Reengineered tricyclic anti-cancer agents

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• 作者：David B. Kastrinsky^a ; Jaya Sangodkar^b ; Nilesh Zaware^a ; Sudeh Izadmehr^b ; Neil S. Dhawan^b ; Goutham Narla^b ; ^c ; Michael Ohlmeyer^a ; ^{michael.ohlmeyer@mssm.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Phenothiazine ; Dibenzazepine ; Clomipramine ; Tricyclic ; Neuroleptic
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2015
• 出版时间：1 October 2015
• 年：2015
• 卷：23
• 期：19
• 页码：6528-6534
• 全文大小：1196 K

文摘

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.