An integrated approach to the discovery of potent agelastatin A analogues for brain tumors: Chemical synthesis and biological, physicochemical and CNS pharmacokinetic analyses

Zhimin Li, Daisuke Shigeoka, Thomas R. Caulfield, Takashi Kawachi, Yushi Qiu, Takuma Kamon, Masayoshi Arai, Han W. Tun, Takehiko Yoshimitsu

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

(-)-Agelastatin A (AA), isolated from the coral sea axinellid sponge Agelas dendromorpha, has shown a high antineoplastic activity. We have synthesized eighteen AA analogues and analyzed their cytotoxicities towards three cancer cell lines. By the structure-activity relationship (SAR) study, we identified three novel analogues with higher or comparable cytotoxic activities to AA. They were subjected to chemoinformatic analysis, which revealed physicochemical properties favoring excellent central nervous system (CNS) penetration. CNS pharmacokinetic analysis in murine models validated the chemoinformatic prediction and revealed that these analogues indeed had better CNS penetration than AA. These novel potent AA analogues deserve further evaluation for therapeutic use against cancers, particularly primary and secondary brain tumors.

Original languageEnglish (US)
Pages (from-to)1093-1098
Number of pages6
JournalMedChemComm
Volume4
Issue number7
DOIs
StatePublished - Jul 1 2013

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry

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