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Reengineered tricyclic anti-cancer agents.

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.

SUBMITTER: Kastrinsky DB

PROVIDER: S-EPMC8293910 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Reengineered tricyclic anti-cancer agents.

Kastrinsky David B DB Sangodkar Jaya J Zaware Nilesh N Izadmehr Sudeh S Dhawan Neil S NS Narla Goutham G Ohlmeyer Michael M

Bioorganic & medicinal chemistry 20150911 19

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 ...[more]

PMID: 26372073

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