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ABSTRACT: Rings beget rings: Benzazepines, well-known structural design elements in medicinal chemistry, are readily prepared by a one-pot palladium-catalyzed oxidative cycloaddition of isatins with various alkynes.
Angewandte Chemie International Edition 12/2012; · 13.45 Impact Factor
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ABSTRACT: 3,4-Dihydrocoumarins, considered to be valuable building blocks, have attracted considerable attention due to their various biological activities. Herein, we have documented an efficient and convenient double decarboxylation process for the synthesis of 4-substituted 3,4-dihydrocoumarin in moderate to excellent yields under mild reaction conditions (up to 98%).
Organic & Biomolecular Chemistry 04/2012; 10(13):2537-41. · 3.70 Impact Factor
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ABSTRACT: An enamine-catalyzed strategy has been utilized to fully promote the Huisgen [3+2] cycloaddition with a broad spectrum of carbonyl compounds and azides, thereby permitting the efficient assembly of a vast pool of highly substituted 1,2,3-triazoles. In particular, the employment of commonly used and commercially available carbonyl compounds has resulted in the introduction of a diverse set of functional groups, such as alkyl, aryl, nitrile, ester, and ketone groups, at the 1-, 4-, or 5-positions of the 1,2,3-triazole scaffold. This approach might be manipulated to access more useful and sophisticated heterocyclic compounds. Most significantly, the reaction process exhibits complete regioselectivity, with the formation of only one regioisomer.
Chemistry 03/2012; 18(19):6088-93. · 5.93 Impact Factor
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ABSTRACT: The diarylalkenyl propargylic complex framework has been found in many natural products and medicinal regents. Herein, we have disclosed an unprecedented FeCl(3) catalyzed ene-type reaction of propargylic alcohols with 1,1-diaryl alkenes which enabled us to furnish a diarylalkenyl propargylic complex framework in moderate to high chemical yields (up to 98%).
Organic & Biomolecular Chemistry 01/2012; 10(2):225-8. · 3.70 Impact Factor
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ABSTRACT: The coupling of coumarins with alkynes is described, which proceeds through a palladium-catalyzed cascade sequence. This process provides a new route to the synthesis of highly substituted cyclopentadiene fused chromones.
Chemical Communications 03/2011; 47(19):5422-4. · 6.17 Impact Factor
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ABSTRACT: The TgCRND8 mouse model of Alzheimer's disease exhibits progressive cortical and hippocampal β-amyloid accumulation, resulting in plaque pathology and spatial memory impairment by 3 months of age. We tested whether TgCRND8 cognitive function is disrupted prior to the appearance of macroscopic plaques in an object recognition task. We found profound deficits in 8-week-old mice. Animals this age were not impaired on the Morris water maze task. TgCRND8 and littermate controls did not differ in their duration of object exploration or optokinetic responses. Thus, visual and motor dysfunction did not confound the phenotype. Object memory deficits point to the frontal cortex and hippocampus as early targets of functional disruption. Indeed, we observed altered levels of brain-derived neurotrophic factor (BDNF) messenger ribonucleic acid (mRNA) in these brain regions of preplaque TgCRND8 mice. Our findings suggest that object recognition provides an early index of cognitive impairment associated with amyloid exposure and reduced brain-derived neurotrophic factor expression in the TgCRND8 mouse.
Neurobiology of aging 05/2010; 33(3):555-63. · 5.94 Impact Factor
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ABSTRACT: Downregulation of brain-derived neurotrophic factor (BDNF) in the cortex occurs early in the progression of Alzheimer's disease (AD). Since BDNF plays a critical role in neuronal survival, synaptic plasticity, and memory, BDNF reduction may contribute to synaptic and cellular loss and memory deficits characteristic of AD. In vitro evidence suggests that amyloid-beta (A beta) contributes to BDNF downregulation in AD, but the specific A beta aggregation state responsible for this downregulation in vivo is unknown. In the present study, we examined cortical levels of BDNF mRNA in three different transgenic AD mouse models harboring mutations in APP resulting in A beta overproduction, and in a genetic mouse model of Down syndrome. Two of the three A beta transgenic strains (APP(NLh) and TgCRND8) exhibited significantly decreased cortical BDNF mRNA levels compared with wild-type mice, whereas neither the other strain (APP(swe)/PS-1) nor the Down syndrome mouse model (Ts65Dn) was affected. Only APP(NLh) and TgCRND8 mice expressed high A beta(42)/A beta(40) ratios and larger SDS-stable A beta oligomers (approximately 115 kDa). TgCRND8 mice exhibited downregulation of BDNF transcripts III and IV; transcript IV is also downregulated in AD. Furthermore, in all transgenic mouse strains, there was a correlation between levels of large oligomers, A beta(42)/A beta(40), and severity of BDNF decrease. These data show that the amount and species of A beta vary among transgenic mouse models of AD and are negatively correlated with BDNF levels. These findings also suggest that the effect of A beta on decreased BDNF expression is specific to the aggregation state of A beta and is dependent on large oligomers.
Journal of Neuroscience 08/2009; 29(29):9321-9. · 7.11 Impact Factor
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ABSTRACT: Brain-derived neurotrophic factor (BDNF) is critical for the function and survival of neurons that degenerate in the late stage of Alzheimer's disease (AD). There are two forms of BDNF, the BDNF precursor (proBDNF) and mature BDNF, in human brain. Previous studies have shown that BDNF mRNA and protein, including proBDNF, are dramatically decreased in end-stage AD brain. To determine whether this BDNF decrease is an early or late event during the progression of cognitive decline, we used western blotting to measure the relative amounts of BDNF proteins in the parietal cortex of subjects clinically classified with no cognitive impairment (NCI), mild cognitive impairment (MCI) or mild to moderate AD. We found that the amount of proBDNF decreased 21 and 30% in MCI and AD groups, respectively, as compared with NCI, consistent with our previous results of a 40% decrease in end-stage AD. Mature BDNF was reduced 34 and 62% in MCI and AD groups, respectively. Thus, the decrease in mature BDNF and proBDNF precedes the decline in choline acetyltransferase activity which occurs later in AD. Both proBDNF and mature BDNF levels were positively correlated with cognitive measures such as the Global Cognitive Score and the Mini Mental State Examination score. These results demonstrate that the reduction of both forms of BDNF occurs early in the course of AD and correlates with loss of cognitive function, suggesting that proBDNF and BDNF play a role in synaptic loss and cellular dysfunction underlying cognitive impairment in AD.
Journal of Neurochemistry 07/2005; 93(6):1412-21. · 4.06 Impact Factor
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ABSTRACT: Nerve growth factor (NGF) is critical for the regulation, differentiation, and survival of basal forebrain cholinergic neurons that degenerate in the late stage of Alzheimer disease (AD). The precursor of NGF (proNGF) is the predominant form of NGF in brain and is increased in end stage AD. To determine whether this increase in proNGF is an early or late change during the progression of cognitive decline, we used Western blotting to measure the relative amounts of proNGF protein in the parietal cortex from subjects clinically classified with no cognitive impairment (NCI; n = 20), mild cognitive impairment (MCI; n = 20), or mild to moderate AD (n = 19). We found that proNGF increased during the prodromal stage of AD. The amount of proNGF protein was 1.4-fold greater in the MCI group as compared to NCI, and was 1.6-fold greater in mild-moderate AD as compared to NCI, similar to our previous findings of a 2-fold increase in end stage AD. There was a negative correlation between proNGF levels and Mini Mental Status Examination (MMSE) score, demonstrating that the accumulation of proNGF is correlated with loss of cognitive function. These findings demonstrate that proNGF levels increase during the preclinical stage of AD and may reflect an early biological marker for the onset of AD.
Journal of Neuropathology and Experimental Neurology 07/2004; 63(6):641-9. · 4.26 Impact Factor
