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Bioorg Med Chem. 2015 Oct 1;23(19):6528-34. doi: 10.1016/j.bmc.2015.07.007. Epub 2015 Sep 11.

Reengineered tricyclic anti-cancer agents.

Author information

1
Department of Structural and Chemical Biology, Icahn School of Medicine at Mt. Sinai, 1425 Madison Avenue, New York, NY 10029, United States.
2
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mt. Sinai, 1425 Madison Avenue, New York, NY 10029, United States.
3
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mt. Sinai, 1425 Madison Avenue, New York, NY 10029, United States; Department of Medicine, Institute for Transformative Molecular Medicine, Case Western Reserve University, 2103 Cornell Road, Cleveland, OH 44106, United States.
4
Department of Structural and Chemical Biology, Icahn School of Medicine at Mt. Sinai, 1425 Madison Avenue, New York, NY 10029, United States. Electronic address: michael.ohlmeyer@mssm.edu.

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

PMID:
26372073
DOI:
10.1016/j.bmc.2015.07.007
[Indexed for MEDLINE]

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