Abstract
Using a rational design strategy for isoform-selective inhibition of PI3Kα, two series of novel 2,3,4,5-tetra-substituted thiophene derivatives containing either diaryl urea or N-Acylarylhydrazone scaffold were designed and synthesized. The most promising compound 12k was demonstrated to bear nanomolar PI3Kα inhibitory potency with 12, 28, 30, 196-fold selectivity against isoforms β, γ, δ and mTOR. Besides, it also showed good developability profiles in cell-based proliferation against a panel of human tumor cells as well as ADME assays. We herein report on their design, synthesis, SAR and potential developability properties.
Keywords:
2,3,4,5-Tetra-substituted thiophene derivatives; Antiproliferative activities; PI3Kα; Synthesis.
Copyright © 2020 Elsevier Masson SAS. All rights reserved.
MeSH terms
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / metabolism
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology*
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Binding Sites
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Drug Design
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Drug Screening Assays, Antitumor
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Humans
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Molecular Docking Simulation
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Molecular Structure
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Phosphatidylinositol 3-Kinases / chemistry
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors / chemical synthesis
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Phosphoinositide-3 Kinase Inhibitors / metabolism
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Phosphoinositide-3 Kinase Inhibitors / pharmacokinetics
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Phosphoinositide-3 Kinase Inhibitors / pharmacology*
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Protein Binding
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Structure-Activity Relationship
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TOR Serine-Threonine Kinases / antagonists & inhibitors
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Thiophenes / chemical synthesis
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Thiophenes / metabolism
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Thiophenes / pharmacokinetics
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Thiophenes / pharmacology*
Substances
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Antineoplastic Agents
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Phosphoinositide-3 Kinase Inhibitors
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Thiophenes
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MTOR protein, human
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TOR Serine-Threonine Kinases