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1.
Angew Chem Int Ed Engl ; 56(45): 14102-14106, 2017 11 06.
Article in English | MEDLINE | ID: mdl-29024282

ABSTRACT

An effective [3+2] annulation tactic for the construction of diverse bicyclic compounds possessing highly functionalized cyclopentane rings has been developed employing soft ketone enolates as the initial nucleophile for anion relay chemistry (ARC). The protocol entails a highly diastereoselective aldol/Brook rearrangement/cyclization cascade.


Subject(s)
Aldehydes/chemistry , Anions/chemistry , Cyclization , Ketones/chemistry , Proton Magnetic Resonance Spectroscopy , Stereoisomerism
2.
Acta Neuropathol Commun ; 4(1): 106, 2016 Sep 29.
Article in English | MEDLINE | ID: mdl-27687527

ABSTRACT

Neurodegenerative disorders referred to as tauopathies, which includes Alzheimer's disease (AD), are characterized by insoluble deposits of the tau protein within neuron cell bodies and dendritic processes in the brain. Tau is normally associated with microtubules (MTs) in axons, where it provides MT stabilization and may modulate axonal transport. However, tau becomes hyperphosphorylated and dissociates from MTs in tauopathies, with evidence of reduced MT stability and defective axonal transport. This has led to the hypothesis that MT-stabilizing drugs may have potential for the treatment of tauopathies. Prior studies demonstrated that the brain-penetrant MT-stabilizing drug, epothilone D, had salutary effects in transgenic (Tg) mouse models of tauopathy, improving MT density and axonal transport, while reducing axonal dystrophy. Moreover, epothilone D enhanced cognitive performance and decreased hippocampal neuron loss, with evidence of reduced tau pathology. To date, epothilone D has been the only non-peptide small molecule MT-stabilizing agent to be evaluated in Tg tau mice. Herein, we demonstrate the efficacy of another small molecule brain-penetrant MT-stabilizing agent, dictyostatin, in the PS19 tau Tg mouse model. Although dictyostatin was poorly tolerated at once-weekly doses of 1 mg/kg or 0.3 mg/kg, likely due to gastrointestinal (GI) complications, a dictyostatin dose of 0.1 mg/kg was better tolerated, such that the majority of 6-month old PS19 mice, which harbor a moderate level of brain tau pathology, completed a 3-month dosing study without evidence of significant body weight loss. Importantly, as previously observed with epothilone D, the dictyostatin-treated PS19 mice displayed improved MT density and reduced axonal dystrophy, with a reduction of tau pathology and a trend toward increased hippocampal neuron survival relative to vehicle-treated PS19 mice. Thus, despite evidence of dose-limiting peripheral side effects, the observed positive brain outcomes in dictyostatin-treated aged PS19 mice reinforces the concept that MT-stabilizing compounds have significant potential for the treatment of tauopathies.

3.
Org Lett ; 17(17): 4232-5, 2015 Sep 04.
Article in English | MEDLINE | ID: mdl-26291547

ABSTRACT

A total synthesis of (-)-secu'amamine A has been achieved exploiting Type II Anion Relay Chemistry (ARC) to provide the full linear carbon and nitrogen skeleton in a single flask with the requisite stereochemistry and functionality. A mechanistic rationale is also proposed to account for the stereochemical outcome of the key aldol reaction leading to the advanced aza tricyclic core.


Subject(s)
Alkaloids/chemical synthesis , Heterocyclic Compounds, Bridged-Ring/chemical synthesis , Alkaloids/chemistry , Euphorbiaceae/chemistry , Heterocyclic Compounds, Bridged-Ring/chemistry , Stereoisomerism
4.
Org Lett ; 13(13): 3328-31, 2011 Jul 01.
Article in English | MEDLINE | ID: mdl-21644563

ABSTRACT

An effective, general protocol for the Diversity-Oriented Synthesis (DOS) of 2,4,6-trisubstituted piperidine congeners has been designed and validated. The successful strategy entails a modular approach to all possible stereoisomers of the selected piperidine scaffold, exploiting Type II Anion Relay Chemistry (ARC), followed in turn by intramolecular S(N)2 cyclization, chemoselective removal of the dithiane moieties and carbonyl reductions.


Subject(s)
Piperidines/chemical synthesis , Anions/chemistry , Cyclization , Ketones/chemistry , Models, Molecular , Molecular Structure , Oxidation-Reduction , Stereoisomerism
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