Abstract
The phenothiazine and dibenzazepine tricyclics are potent neurotropic drugs with a documented but underutilized anti-cancer side effect. Reengineering these agents (TFP, CPZ, CIP) by replacing the basic amine with a neutral polar functional group (e.g., RTC-1, RTC-2) abrogated their CNS effects as demonstrated by in vitro pharmacological assays and in vivo behavioral models. Further optimization generated several phenothiazines and dibenzazepines with improved anti-cancer potency, exemplified by RTC-5. This new lead demonstrated efficacy against a xenograft model of an EGFR driven cancer without the neurotropic effects exhibited by the parent molecules. Its effects were attributed to concomitant negative regulation of PI3K-AKT and RAS-ERK signaling.
Keywords:
Clomipramine; Dibenzazepine; Neuroleptic; Phenothiazine; Tricyclic.
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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Animals
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Antineoplastic Agents / chemistry*
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use
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Cell Line, Tumor
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Cell Survival / drug effects
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Dibenzazepines / chemistry
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Heterocyclic Compounds, 3-Ring / chemistry*
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Heterocyclic Compounds, 3-Ring / pharmacology
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Heterocyclic Compounds, 3-Ring / therapeutic use
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Humans
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Mice
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Neoplasms / drug therapy
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Neoplasms / metabolism
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Phenothiazines / chemistry
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Phosphatidylinositol 3-Kinases / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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Signal Transduction / drug effects
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Transplantation, Heterologous
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Vesicular Monoamine Transport Proteins / antagonists & inhibitors
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Vesicular Monoamine Transport Proteins / metabolism
Substances
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Antineoplastic Agents
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Dibenzazepines
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Heterocyclic Compounds, 3-Ring
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Phenothiazines
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Vesicular Monoamine Transport Proteins
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Phosphatidylinositol 3-Kinases
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Proto-Oncogene Proteins c-akt
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phenothiazine
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dibenzazepine