Abstract
SIS3 is a specific inhibitor of Smad3 that inhibits the TGFβ1-induced phosphorylation of Smad3. In this article, a variety of SIS3 derivatives were designed and synthesized to discover potential inhibitors against P-glycoprotein-mediated multidrug resistance aided by late-stage functionalization of a 2-(4-(pyridin-2-yl)phenoxy)pyridine analogue. A novel class of potent P-gp reversal agents were investigated, and a lead compound 37 was identified as a potent P-gp reversal agent with strong bioactivity and outstanding affinity for P-gp.
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 / antagonists & inhibitors
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ATP Binding Cassette Transporter, Subfamily B / metabolism
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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 / metabolism
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Animals
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Drug Discovery / methods*
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Drug Resistance, Multiple / drug effects*
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Drug Resistance, Multiple / physiology
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Humans
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Isoquinolines / chemistry*
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Isoquinolines / metabolism
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Isoquinolines / pharmacology*
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K562 Cells
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Molecular Docking Simulation / methods
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Pyridines / chemistry*
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Pyridines / metabolism
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Pyridines / pharmacology*
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Pyrroles / chemistry*
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Pyrroles / metabolism
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Pyrroles / pharmacology*
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Smad3 Protein / antagonists & inhibitors
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Smad3 Protein / metabolism
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Xenograft Model Antitumor Assays / methods
Substances
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6,7-dimethyl-2-(2E)-3-(1-methyl-2-phenyl-1H-pyrrolo(2,3-b)pyridin-3-yl-prop-2-enoyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride
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ABCB1 protein, human
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Isoquinolines
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Pyridines
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Pyrroles
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Smad3 Protein