Ruthenium Catalyzed Synthesis of Enaminones

Koduri, Naga D.; Scott, Halee; Hileman, Bethany; Cox, Justin D.; Coffin, Michael; Glicksberg, Lindsay; Hussaini, Syed R.

doi:10.1021/ol202812d

Cited by 69 publications

(73 citation statements)

References 43 publications

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“…For 1a, diethyl diazomalonate 12 9 was treated with methylamine to yield the desired triazole as the primary ammonium salt 13 (yield 79%). After acidification and extraction with ethyl acetate, the free hydroxytriazole 1a was isolated without any further purification (quantitative yield).…”

Section: 7mentioning

confidence: 99%

Substituted 4-hydroxy-1,2,3-triazoles: synthesis, characterization and first drug design applications through bioisosteric modulation and scaffold hopping approaches

et al. 2015

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aBioisosterism and scaffold hopping are two widely used approaches in medicinal chemistry for the purpose of lead optimization. The study highlights the physicochemical properties of the 4-hydroxy-1,2,3-triazole scaffold, a less investigated heterocyclic system. Synthetic strategies to obtain different N-substituted 4-hydroxy-1,2,3-triazole isomers are presented, and their role as possible isosteres of the carboxylic acid is discussed. The aim is to use this system to modulate the acidic moieties present in lead compounds and, at the same time, to regiodirect substituents in set directions, through targeted substitution on the three nitrogen atoms of the triazole ring. Through this approach, compounds having enhanced binding affinity, will be sought. Two examples of bioisosteric applications of this moiety are presented. In the first example, a classical bioisosteric approach mimicking the distal (S)-glutamic acid carboxyl group using the 4-hydroxy-1,2,3-triazole moiety is applied, to obtain two promising glutamate analogs. In the second example, a scaffold hopping approach is applied, replacing the phenolic moiety present in MDG-1-33A, a potent inhibitor of Onchocerca volvulus chitinase, with the 4-hydroxy-1,2,3-triazole scaffold. The 4-hydroxy-1,2,3-triazole system appears to be useful and versatile in drug design.

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Section: 7mentioning

confidence: 99%

Substituted 4-hydroxy-1,2,3-triazoles: synthesis, characterization and first drug design applications through bioisosteric modulation and scaffold hopping approaches

et al. 2015

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“…27 The amide can also be converted into the corresponding thioamide ( 5 ) without racemization. 28 This heteroatom conversion provides a platform for further known transformations (e.g., annulations and amidine formation) to access potentially bioactive architectures. 29 …”

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confidence: 99%

Enantioselective Annulations for Dihydroquinolones by in Situ Generation of Azolium Enolates

et al. 2014

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“…Previous work developed a modified method of enaminone synthesis in which sonication or Ru(II) catalysis was employed during the Eschenmoser coupling reaction (Figure ) . The coupling partners with sonication were thioamide and α‐bromocarbonyl compounds, which causes a reduction in particle size via rapid bubble collapse and mechanical heat generation that facilitates mass/heat transfer and faster reaction times .…”

Section: Resultsmentioning

confidence: 99%

“…The Hussaini group previously synthesized a library of enaminones in which some of the starting materials and end products contained amino acidlike functional groups (21)(22)(23). We hypothesized they might inhibit proteases like the proteasome, a therapeutically important multisubunit complex that degrades essential cellular proteins (24)(25)(26)(27)(28)(29).…”

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confidence: 99%

Identification of Novel Proteasome Inhibitors from an Enaminone Library

et al. 2015

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A library of structurally distinct enaminones was synthesized using sonication or Ru(II) catalysis to couple primary, secondary, and tertiary thioamides with α-halocarbonyls or α-diazocarbonyls. Screening the library for proteasome inhibition using a luciferase-based assay identified seven structurally diverse compounds. Two of these molecules targeted luciferase, while the remaining five exhibited varying potency and specificity for the trypsin-like, chymotrypsin-like, or caspase-like protease activities of the proteasome. Physiological relevance was confirmed by showing these molecules inhibited proteasomal degradation of the full-length protein substrate p21cip1 expressed in tissue culture cells. A cell viability analysis revealed that the proteasome inhibitors differentially affected cell survival. Results indicate a subset of enaminones and precursor molecules identified in this study are good candidates for further development into novel proteasome inhibitors with potential therapeutic value.

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Ruthenium Catalyzed Synthesis of Enaminones

Cited by 69 publications

References 43 publications

Substituted 4-hydroxy-1,2,3-triazoles: synthesis, characterization and first drug design applications through bioisosteric modulation and scaffold hopping approaches

Substituted 4-hydroxy-1,2,3-triazoles: synthesis, characterization and first drug design applications through bioisosteric modulation and scaffold hopping approaches

Enantioselective Annulations for Dihydroquinolones by in Situ Generation of Azolium Enolates

Identification of Novel Proteasome Inhibitors from an Enaminone Library

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