Identification of cytotoxic, T-cell-selective 1,4-benzodiazepine-2,5-diones.
A family of 1,4-benzodiazepine-2,5-diones (BZDs) has been synthesized and evaluated against transformed B- and T-cells for lymphotoxic members. A large aromatic group on the C3 position is critical for cytotoxicity. When the C3 moiety contains an electron-rich heterocycle, the resulting BZDs have sub-micromolar potency and are selective for T-cells. Cell death is consistent with apoptosis and does not result from inhibition of the mitochondrial F(o)F1-ATPase, which is the molecular target of recently reported cytotoxic 1,4-benzodiazepines. Collectively, these studies begin to characterize some of the structural elements required for the activity of a novel family of T-cell-selective lymphotoxic agents.
Chemical Biology Graduate Program, University of Michigan, Ann Arbor, MI 48109-1055, USA.
Tasha M
TM
Francis
Thomas B
TB
Sundberg
Joanne
J
Cleary
Todd
T
Groendyke
Anthony W
AW
Opipari
Gary D
GD
Glick
D001402:B-Lymphocytes / Q000187:drug effects; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D006801:Humans; D019169:Jurkat Cells; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects*
D001569:Benzodiazepines