Synthesis and biological activity of novel neuroprotective diketopiperazines.
The cyclic dipeptide cyclo[His-Pro] (CHP) is synthesized endogenously de novo and as a breakdown product of thyrotropin-releasing hormone (TRH), a tripeptide with known neuroprotective activity. We synthesized two isomeric compounds based on the structure of CHP, in which the histidine residue was replaced by 3,5-di-tert-butyltyrosine (DBT), a phenolic amino acid that traps reactive oxygen species. These novel diketopiperazines prevented neuronal death in an in vitro model of traumatic injury. In addition, they dose-dependently prevented death caused by the direct induction of free radicals, and by calcium mobilization through an agent that evokes rapid, necrotic death. The drugs showed activity in the latter system at picomolar concentrations. The neuroprotective profile of these compounds suggests that they may be useful as treatments for neuronal degeneration in vivo, potentially through several different mechanisms.
Prakash
K R C
KR
Drug Discovery Program, Department of Neurology, Georgetown University Medical Center, 3900 Reservoir Road, N. W., Washington, DC 20007-2197, USA.
Tang
Y
Y
Kozikowski
Alan P
AP
Flippen-Anderson
Judith L
JL
Knoblach
Susan M
SM
Faden
Alan I
AI
D000818:Animals; D002118:Calcium; D016923:Cell Death / Q000187:drug effects; D054659:Diketopiperazines; D004151:Dipeptides; D004305:Dose-Response Relationship, Drug; D005609:Free Radicals; D006801:Humans; D015394:Molecular Structure; D009457:Neuroglia / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D010456:Peptides, Cyclic; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology
D054659:Diketopiperazines; D004151:Dipeptides; D005609:Free Radicals; D018696:Neuroprotective Agents; D010456:Peptides, Cyclic; D010879:Piperazines; C015924:histidyl-proline diketopiperazine; D002118:Calcium