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.
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Authors | Michelle S Miller, Jo-Anne Pinson, Zhaohua Zheng, Ian G Jennings, Philip E Thompson |
Journal | Bioorganic & medicinal chemistry letters
(Bioorg Med Chem Lett)
Vol. 23
Issue 3
Pg. 802-5
(Feb 01 2013)
ISSN: 1464-3405 [Electronic] England |
PMID | 23265896
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 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
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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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