Abstract
A new hybrid template was designed by combining the structural features of phosphodiesterase 4 (PDE4) inhibitors with several heterocyclic moieties which present an integral part in the skeleton of many apoptotic agents. Thirteen compounds of the synthesized hybrids displayed higher inhibitory activity against PDE4B than the reference drug, roflumilast. Further investigation indicated that compounds 13b and 20 arrested the cell cycle at the G2/M phase and the pre-G1 phase, and induced cell death by apoptosis of A549 cells in a caspase-dependent manner.
Keywords:
apoptosis; caspase; cell cycle arrest; phosphodiesterase 4.
© 2018 Deutsche Pharmazeutische Gesellschaft.
MeSH terms
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Aminopyridines / chemical synthesis
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Aminopyridines / chemistry
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Aminopyridines / pharmacology*
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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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Apoptosis / drug effects
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Benzamides / chemical synthesis
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Benzamides / chemistry
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Benzamides / pharmacology*
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Cell Cycle / drug effects
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism*
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Cyclopropanes / chemical synthesis
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Cyclopropanes / chemistry
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Cyclopropanes / pharmacology
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Dose-Response Relationship, Drug
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Drug Design*
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Drug Screening Assays, Antitumor
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Heterocyclic Compounds / chemical synthesis
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Heterocyclic Compounds / chemistry
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Heterocyclic Compounds / pharmacology*
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Humans
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Models, Molecular
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Molecular Structure
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Phosphodiesterase 4 Inhibitors / chemical synthesis
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Phosphodiesterase 4 Inhibitors / chemistry
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Phosphodiesterase 4 Inhibitors / pharmacology*
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Structure-Activity Relationship
Substances
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Aminopyridines
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Antineoplastic Agents
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Benzamides
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Cyclopropanes
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Heterocyclic Compounds
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Phosphodiesterase 4 Inhibitors
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Roflumilast
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Cyclic Nucleotide Phosphodiesterases, Type 4
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PDE4B protein, human