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Regioselective synthesis of 5- and 6-methoxybenzimidazole-1,3,5-triazines as inhibitors of phosphoinositide 3-kinase.

Abstract
Phosphoinositide 3-kinases (PI3K) hold significant therapeutic potential as novel targets for the treatment of cancer. ZSTK474 (4a) is a potent, pan-PI3K inhibitor currently under clinical evaluation for the treatment of cancer. Structural studies have shown that derivatisation at the 5- or 6-position of the benzimidazole ring may influence potency and isoform selectivity. However, synthesis of these derivatives by the traditional route results in a mixture of the two regioisomers. We have developed a straightforward regioselective synthesis that gave convenient access to 5- and 6-methoxysubstituted benzimidazole derivatives of ZSTK474. While 5-methoxy substitution abolished activity at all isoforms, the 6-methoxy substitution is consistently 10-fold more potent. This synthesis will allow convenient access to further 6-position derivatives, thus allowing the full scope of the structure-activity relationships of ZSTK474 to be probed.
AuthorsMichelle S Miller, Jo-Anne Pinson, Zhaohua Zheng, Ian G Jennings, Philip E Thompson
JournalBioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 23 Issue 3 Pg. 802-5 (Feb 01 2013) ISSN: 1464-3405 [Electronic] England
PMID23265896 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2012 Elsevier Ltd. All rights reserved.
Chemical References
  • Aniline Compounds
  • Benzimidazoles
  • Enzyme Inhibitors
  • Nitro Compounds
  • Phosphoinositide-3 Kinase Inhibitors
  • Triazines
  • ZSTK474
  • 2-methoxy-5-methyl-4-nitroaniline
Topics
  • Aniline Compounds (chemistry)
  • Benzimidazoles (chemical synthesis, chemistry, pharmacology)
  • Enzyme Activation (drug effects)
  • Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
  • Nitro Compounds (chemistry)
  • Phosphoinositide-3 Kinase Inhibitors
  • Stereoisomerism
  • Structure-Activity Relationship
  • Triazines (chemical synthesis, chemistry, pharmacology)

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