Abstract
A series of imidazole-containing methyl ethers (4-5) have been designed and synthesized as potent and selective farnesyltransferase inhibitors (FTIs) by transposition of the D-ring to the methyl group on the imidazole of the previously reported FTIs 3. Several compounds such as 4h and 5b demonstrate superior enzymatic activity to the current benchmark compound tipifarnib (1) with IC(50) values in the lower subnanomolar range, while maintaining excellent cellular activity comparable to tipifarnib. The compounds are characterized as being simple, easier to make, and possess no chiral center involved.
MeSH terms
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Alkyl and Aryl Transferases / antagonists & inhibitors*
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Alkyl and Aryl Transferases / chemistry*
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Cell Line, Transformed
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Crystallography, X-Ray
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Ethers / chemical synthesis*
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Ethers / chemistry
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Ethers / pharmacology
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Farnesyltranstransferase
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Genes, ras
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Humans
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Imidazoles / chemical synthesis*
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Imidazoles / chemistry
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Imidazoles / pharmacology
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Mice
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Models, Molecular
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NIH 3T3 Cells
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Quinolones / chemistry
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Structure-Activity Relationship
Substances
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Antineoplastic Agents
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Ethers
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Imidazoles
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Quinolones
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Alkyl and Aryl Transferases
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Farnesyltranstransferase
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tipifarnib