The PI3K-AKT and RAS-MAPK oncogenic kinase pathways are responsible for the phosphorylation, inactivation, and cytoplasmic sequesteration of tumor suppressor -�FoxO1�.  In a cell based FOXO localization screen reported by Kau et al, it was discovered that tricyclic neuroleptics (chlorpromazine, trifluoperazine) restore FoxO1 to the nucleus in tumor cells. As part of our program to develop FoxO1 modulators, devoid of the dose limiting CNS toxicities characteristic of the parent tricyclic neuroleptics, seven novel N-(3',4',5',6',10,11-hexahydrospiro[dibenzo[a,d][7]annulene-5,2'-pyran]-4'/5'-yl)benzenesulfonamides were synthesized and evaluated. The synthesis commenced from dibenzosuberone, and involved, among key steps - Grignard addition, Grubbs-I catalyzed intramolecular ring closing metathesis, and hydroboration-oxidation reactions. Compounds were tested in H1650 cell viability assay at 1, 10, 20, 30, 40 micromolar concentrations. The most potent compound was tested in the clonogenicity assay; it also demonstrated coordinated down regulation of Akt and Erk. The synthesis and in vitro biological activity of these compounds will be presented in this report.

Tricyclic FOXO modulators

246th National Meeting (2013)

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