Synthesis of a potent α-glucosidase inhibitor epimeric to fr 900483

Witte, John F.; McClard, Ronald W.

doi:10.1016/0040-4039(91)80591-s

Cited by 36 publications

(25 citation statements)

References 16 publications

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“…The existence of azahemiacetals in equilibrium with dehydrated form (imine) as well as with open aldehyde and dimeric forms was reported for 4-azapentofuranoses. 42-43 It is noteworthy that sugar N,O -acetals were found to be stable enough to undergo coupling with nucleoside bases, 41 or transformation to proline. 44 Although direct reduction of lactam 21 (or 19a ) with LiBEt 3 H failed to yield hemiaminal 23 (or 22 ), the protection of the ring nitrogen with a Boc group facilitated the reduction reaction.…”

Section: Resultsmentioning

confidence: 99%

“…Desilylation with TBAF yielded 24b , which was treated with TFA to give deprotected hemiaminal 25a as a mixture of anomers susceptible to dehydration at pH higher than 7 to form imine 25c . 43 Subsequent treatment of 25a with O -benzylhydroxylamine gave expected oxime 26 as the only product. The formation of oxime 26 indicates that azasugar 25a exists in equilibrium with the open aldehyde form ( 25b ) and that the equilibrium could be shifted by subsequent transformations.…”

Section: Resultsmentioning

confidence: 99%

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Inhibition of LuxS by S-ribosylhomocysteine analogues containing a [4-aza]ribose ring

Malladi

Sobczak

Meyer

et al. 2011

Bioorganic & Medicinal Chemistry

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LuxS (S-ribosylhomocysteinase) catalyzes the cleavage of the thioether linkage of S- ribosylhomocysteine (SRH) to produce homocysteine and 4,5-dihydroxy-2,3-pentanedione (DPD), the precursor to a small signaling molecule that mediates interspecies bacterial communication called autoinducer 2 (AI-2). Inhibitors of LuxS should interfere with bacterial interspecies communication and potentially provide a novel class of antibacterial agents. In this work, SRH analogues containing substitution of a nitrogen atom for the endocyclic oxygen as well as various deoxyriboses were synthesized and evaluated for LuxS inhibition. Two of the [4-aza]SRH analogues showed modest competitive inhibition (KI ~40 μM), while most of the others were inactive. One compound that contains a hemiaminal moiety exhibited time-dependent inhibition, consistent with enzyme-catalyzed ring opening and conversion into a more potent species (KI* = 3.5 μM). The structure-activity relationship of the designed inhibitors highlights the importance of both the homocysteine and ribose moieties for high-affinity binding to LuxS active site.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Inhibition of LuxS by S-ribosylhomocysteine analogues containing a [4-aza]ribose ring

Malladi

Sobczak

Meyer

et al. 2011

Bioorganic & Medicinal Chemistry

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“…Subsequent deprotection with TFA provided (5 S )-(alkylthiomethyl)-3,4-dihydroxypyrrolidin-2-ols 23 and 24 as a complex mixture of azahemiacetals existing in equilibrium with dehydrated form (imine) as well as with open aldehyde and dimeric forms, as reported for such class of 4-azaribofuranoses. 25,28,33 These azahemiacetals can be considered as aza analogues of S -ribosyl-L-homocysteine 28 (SRH) in which (a ) ribose oxygen is replaced by nitrogen atom and ( b ) the homocysteine moiety is substituted with n- alkylthiols with different length of carbon chain.…”

Section: Resultsmentioning

confidence: 99%

Substituted lactam and cyclic azahemiacetals modulate Pseudomonas aeruginosa quorum sensing

Malladi

Sobczak

Maricic

et al. 2011

Bioorganic & Medicinal Chemistry

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Quorum sensing (QS) is a population-dependent signaling process bacteria use to control multiple processes including virulence that is critical for establishing infection. The most common QS signaling molecule used by Gram-negative bacteria are acylhomoserine lactones. The development of non-native acylhomoserine lactone (AHL) ligands has emerged as a promising new strategy to inhibit QS in Gram-negative bacteria. In this work, we have synthesized a set of optically pure γ-lactams and their reduced cyclic azahemiacetal analogues, bearing the additional alkylthiomethyl substituent, and evaluated their effect on the AHL-dependent Pseudomonas aeruginosa las and rhl QS pathways. The concentration of these ligands and the simple structural modification such as the length of the alkylthio substituent has notable effect on activity. The γ-lactam derivatives with nonylthio or dodecylthio chains acted as inhibitors of las signaling with moderate potency. The cyclic azahemiacetal with shorter propylthio or hexylthio substituent was found to strongly inhibit both las and rhl signaling at higher concentrations while the propylthio analogue strongly stimulated the las QS system at lower concentrations.

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“…Results and Discussion. -Our synthesis of compound (À)-1 was inspired by the synthesis of 2, developed by Schramm and co-workers in 1993 [34], and started from 1,4-dideoxy-1,4-imino-d-ribitol (3), prepared according to the procedure of Witte and McClard [35]. The 2,3-cis-diol moiety of 3 was protected as an acetonide and the 5-OH group as a silyl ether applying standard conditions (Scheme) to give 4 [36].…”

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confidence: 99%

Synthesis of a C‐Iminoribofuranoside Analog of the Nicotinamide Phosphoribosyltransferase (NAMPT) Inhibitor FK866

Gillig¹,

Majjigapu

Sordat

et al. 2012

Helvetica Chimica Acta

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Synthesis of a potent α-glucosidase inhibitor epimeric to fr 900483

Cited by 36 publications

References 16 publications

Inhibition of LuxS by S-ribosylhomocysteine analogues containing a [4-aza]ribose ring

Inhibition of LuxS by S-ribosylhomocysteine analogues containing a [4-aza]ribose ring

Substituted lactam and cyclic azahemiacetals modulate Pseudomonas aeruginosa quorum sensing

Synthesis of a C‐Iminoribofuranoside Analog of the Nicotinamide Phosphoribosyltransferase (NAMPT) Inhibitor FK866

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