Abstract
We are interested in developing novel natural product-derived P-gp inhibitors to reverse cancer drug resistance. Here, we have synthesized 55 novel derivatives of methylated epigallocatechin (EGC), gallocatechin (GC), and dihydromyricetin (DHM). Three EGC derivatives (23, 35, and 36) and three GC derivatives (50, 51, and 53) are significantly better than epigallocatechin gallate (EGCG) with a relative fold (RF) ranging from 31.4 to 53.6. The effective concentration (EC50) of 23 and 51 ranges from 102 to 195 nM. Compounds 23 and 51 are noncytotoxic to fibroblasts with IC50 > 100 μM. Compound 23 is specific for P-gp without modulating activity toward MRP1 or BCRP. Compounds 23 and 51 are non-P-gp substrates. Important pharmacophores for P-gp modulation were identified. In summary, methylated EGC and GC derivatives represent a new class of potent, specific, noncytotoxic, and nonsubstrate P-gp modulators.
Publication types
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Evaluation Study
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B / metabolism*
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ATP Binding Cassette Transporter, Subfamily G, Member 2
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ATP-Binding Cassette Transporters / metabolism
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Catechin / analogs & derivatives*
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Catechin / chemistry
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Catechin / pharmacology
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Cell Proliferation / drug effects
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Drug Resistance, Multiple / drug effects*
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Drug Resistance, Neoplasm / drug effects*
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Flavonols / chemistry
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Flavonols / pharmacology*
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Humans
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Methylation
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Models, Molecular
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Molecular Structure
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Neoplasm Proteins / metabolism
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Neoplasms / drug therapy
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Neoplasms / pathology
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Structure-Activity Relationship
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Tumor Cells, Cultured
Substances
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ABCG2 protein, human
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily G, Member 2
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ATP-Binding Cassette Transporters
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Antineoplastic Agents
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Flavonols
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Neoplasm Proteins
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Catechin
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epigallocatechin gallate
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gallocatechol
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dihydromyricetin