A new class of C-nucleoside analogues. 1-(S)-aryl-1,4-dideoxy-1,4-imino-D-ribitols, transition state analogue inhibitors of nucleoside hydrolase

Benjamin A. Horenstein, Roger F. Zabinski, Vern L. Schramm

Research output: Contribution to journalArticle

84 Citations (Scopus)

Abstract

The first members of a new class of N-glycohydrolase transition state analogue inhibitors, 1,4-dideoxy-1,4-imino-1-(S)-phenyl-D-ribitol, 1, and 1,4-dideoxy-1,4-imino-1-(S)-(4-imidazolyl)-D-ribitol, 2, have been synthesized. These compounds represent a new type of C-nucleoside analogue in which the endocyclic ribosyl ring oxygen has been replaced with nitrogen. The key synthetic step involves reaction of a protected ribosylimine with a metallated aryl species. The compounds are transition state analogues for enzymes which catalyzed CN glycosidic bond hydrolyses of nucleosides and have transition states with oxocarbenium ion character. Compounds 1 and 2 are potent competitive inhibitors with dissociation constants of 0.03 and 2.5 μM, for nucleoside hydrolase from the trypanosome Crithidia fasciculata. The highly effective inhibition observed demonstrates the importance of including both charge and aglycon mimicry in a glycosylase transition state analogue and differentiates it from simpler analogues.

Original languageEnglish (US)
Pages (from-to)7213-7216
Number of pages4
JournalTetrahedron Letters
Volume34
Issue number45
DOIs
StatePublished - Nov 5 1993
Externally publishedYes

Fingerprint

N-Glycosyl Hydrolases
Ribitol
Nucleosides
Crithidia fasciculata
Trypanosomiasis
Glycoside Hydrolases
Hydrolysis
Nitrogen
Ions
Oxygen
Enzymes

ASJC Scopus subject areas

  • Biochemistry
  • Organic Chemistry
  • Drug Discovery

Cite this

A new class of C-nucleoside analogues. 1-(S)-aryl-1,4-dideoxy-1,4-imino-D-ribitols, transition state analogue inhibitors of nucleoside hydrolase. / Horenstein, Benjamin A.; Zabinski, Roger F.; Schramm, Vern L.

In: Tetrahedron Letters, Vol. 34, No. 45, 05.11.1993, p. 7213-7216.

Research output: Contribution to journalArticle

@article{84c92bfda91e402bb2dfa68a0879c5e4,
title = "A new class of C-nucleoside analogues. 1-(S)-aryl-1,4-dideoxy-1,4-imino-D-ribitols, transition state analogue inhibitors of nucleoside hydrolase",
abstract = "The first members of a new class of N-glycohydrolase transition state analogue inhibitors, 1,4-dideoxy-1,4-imino-1-(S)-phenyl-D-ribitol, 1, and 1,4-dideoxy-1,4-imino-1-(S)-(4-imidazolyl)-D-ribitol, 2, have been synthesized. These compounds represent a new type of C-nucleoside analogue in which the endocyclic ribosyl ring oxygen has been replaced with nitrogen. The key synthetic step involves reaction of a protected ribosylimine with a metallated aryl species. The compounds are transition state analogues for enzymes which catalyzed CN glycosidic bond hydrolyses of nucleosides and have transition states with oxocarbenium ion character. Compounds 1 and 2 are potent competitive inhibitors with dissociation constants of 0.03 and 2.5 μM, for nucleoside hydrolase from the trypanosome Crithidia fasciculata. The highly effective inhibition observed demonstrates the importance of including both charge and aglycon mimicry in a glycosylase transition state analogue and differentiates it from simpler analogues.",
author = "Horenstein, {Benjamin A.} and Zabinski, {Roger F.} and Schramm, {Vern L.}",
year = "1993",
month = "11",
day = "5",
doi = "10.1016/S0040-4039(00)79290-2",
language = "English (US)",
volume = "34",
pages = "7213--7216",
journal = "Tetrahedron Letters",
issn = "0040-4039",
publisher = "Elsevier Limited",
number = "45",

}

TY - JOUR

T1 - A new class of C-nucleoside analogues. 1-(S)-aryl-1,4-dideoxy-1,4-imino-D-ribitols, transition state analogue inhibitors of nucleoside hydrolase

AU - Horenstein, Benjamin A.

AU - Zabinski, Roger F.

AU - Schramm, Vern L.

PY - 1993/11/5

Y1 - 1993/11/5

N2 - The first members of a new class of N-glycohydrolase transition state analogue inhibitors, 1,4-dideoxy-1,4-imino-1-(S)-phenyl-D-ribitol, 1, and 1,4-dideoxy-1,4-imino-1-(S)-(4-imidazolyl)-D-ribitol, 2, have been synthesized. These compounds represent a new type of C-nucleoside analogue in which the endocyclic ribosyl ring oxygen has been replaced with nitrogen. The key synthetic step involves reaction of a protected ribosylimine with a metallated aryl species. The compounds are transition state analogues for enzymes which catalyzed CN glycosidic bond hydrolyses of nucleosides and have transition states with oxocarbenium ion character. Compounds 1 and 2 are potent competitive inhibitors with dissociation constants of 0.03 and 2.5 μM, for nucleoside hydrolase from the trypanosome Crithidia fasciculata. The highly effective inhibition observed demonstrates the importance of including both charge and aglycon mimicry in a glycosylase transition state analogue and differentiates it from simpler analogues.

AB - The first members of a new class of N-glycohydrolase transition state analogue inhibitors, 1,4-dideoxy-1,4-imino-1-(S)-phenyl-D-ribitol, 1, and 1,4-dideoxy-1,4-imino-1-(S)-(4-imidazolyl)-D-ribitol, 2, have been synthesized. These compounds represent a new type of C-nucleoside analogue in which the endocyclic ribosyl ring oxygen has been replaced with nitrogen. The key synthetic step involves reaction of a protected ribosylimine with a metallated aryl species. The compounds are transition state analogues for enzymes which catalyzed CN glycosidic bond hydrolyses of nucleosides and have transition states with oxocarbenium ion character. Compounds 1 and 2 are potent competitive inhibitors with dissociation constants of 0.03 and 2.5 μM, for nucleoside hydrolase from the trypanosome Crithidia fasciculata. The highly effective inhibition observed demonstrates the importance of including both charge and aglycon mimicry in a glycosylase transition state analogue and differentiates it from simpler analogues.

UR - http://www.scopus.com/inward/record.url?scp=0027524581&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0027524581&partnerID=8YFLogxK

U2 - 10.1016/S0040-4039(00)79290-2

DO - 10.1016/S0040-4039(00)79290-2

M3 - Article

VL - 34

SP - 7213

EP - 7216

JO - Tetrahedron Letters

JF - Tetrahedron Letters

SN - 0040-4039

IS - 45

ER -