Abstract
Continuous optimization of benzylic substituents on 1-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-phenylethan-1-one structure as Akt inhibitors was described in this paper. Particularly, compounds 8 and 14g exhibited high enzymatic potency against all Akt isoforms and antiproliferative effects in mantle cell lymphoma cell lines, as well as favorable cytotoxicities in patient primary cancer cells. Low micromolar doses of both 8 and 14g dose-dependently induced cell apoptosis and G2/M cell cycle arrest, also suppressed the phosphorylation level of Akt downstream targets GSK3β and S6.
Keywords:
Akt; Anticancer; Docking; Mantle cell lymphoma; Pyrrolopyrimidines.
Copyright © 2020 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Cell Cycle Checkpoints / drug effects
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Cell Proliferation / drug effects
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Drug Screening Assays, Antitumor
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Humans
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Lymphoma / drug therapy*
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Lymphoma / metabolism
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Lymphoma / pathology
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Molecular Docking Simulation
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology*
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
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Proto-Oncogene Proteins c-akt / metabolism
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Pyrimidines / chemistry
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Pyrimidines / pharmacology*
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Pyrroles / chemistry
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Pyrroles / pharmacology*
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Tumor Cells, Cultured
Substances
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Antineoplastic Agents
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Protein Kinase Inhibitors
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Pyrimidines
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Pyrroles
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pyrrolopyrimidine
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Proto-Oncogene Proteins c-akt