- Oxidation of Alkynyl Boronates to Carboxylic Acids, Esters, and Amides
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A general efficient protocol was developed for the synthesis of carboxylic acids, esters, and amides through oxidation of alkynyl boronates, generated directly from terminal alkynes. This protocol represents the first example of C(sp)?B bond oxidation. This approach displays a broad substrate scope, including aryl and alkyl alkynes, and exhibits excellent functional group tolerance. Water, primary and secondary alcohols, and amines are suitable nucleophiles for this transformation. Notably, amino acids and peptides can be used as nucleophiles, providing an efficient method for the synthesis and modification of peptides. The practicability of this methodology was further highlighted by the preparation of pharmaceutical molecules.
- Li, Chenchen,Li, Ruoling,Zhang, Bing,Zhao, Pei,Zhao, Wanxiang
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supporting information
p. 10913 - 10917
(2020/05/25)
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- COMPOSITIONS AND METHODS FOR SUBSTRATE-SELECTIVE INHIBITION OF ENDOCANNABINOID OXYGENATION
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Methods for selectively inhibiting endocannabinoid oxygenation but not arachidonic acid oxygenation. In some embodiments, the methods include contacting a COX-2 polypeptide with an effective amount of a substrate-selective COX-2 inhibitor. Also provided are methods for elevating a local endogenous cannabinoid concentrations; methods of reducing depletion of an endogenous cannabinoid; methods for inducing analgesia; methods of providing anxiolytic therapy; methods for providing anti-depressant therapy; and compositions for performing the disclosed methods.
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- New flurbiprofen derivatives: Synthesis, membrane affinity and evaluation of in vitro effect on β-amyloid levels
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Alzheimer′s disease (AD) is characterized by irreversible and progressive loss of memory and cognition and profound neuronal loss. Current therapeutic strategies for the treatment of AD have been directed to a variety of targets with the aim of reversing or preventing the disease but, unfortunately, the available treatments often produce no significant clinical benefits. During the last decades compounds that inhibit or modulate γ-secretase, reducing β amyloid (Aβ) levels, have been considered as potential therapeutics for AD. Among these the (R)-enantiomer of flurbiprofen (FLU) seems to be very promising, but it shows low brain penetration. In this study, in order to improve the properties of FLU against Alzheimer′s pathogenesis we synthesized some novel FLU lipophilic analogues. Lipophilicity of the new molecules has been characterized in terms of clogP, log KC18/W and log K IAM/W values. Permeability has been determined in both gastrointestinal PAMPA (PAMPA-GI) at different pH values and in brain blood barrier PAMPA (PAMPA-BBB) models. They were also tested for their ability to inhibit in vitro γ-secretase activity using rat CTXTNA2 astrocytes. Interestingly, the investigated molecules demonstrated to reduce Aβ 42 levels without affecting the amyloid precursor protein APP level in a clear concentrations-dependent manner.
- Sozio, Piera,Marinelli, Lisa,Cacciatore, Ivana,Fontana, Antonella,Tuerkez, Hasan,Giorgioni, Gianfabio,Ambrosini, Dario,Barbato, Francesco,Grumetto, Lucia,Pacella, Stephanie,Cataldi, Amelia,Di Stefano, Antonio
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p. 10747 - 10767
(2013/10/22)
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- Substrate-selective inhibition of cyclooxygenase-2: Development and evaluation of achiral profen probes
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Cyclooxygenase-2 (COX-2) oxygenates arachidonic acid and the endocannabinoids 2-arachidonoylglycerol (2-AG) and arachidonoylethanolamide (AEA). We recently reported that (R)-profens selectively inhibit endocannabinoid oxygenation but not arachidonic acid oxygenation. In this work, we synthesized achiral derivatives of five profen scaffolds and evaluated them for substrate-selective inhibition using in vitro and cellular assays. The size of the substituents dictated the inhibitory strength of the analogs, with smaller substituents enabling greater potency but less selectivity. Inhibitors based on the flurbiprofen scaffold possessed the greatest potency and selectivity, with desmethylflurbiprofen (3a) exhibiting an IC50 of 0.11 μM for inhibition of 2-AG oxygenation. The crystal structure of desmethylflurbiprofen complexed to mCOX-2 demonstrated a similar binding mode to other profens. Desmethylflurbiprofen exhibited a half-life in mice comparable to that of ibuprofen. The data presented suggest that achiral profens can act as lead molecules toward in vivo probes of substrate-selective COX-2 inhibition.
- Windsor, Matthew A.,Hermanson, Daniel J.,Kingsley, Philip J.,Xu, Shu,Crews, Brenda C.,Ho, Winnie,Keenan, Catherine M.,Banerjee, Surajit,Sharkey, Keith A.,Marnett, Lawrence J.
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p. 759 - 763
(2012/10/29)
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- Inhibition of amyloidogenesis by nonsteroidal anti-inflammatory drugs and their hybrid nitrates
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Poor blood-brain barrier penetration of nonsteroidal anti-inflammatory drugs (NSAIDs) has been blamed for the failure of the selective amyloid lowering agent (SALA) R-flurbiprofen in phase 3 clinical trials for Alzheimer's disease (AD). NO-donor NSAIDs (NO-NSAIDs) provide an alternative, gastric-sparing approach to NSAID SALAs, which may improve bioavailability. NSAID analogues were studied for anti-inflammatory activity and for SALA activity in N2a neuronal cells transfected with human amyloid precursor protein (APP). Flurbiprofen (1) analogues were obtained with enhanced anti-inflammatory and antiamyloidogenic properties compared to 1, however, esterification led to elevated A 1-42 levels. Hybrid nitrate prodrugs possessed superior anti-inflammatory activity and reduced toxicity relative to the parent NSAIDs, including clinical candidate CHF5074. Although hybrid nitrates elevated A 1-42 at higher concentration, SALA activity was observed at low concentrations (1 μM): both A1-42 and the ratio of A 42/A1-40 were lowered. This biphasic SALA activity was attributed to the intact nitrate drug. For several compounds, the selective modulation of amyloidogenesis was tested using an immunoprecipitation MALDI-TOF approach. These data support the development of NO-NSAIDs as an alternative approach toward a clinically useful SALA.
- Schiefer, Isaac T.,Abdul-Hay, Samer,Wang, Huali,Vanni, Michael,Qin, Zhihui,Thatcher, Gregory R. J.
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p. 2293 - 2306
(2011/06/20)
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- Compositions and methods of treating cell proliferation disorders
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The invention relates to compounds and methods for treating cell proliferation disorders.
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Page/Page column 78
(2008/06/13)
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- The superbase approach to flurbiprofen: An exercise in optionally site-selective metalation
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A superior route to the analgesic flurbiprofen has been devised. Key steps are the selective deprotonation of 3-fluorotoluene with tert-butyllithium in the presence of potassium tert-butoxide (LIT-KOR) at the 4-position and the selective deprotonation of the 4-methyl-2-fluorobiphenyl with lithium diisopropylamide in the presence of potassium tert-butoxide (LIDA-KOR) at the benzylic position. Depending on the reagent and the substituent pattern, the 3- and 5-positions of 2-fluorobiphenyls can also be specifically attacked.
- Schlosser, Manfred,Geneste, Herve
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p. 1969 - 1973
(2007/10/03)
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- Therapeutically active phenylalkane derivatives
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2-(2-Fluoro-4-biphenylyl)propan-1-ol, 2-(2'-Fluoro-4-biphenylyl)propan-1-ol and 2-(2,2'-Difluoro-4-biphenylyl)propan-1-ol Possessing great anti-inflammatory, analgesic and antipyretic activities.
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