Abstract
The synthesis of new indolopyrrolobenzodiazepine derivatives is described. Six compounds were selected for evaluation of cytotoxicity towards acute myeloid leukemia (AML) cells and normal fibroblasts. One compound (29) showed selective AML cell death induction. Its action was only partly overcome by knock-down of p53 or Bcl-2 overexpression, suggesting a strong activation of intrinsic apoptotic pathways.
Keywords:
Acute myeloid leukemia; Apoptosis; Fibroblasts; Indolopyrrolobenzodiazepine; Pim kinase inhibition.
Copyright © 2015 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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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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Benzodiazepines / chemical synthesis
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Benzodiazepines / chemistry*
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Benzodiazepines / pharmacology*
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Cell Line, Tumor
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Cell Survival / drug effects
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Humans
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Leukemia, Myeloid, Acute / metabolism
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Leukemia, Myeloid, Acute / pathology
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Proto-Oncogene Proteins c-pim-1 / antagonists & inhibitors
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Proto-Oncogene Proteins c-pim-1 / metabolism
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Structure-Activity Relationship
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Tumor Suppressor Protein p53 / antagonists & inhibitors
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism
Substances
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Antineoplastic Agents
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Tumor Suppressor Protein p53
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Benzodiazepines
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PIM3 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-pim-1