Abstract
Novel disubstituted adamantyl derivatives were synthesized and evaluated in a P-glycoprotein dependent multidrug resistance cancer cell line. The hit to lead optimization provided potent MDR reversal agents. Some potent adamantyl derivatives were more than 10-fold more potent than verapamil without considerable intrinsic cytotoxicity. The 3-trifluorophenyl derivative 14f did not affect the metabolism of CYP450 3A4, whereas most of MDR revertants had a weak inhibitory effect.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
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Adamantane / chemical synthesis
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Adamantane / chemistry*
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Adamantane / pharmacology*
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Cell Line, Tumor
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Cytochrome P-450 CYP3A / metabolism
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Drug Resistance, Multiple / drug effects*
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Drug Resistance, Neoplasm / drug effects
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Humans
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Sarcoma / drug therapy
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Structure-Activity Relationship
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Cytochrome P-450 CYP3A
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CYP3A4 protein, human
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Adamantane