Synthesis and biological activity of novel neuroprotective diketopiperazines

K. R C Prakash, Y. Tang, Alan P. Kozikowski, Judith L. Flippen-Anderson, Susan M. Knoblach, Alan I. Faden

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3043-3048
Number of pages6
JournalBioorganic and Medicinal Chemistry
Volume10
Issue number9
DOIs
StatePublished - 2002
Externally publishedYes

Fingerprint

Diketopiperazines
Thyrotropin-Releasing Hormone
Dipeptides
Bioactivity
Histidine
Free Radicals
Reactive Oxygen Species
Calcium
Amino Acids
Pharmaceutical Preparations
Wounds and Injuries
histidyl-proline diketopiperazine

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

Cite this

Prakash, K. R. C., Tang, Y., Kozikowski, A. P., Flippen-Anderson, J. L., Knoblach, S. M., & Faden, A. I. (2002). Synthesis and biological activity of novel neuroprotective diketopiperazines. Bioorganic and Medicinal Chemistry, 10(9), 3043-3048. https://doi.org/10.1016/S0968-0896(02)00132-3

Synthesis and biological activity of novel neuroprotective diketopiperazines. / Prakash, K. R C; Tang, Y.; Kozikowski, Alan P.; Flippen-Anderson, Judith L.; Knoblach, Susan M.; Faden, Alan I.

In: Bioorganic and Medicinal Chemistry, Vol. 10, No. 9, 2002, p. 3043-3048.

Research output: Contribution to journalArticle

Prakash, KRC, Tang, Y, Kozikowski, AP, Flippen-Anderson, JL, Knoblach, SM & Faden, AI 2002, 'Synthesis and biological activity of novel neuroprotective diketopiperazines', Bioorganic and Medicinal Chemistry, vol. 10, no. 9, pp. 3043-3048. https://doi.org/10.1016/S0968-0896(02)00132-3
Prakash KRC, Tang Y, Kozikowski AP, Flippen-Anderson JL, Knoblach SM, Faden AI. Synthesis and biological activity of novel neuroprotective diketopiperazines. Bioorganic and Medicinal Chemistry. 2002;10(9):3043-3048. https://doi.org/10.1016/S0968-0896(02)00132-3
Prakash, K. R C ; Tang, Y. ; Kozikowski, Alan P. ; Flippen-Anderson, Judith L. ; Knoblach, Susan M. ; Faden, Alan I. / Synthesis and biological activity of novel neuroprotective diketopiperazines. In: Bioorganic and Medicinal Chemistry. 2002 ; Vol. 10, No. 9. pp. 3043-3048.
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