(3): 329-33, 2003 Mar.
Article in English | MEDLINE | ID: mdl-12631637

ABSTRACT

PURPOSE: To determine the prevalence of new renal perfusion defects and the association of these events with aneurysm neck atheroma during endovascular stent-graft repair of abdominal aortic aneurysm (AAA). MATERIALS AND METHODS: A retrospective review was performed of 50 patients who underwent AAA repair with bifurcated endovascular stent-grafts without suprarenal components between June 1998 and May 1999. Pre- and postprocedural computed tomographic (CT) angiograms were reviewed to determine the prevalence of new renal perfusion defects. The percent volume of atheroma of the aneurysm neck was determined by three-dimensional volumetric reformation and correlated with prevalence of new postprocedural renal perfusion defects. Follow-up CT angiography was performed between 6 months and 2 years after the procedure and used to evaluate the presence of residual defects and interval changes. RESULTS: Of 50 subjects, 18% (n = 9) had new perfusion defects presumed to be embolic in origin. Follow-up was available for four patients: scarring and cortical thinning consistent with infarction developed in two, whereas the defects resolved in the other two. Analysis of aneurysm neck revealed an average percentage of atheroma of 32% and a range of 0%-73%. In subjects with >/=40% neck atheroma, the prevalence of new renal perfusion defects was 45.4% (five of 11), compared to 10.3% (four of 39) in subjects with <40% neck atheroma. This difference was significant (P =.0170). CONCLUSIONS: In this series, the frequency of renal embolic events associated with AAA endovascular repair was 18%. Prevalence of renal embolic perfusion defects was shown to correlate with volume of aneurysm neck atheroma.


Subject(s)
Aortic Aneurysm, Abdominal/surgery , Blood Vessel Prosthesis , Embolism/etiology , Kidney/blood supply , Stents , Angiography , Female , Follow-Up Studies , Humans , Male , Postoperative Complications , Retrospective Studies , Tomography, X-Ray Computed
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