Preparation of Unsymmetrical Sulfonylureas from N,N′‐Sulfuryldiimidazoles.

Beaudoin, Serge; Kinsey, Kenneth E.; Burns, James F.

doi:10.1002/chin.200319097

Cited by 4 publications

(8 citation statements)

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“…The nitro function was reduced with iron or via catalytic hydrogenation to provide the corresponding amines. Reaction of the amines with appropriate sulfonyl or acyl chlorides or 3-methyl-1-((4-phenylpiperazin-1-yl)sulfonyl)-1 H -imidazol-3-ium provided the penultimate compounds ( 49 ), which were demethylated with BBr 3 followed by purification by trituration or reverse-phase HPLC to afford the target compounds ( 1 – 3 , 9 – 14 , 16 – 23 , 25 – 26 , 28 – 29 , 31 – 38 ) of >95% purity (Tables –). In the case of analogues with an ester side chain, the BBr 3 step provided a convenient way to concomitantly hydrolyze the ester in a single pot.…”

Section: Resultsmentioning

confidence: 99%

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3-Substituted-N-(4-Hydroxynaphthalen-1-yl)arylsulfonamides as a Novel Class of Selective Mcl-1 Inhibitors: Structure-Based Design, Synthesis, SAR, and Biological Evaluation

Abulwerdi¹,

Liao²,

Mady³

et al. 2014

J. Med. Chem.

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Mcl-1, an antiapoptotic member of the Bcl-2 family of proteins, is a validated and attractive target for cancer therapy. Overexpression of Mcl-1 in many cancers results in disease progression and resistance to current chemotherapeutics. Utilizing high-throughput screening, compound 1 was identified as a selective Mcl-1 inhibitor and its binding to the BH3 binding groove of Mcl-1 was confirmed by several different, but complementary, biochemical and biophysical assays. Guided by structure-based drug design and supported by NMR experiments, comprehensive SAR studies were undertaken and a potent and selective inhibitor, compound 21, was designed which binds to Mcl-1 with a Ki of 180 nM. Biological characterization of 21 showed that it disrupts the interaction of endogenous Mcl-1 and biotinylated Noxa-BH3 peptide, causes cell death through a Bak/Bax-dependent mechanism, and selectively sensitizes Eμ-myc lymphomas overexpressing Mcl-1, but not Eμ-myc lymphoma cells overexpressing Bcl-2. Treatment of human leukemic cell lines with compound 21 resulted in cell death through activation of caspase-3 and induction of apoptosis.

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Section: Resultsmentioning

confidence: 99%

“…As reported previously, to a solution of 1,1′-sulfonyldiimidazole (1.98 g, 10 mmol) in CH 2 Cl 2 (40 mL) was added methyl trifluoromethanesulfonate (1.64 g, 10 mmol) at 0 °C. The solvent was removed after 3 h stirring.…”

Section: Methodsmentioning

confidence: 99%

3-Substituted-N-(4-Hydroxynaphthalen-1-yl)arylsulfonamides as a Novel Class of Selective Mcl-1 Inhibitors: Structure-Based Design, Synthesis, SAR, and Biological Evaluation

Abulwerdi¹,

Liao²,

Mady³

et al. 2014

J. Med. Chem.

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“…Following the conditions of Beaudoin, using the triflate salt of mono-N-methyl-N,N′sulfuryldiimidazole (7), the ring closure was successfully achieved in 30% yield. 25 Further optimization by the dropwise addition of 6 to a solution of triflate salt 7 in acetonitrile decreased side product formation and provided 9 in 44% yield. Conversion of 9 into the desired piperidine analogues 11a−h was accomplished by deprotection of the Cbz group using H 2 / Pd(OH) 2 followed by reductive amination with an appropriate benzaldehyde.…”

Section: ■ Chemistrymentioning

confidence: 99%

“…The triflate salt of mono-N-methyl-N,N′-sulfuryldiimidazole25 (compound 7, 2.45 g, 6.7 mmol) was dissolved in acetonitrile (20 mL). To this stirred solution was added a solution of 6 (2.0 g, 5.4 mmol) in acetonitrile (10 mL) dropwise via an addition funnel.…”

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confidence: 99%

Spirocyclic Sulfamides as β-Secretase 1 (BACE-1) Inhibitors for the Treatment of Alzheimer’s Disease: Utilization of Structure Based Drug Design, WaterMap, and CNS Penetration Studies To Identify Centrally Efficacious Inhibitors

et al. 2012

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β-Secretase 1 (BACE-1) is an attractive therapeutic target for the treatment and prevention of Alzheimer's disease (AD). Herein, we describe the discovery of a novel class of BACE-1 inhibitors represented by sulfamide 14g, using a medicinal chemistry strategy to optimize central nervous system (CNS) penetration by minimizing hydrogen bond donors (HBDs) and reducing P-glycoprotein (P-gp) mediated efflux. We have also taken advantage of the combination of structure based drug design (SBDD) to guide the optimization of the sulfamide analogues and the in silico tool WaterMap to explain the observed SAR. Compound 14g is a potent inhibitor of BACE-1 with excellent permeability and a moderate P-gp liability. Administration of 14g to mice produced a significant, dose-dependent reduction in central Aβ(X-40) levels at a free drug exposure equivalent to the whole cell IC(50) (100 nM). Furthermore, studies of the P-gp knockout mouse provided evidence that efflux transporters affected the amount of Aβ lowering versus that observed in wild-type (WT) mouse at an equivalent dose.

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“…Moreover, even negation of religion in the form of heresy, profanity or obscenity might indicate the presence of religious meaning. 46 To reiterate, the meaning of a term depends on its use. For example, the term God or OMG can mean different things, but a change of meaning or lost meaning may not signal the end of our ability to speak of God.…”

Section: Contributions Of Linguisticsmentioning

confidence: 99%

The Urban Dictionary, Street Wisdom and God: An Intersection of Linguistics and Theology

Willhauck

2013

International Journal of Practical Theology

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One intriguing cultural phenomenon today is changes in language. While language has always evolved, there is an emerging linguistically based cultural wisdom that is worthy of exploration in theology. The Urban Dictionary contains thousands of entries; words and phrases perhaps unknown a decade or so ago. Some of these have crept into mainstream English, while others fall into a category that might be reckoned as "street wisdom." Many new words have been born from technology, social networking and globalization, as words and wisdom cross cultures and are highly influential in the worldviews of young people. The Urban Dictionary website boasts that this is "the dictionary you wrote" and tells people to "define your world." The implicit claim is that we are no longer bound by traditional language and meanings and that we can name reality for ourselves.Zusammenfassung: Die Veränderung der Sprache ist heute ein faszinierendes kulturelles Phänomen. Obwohl sich die Sprache immer weiterentwickelt hat, zeichnet sich eine linguistisch fundierte kulturelle Weisheit ab, die es wert ist, in der Theologie untersucht zu werden. Das "Urban Dictionary" enthält mehrere tausend Einträge, Wörter und Sätze, die vielleicht vor etwa einem Jahrzehnt noch unbekannt waren. Einige davon haben ihren Einzug in den allgemeinen englischen Sprachgebrauch gefunden, während andere in eine Kategorie fallen, die mehr zum "Alltagswissen" gehört. Viele neue Wörter haben ihren Ursprung in der Technologie, in sozialen Netzwerken und der Globalsierung, da Wörter und Weisheiten interkulturell sind und einen großen Einfluss auf die Weltsicht von jungen Menschen haben. Die Internetseite des "Urban Dictionary" verkündet stolz, dass es "das Wörterbuch, dass Sie verfasst haben" sei und sagt Menschen "definieren Sie Ihre Welt." Die implizite Behauptung ist dabei, dass wir durch die traditionelle Sprache und ihre Bedeutung nicht mehr gebunden sind und dass wir die Realität selbst für uns bestimmen können.

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Preparation of Unsymmetrical Sulfonylureas from N,N′‐Sulfuryldiimidazoles.

Cited by 4 publications

References 1 publication

3-Substituted-N-(4-Hydroxynaphthalen-1-yl)arylsulfonamides as a Novel Class of Selective Mcl-1 Inhibitors: Structure-Based Design, Synthesis, SAR, and Biological Evaluation

3-Substituted-N-(4-Hydroxynaphthalen-1-yl)arylsulfonamides as a Novel Class of Selective Mcl-1 Inhibitors: Structure-Based Design, Synthesis, SAR, and Biological Evaluation

Spirocyclic Sulfamides as β-Secretase 1 (BACE-1) Inhibitors for the Treatment of Alzheimer’s Disease: Utilization of Structure Based Drug Design, WaterMap, and CNS Penetration Studies To Identify Centrally Efficacious Inhibitors

The Urban Dictionary, Street Wisdom and God: An Intersection of Linguistics and Theology

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