Abstract
To find a drug to overcome P-glycoprotein associated multidrug resistance, we synthesized 43 new isoprenoid derivatives. Ten compounds were effective in an in vitro assay with the human MDR-type resistant carcinoma KB/VJ-300 and MRP-type KB/VP-4 cell lines. One of the most effective compounds, N-5228 [trans-N,N'-bis(3,4-dimethoxybenzyl)-N-solanesyl-1,2-diaminocyclohexane, mol. wt 1100.481, was tested in P388/VCR-bearing mice. It showed a antitumor effect on MDR-type resistant tumor cells. Moreover, N-5228 potentiated the accumulation of [3H]vincristine in drug-resistant cells and blocked [3H]azidopine photoaffinity labeling of P-glycoprotein molecules in MDR-type resistant cell membranes. We think that N-5228 is promising as a lead compound in the screening of resistance reversing drugs for multidrug resistant cancers.
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 / antagonists & inhibitors*
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / physiology
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Affinity Labels
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Animals
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Antibiotics, Antineoplastic / pharmacology
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Antineoplastic Agents, Phytogenic / pharmacology
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Cell Membrane / metabolism
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Cyclohexanes / chemical synthesis
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Cyclohexanes / chemistry
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Cyclohexanes / pharmacology*
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Doxorubicin / pharmacology
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Drug Resistance, Multiple
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Drug Resistance, Neoplasm
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Female
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Humans
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Leukemia P388 / drug therapy
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Mice
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Mice, Inbred Strains
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Terpenes / chemical synthesis
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Terpenes / chemistry
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Terpenes / pharmacology*
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Tumor Cells, Cultured
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Vincristine / pharmacology
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Affinity Labels
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Antibiotics, Antineoplastic
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Antineoplastic Agents, Phytogenic
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Cyclohexanes
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Terpenes
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Vincristine
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Doxorubicin