Dihydrofuro[3,4-c]pyridinones as inhibitors of the cytolytic effects of the pore-forming glycoprotein perforin

Gersande Lena; Joseph A Trapani; Vivien R Sutton; Annette Ciccone; Kylie A Browne; Mark J Smyth; William A Denny; Julie A Spicer

doi:10.1021/jm801063n

Dihydrofuro[3,4-c]pyridinones as inhibitors of the cytolytic effects of the pore-forming glycoprotein perforin

J Med Chem. 2008 Dec 11;51(23):7614-24. doi: 10.1021/jm801063n.

Authors

Gersande Lena¹, Joseph A Trapani, Vivien R Sutton, Annette Ciccone, Kylie A Browne, Mark J Smyth, William A Denny, Julie A Spicer

Affiliation

¹ Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.

PMID: 19007200
DOI: 10.1021/jm801063n

Abstract

Dihydrofuro[3,4-c]pyridinones are the first class of small molecules reported to inhibit the cytolytic effects of the lymphocyte toxin perforin. A lead structure was identified from a high throughput screen, and a series of analogues were designed and prepared to explore structure-activity relationships around the core bicyclic thioxofuropyridinone and pendant furan ring. This resulted in the identification of a submicromolar inhibitor of the perforin-induced lysis of Jurkat T-lymphoma cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / drug effects
Dose-Response Relationship, Drug
Drug Design
Erythrocytes / drug effects*
Erythrocytes / metabolism
Furans / chemical synthesis
Furans / chemistry
Furans / pharmacology*
Humans
Jurkat Cells
Killer Cells, Natural / drug effects*
Killer Cells, Natural / metabolism
Molecular Structure
Perforin / antagonists & inhibitors*
Perforin / metabolism
Pyridones / chemical synthesis
Pyridones / chemistry
Pyridones / pharmacology*
Sheep
Stereoisomerism
Structure-Activity Relationship
Thiones / chemical synthesis
Thiones / chemistry
Thiones / pharmacology*

Substances

Furans
Pyridones
Thiones
Perforin