Zipped synthesis by cross-metathesis provides a cystathionine ß-synthase inhibitor that attenuates cellular H2S levels and reduces neuronal infarction in a rat ischemic stroke model

Christopher D. McCune, Su Jing Chan, Matthew L. Beio, Weijun Shen, Woo Jin Chung, Laura M. Szczesniak, Chou Chai, Shu Qing Koh, Peter T.H. Wong, David B Berkowitz

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

The gaseous neuromodulator H2S is associated with neuronal cell death pursuant to cerebral ischemia. As cystathionine ß-synthase (CBS) is the primary mediator of H2S biogenesis in the brain, it has emerged as a potential target for the treatment of stroke. Herein, a "zipped" approach by alkene cross-metathesis into CBS inhibitor candidate synthesis is demonstrated. The inhibitors are modeled after the pseudo-C2-symmetric CBS product (L,L)-cystathionine. The "zipped" concept means only half of the inhibitor needs be constructed; the two halves are then fused by olefin cross-metathesis. Inhibitor design is also mechanism-based, exploiting the favorable kinetics associated with hydrazine-imine interchange as opposed to the usual imine-imine interchange. It is demonstrated that the most potent "zipped" inhibitor 6S reduces H2S production in SHSY5Y cells overexpressing CBS, thereby reducing cell death. Most importantly, CBS inhibitor 6S dramatically reduces infarct volume (1 h post-stroke treatment; 70% reduction) in a rat transient middle cerebral artery occlusion model for ischemia.

Original languageEnglish (US)
Pages (from-to)242-252
Number of pages11
JournalACS Central Science
Volume2
Issue number4
DOIs
StatePublished - Apr 27 2016

Fingerprint

Cystathionine
Imines
Interchanges
Cell death
Olefins
Rats
hydrazine
Alkenes
Hydrazine
Brain
Kinetics
Neurotransmitter Agents

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)

Cite this

Zipped synthesis by cross-metathesis provides a cystathionine ß-synthase inhibitor that attenuates cellular H2S levels and reduces neuronal infarction in a rat ischemic stroke model. / McCune, Christopher D.; Chan, Su Jing; Beio, Matthew L.; Shen, Weijun; Chung, Woo Jin; Szczesniak, Laura M.; Chai, Chou; Koh, Shu Qing; Wong, Peter T.H.; Berkowitz, David B.

In: ACS Central Science, Vol. 2, No. 4, 27.04.2016, p. 242-252.

Research output: Contribution to journalArticle

McCune, Christopher D. ; Chan, Su Jing ; Beio, Matthew L. ; Shen, Weijun ; Chung, Woo Jin ; Szczesniak, Laura M. ; Chai, Chou ; Koh, Shu Qing ; Wong, Peter T.H. ; Berkowitz, David B. / Zipped synthesis by cross-metathesis provides a cystathionine ß-synthase inhibitor that attenuates cellular H2S levels and reduces neuronal infarction in a rat ischemic stroke model. In: ACS Central Science. 2016 ; Vol. 2, No. 4. pp. 242-252.
@article{77bd2c45aa62487da86291dab814bb93,
title = "Zipped synthesis by cross-metathesis provides a cystathionine {\ss}-synthase inhibitor that attenuates cellular H2S levels and reduces neuronal infarction in a rat ischemic stroke model",
abstract = "The gaseous neuromodulator H2S is associated with neuronal cell death pursuant to cerebral ischemia. As cystathionine {\ss}-synthase (CBS) is the primary mediator of H2S biogenesis in the brain, it has emerged as a potential target for the treatment of stroke. Herein, a {"}zipped{"} approach by alkene cross-metathesis into CBS inhibitor candidate synthesis is demonstrated. The inhibitors are modeled after the pseudo-C2-symmetric CBS product (L,L)-cystathionine. The {"}zipped{"} concept means only half of the inhibitor needs be constructed; the two halves are then fused by olefin cross-metathesis. Inhibitor design is also mechanism-based, exploiting the favorable kinetics associated with hydrazine-imine interchange as opposed to the usual imine-imine interchange. It is demonstrated that the most potent {"}zipped{"} inhibitor 6S reduces H2S production in SHSY5Y cells overexpressing CBS, thereby reducing cell death. Most importantly, CBS inhibitor 6S dramatically reduces infarct volume (1 h post-stroke treatment; 70{\%} reduction) in a rat transient middle cerebral artery occlusion model for ischemia.",
author = "McCune, {Christopher D.} and Chan, {Su Jing} and Beio, {Matthew L.} and Weijun Shen and Chung, {Woo Jin} and Szczesniak, {Laura M.} and Chou Chai and Koh, {Shu Qing} and Wong, {Peter T.H.} and Berkowitz, {David B}",
year = "2016",
month = "4",
day = "27",
doi = "10.1021/acscentsci.6b00019",
language = "English (US)",
volume = "2",
pages = "242--252",
journal = "ACS Central Science",
issn = "2374-7943",
publisher = "American Chemical Society",
number = "4",

}

TY - JOUR

T1 - Zipped synthesis by cross-metathesis provides a cystathionine ß-synthase inhibitor that attenuates cellular H2S levels and reduces neuronal infarction in a rat ischemic stroke model

AU - McCune, Christopher D.

AU - Chan, Su Jing

AU - Beio, Matthew L.

AU - Shen, Weijun

AU - Chung, Woo Jin

AU - Szczesniak, Laura M.

AU - Chai, Chou

AU - Koh, Shu Qing

AU - Wong, Peter T.H.

AU - Berkowitz, David B

PY - 2016/4/27

Y1 - 2016/4/27

N2 - The gaseous neuromodulator H2S is associated with neuronal cell death pursuant to cerebral ischemia. As cystathionine ß-synthase (CBS) is the primary mediator of H2S biogenesis in the brain, it has emerged as a potential target for the treatment of stroke. Herein, a "zipped" approach by alkene cross-metathesis into CBS inhibitor candidate synthesis is demonstrated. The inhibitors are modeled after the pseudo-C2-symmetric CBS product (L,L)-cystathionine. The "zipped" concept means only half of the inhibitor needs be constructed; the two halves are then fused by olefin cross-metathesis. Inhibitor design is also mechanism-based, exploiting the favorable kinetics associated with hydrazine-imine interchange as opposed to the usual imine-imine interchange. It is demonstrated that the most potent "zipped" inhibitor 6S reduces H2S production in SHSY5Y cells overexpressing CBS, thereby reducing cell death. Most importantly, CBS inhibitor 6S dramatically reduces infarct volume (1 h post-stroke treatment; 70% reduction) in a rat transient middle cerebral artery occlusion model for ischemia.

AB - The gaseous neuromodulator H2S is associated with neuronal cell death pursuant to cerebral ischemia. As cystathionine ß-synthase (CBS) is the primary mediator of H2S biogenesis in the brain, it has emerged as a potential target for the treatment of stroke. Herein, a "zipped" approach by alkene cross-metathesis into CBS inhibitor candidate synthesis is demonstrated. The inhibitors are modeled after the pseudo-C2-symmetric CBS product (L,L)-cystathionine. The "zipped" concept means only half of the inhibitor needs be constructed; the two halves are then fused by olefin cross-metathesis. Inhibitor design is also mechanism-based, exploiting the favorable kinetics associated with hydrazine-imine interchange as opposed to the usual imine-imine interchange. It is demonstrated that the most potent "zipped" inhibitor 6S reduces H2S production in SHSY5Y cells overexpressing CBS, thereby reducing cell death. Most importantly, CBS inhibitor 6S dramatically reduces infarct volume (1 h post-stroke treatment; 70% reduction) in a rat transient middle cerebral artery occlusion model for ischemia.

UR - http://www.scopus.com/inward/record.url?scp=84982096004&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84982096004&partnerID=8YFLogxK

U2 - 10.1021/acscentsci.6b00019

DO - 10.1021/acscentsci.6b00019

M3 - Article

VL - 2

SP - 242

EP - 252

JO - ACS Central Science

JF - ACS Central Science

SN - 2374-7943

IS - 4

ER -