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 Citations (Scopus)

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
Pages (from-to)1093-1098
Number of pages6
JournalMedChemComm
Volume4
Issue number7
DOIs
Publication statusPublished - Jul 2013
Externally publishedYes

Fingerprint

Pharmacokinetics
Neurology
Brain Neoplasms
Tumors
Brain
Central Nervous System
Agelas
Anthozoa
Porifera
Therapeutic Uses
Structure-Activity Relationship
Cytotoxicity
Oceans and Seas
Antineoplastic Agents
Neoplasms
Cells
agelastatin A
Cell Line

ASJC Scopus subject areas

  • Biochemistry
  • Pharmaceutical Science

Cite this

An integrated approach to the discovery of potent agelastatin A analogues for brain tumors : Chemical synthesis and biological, physicochemical and CNS pharmacokinetic analyses. / Li, Zhimin; Shigeoka, Daisuke; Caulfield, Thomas R.; Kawachi, Takashi; Qiu, Yushi; Kamon, Takuma; Arai, Masayoshi; Tun, Han W.; Yoshimitsu, Takehiko.

In: MedChemComm, Vol. 4, No. 7, 07.2013, p. 1093-1098.

Research output: Contribution to journalArticle

Li, Zhimin ; Shigeoka, Daisuke ; Caulfield, Thomas R. ; Kawachi, Takashi ; Qiu, Yushi ; Kamon, Takuma ; Arai, Masayoshi ; Tun, Han W. ; Yoshimitsu, Takehiko. / An integrated approach to the discovery of potent agelastatin A analogues for brain tumors : Chemical synthesis and biological, physicochemical and CNS pharmacokinetic analyses. In: MedChemComm. 2013 ; Vol. 4, No. 7. pp. 1093-1098.
@article{fb4abeba3762407f9a4d8fa2a5aeb162,
title = "An integrated approach to the discovery of potent agelastatin A analogues for brain tumors: Chemical synthesis and biological, physicochemical and CNS pharmacokinetic analyses",
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.",
author = "Zhimin Li and Daisuke Shigeoka and Caulfield, {Thomas R.} and Takashi Kawachi and Yushi Qiu and Takuma Kamon and Masayoshi Arai and Tun, {Han W.} and Takehiko Yoshimitsu",
year = "2013",
month = "7",
doi = "10.1039/c3md00094j",
language = "English",
volume = "4",
pages = "1093--1098",
journal = "MedChemComm",
issn = "2040-2503",
publisher = "Royal Society of Chemistry",
number = "7",

}

TY - JOUR

T1 - An integrated approach to the discovery of potent agelastatin A analogues for brain tumors

T2 - Chemical synthesis and biological, physicochemical and CNS pharmacokinetic analyses

AU - Li, Zhimin

AU - Shigeoka, Daisuke

AU - Caulfield, Thomas R.

AU - Kawachi, Takashi

AU - Qiu, Yushi

AU - Kamon, Takuma

AU - Arai, Masayoshi

AU - Tun, Han W.

AU - Yoshimitsu, Takehiko

PY - 2013/7

Y1 - 2013/7

N2 - (-)-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.

AB - (-)-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.

UR - http://www.scopus.com/inward/record.url?scp=84879863287&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84879863287&partnerID=8YFLogxK

U2 - 10.1039/c3md00094j

DO - 10.1039/c3md00094j

M3 - Article

AN - SCOPUS:84879863287

VL - 4

SP - 1093

EP - 1098

JO - MedChemComm

JF - MedChemComm

SN - 2040-2503

IS - 7

ER -