Reengineered tricyclic anti-cancer agents. Issue 19 (1st October 2015)

• Record Type: Journal Article
• Authors: Kastrinsky, David B.; Sangodkar, Jaya; Zaware, Nilesh; Izadmehr, Sudeh; Dhawan, Neil S.; Narla, Goutham; Ohlmeyer, Michael
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 19(2015)
• Page Start: 6528
• Page End: 6534
• Publication Date: 2015-10-01
• Subjects: Phenothiazine -- Dibenzazepine -- Clomipramine -- Tricyclic -- Neuroleptic; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.07.007
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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.