Abstract
We synthesized 3-aroyl-1-arylpyrrole (ARAP) derivatives as potential anticancer agents having different substituents at the pendant 1-phenyl ring. Both the 1-phenyl ring and 3-(3,4,5-trimethoxyphenyl)carbonyl moieties were mandatory to achieve potent inhibition of tubulin polymerization, binding of colchicine to tubulin, and cancer cell growth. ARAP 22 showed strong inhibition of the P-glycoprotein-overexpressing NCI-ADR-RES and Messa/Dx5MDR cell lines. Compounds 22 and 27 suppressed in vitro the Hedgehog signaling pathway, strongly reducing luciferase activity in SAG treated NIH3T3 Shh-Light II cells, and inhibited the growth of medulloblastoma D283 cells at nanomolar concentrations. ARAPs 22 and 27 represent a new potent class of tubulin polymerization and cancer cell growth inhibitors with the potential to inhibit the Hedgehog signaling pathway.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aniline Compounds / chemical synthesis
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Aniline Compounds / chemistry*
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Aniline Compounds / pharmacology
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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 Death / drug effects
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Cell Line, Tumor
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Cell Membrane Permeability / drug effects
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Colchicine / chemistry
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Drug Screening Assays, Antitumor
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Guanidines / chemical synthesis
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Guanidines / chemistry*
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Guanidines / pharmacology
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Hedgehog Proteins / antagonists & inhibitors
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Hedgehog Proteins / metabolism*
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Humans
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M Phase Cell Cycle Checkpoints / drug effects
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Mice
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Molecular Docking Simulation
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Neoplasms / drug therapy
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Neoplasms / metabolism*
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Neoplasms / pathology
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Polymerization
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Protein Binding
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Pyrroles / chemical synthesis
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Pyrroles / chemistry*
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Pyrroles / pharmacology
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Signal Transduction
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Structure-Activity Relationship
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Tubulin / chemistry
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Tubulin Modulators / chemical synthesis
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Tubulin Modulators / chemistry*
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Tubulin Modulators / pharmacology
Substances
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(1-(3-aminophenyl)-1H-pyrrol-3-yl)(3,4,5-trimethoxyphenyl)methanone
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1-(3-(3-(3,4,5-trimethoxybenzoyl)-1H-pyrrol-1-yl)phenyl)guanidine
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Aniline Compounds
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Antineoplastic Agents
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Guanidines
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Hedgehog Proteins
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Pyrroles
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Tubulin
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Tubulin Modulators
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Colchicine