The FOXO (Forkhead transcription factors, Class O) proteins are a group of tumor suppressors. �FOXO1� is rendered inactive on phosphorylation, and cytoplasmic localization by the PI3K-AKT and RAS-MAPK oncogenic kinase pathways. In a cell based FOXO sequestration screen reported by Kau et al, it was revealed that tricyclic neuroleptics (chlorpromazine, trifluoperazine) reinstate FOXO1 to the nucleus in tumor cells. As part of our program to develop FOXO1 modulators, devoid of the dose limiting CNS toxicities of parent tricyclic neuroleptics, we synthesized and evaluated novel dibenzazepine and dibenzocycloheptane based analogs. Some of the key steps in the synthetic schemes include an allyl-silane addition to dibenzosuberol, and opening of functionalized epoxides with a weak dibenzazepine nucleophile in base/lewis acid free microwave conditions. These compounds demonstrated anti-proliferative activities in lung cancer H1650 cell lines. The synthesis and biological activity of these compounds will be presented in this report.

Dibenzazepine and dibenzocycloheptane based FOXO modulators

248th National Meeting (2014)

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