Highly twisted adamantyl arotinoids: Synthesis, antiproliferative effects and RXR transactivation profiles

Retinoid-related molecules with an adamantyl group (adamantyl arotinoids) have been described with selective activities towards the retinoid receptors as agonists for NR1B2 and NR1B3 (RARβ,γ) (CD437, MX3350-1) or RAR antagonists (MX781) that induce growth arrest and apoptosis in cancer cells. Since these molecules induce apoptosis independently of RAR transactivation, we set up to synthesize novel analogs with impaired RAR binding. Here we describe adamantyl arotinoids with 2,2′-disubstituted biaryl rings prepared using the Suzuki coupling of the corresponding fragments. Those with cinnamic and naphthoic acid end groups showed significant antiproliferative activity in several cancer cell lines, and this effect correlated with the induction of apoptosis as measured by caspase activity. Strikingly, some of these compounds, whereas devoid of RAR binding capacity, were able to activate RXR.

Adamantyl arotinoids (AdArs) are a subclass of atypical retinoids with strong growth inhibitory activity that induce apoptosis independently of RARs. We report herein the synthesis and biological characterization of novel AdAr derivatives designed to eliminate RAR activity and thus reduce potential toxic effects. Some of the AdArs exhibit substantial activation of RXRα, which may or may not mediate their anticancer activity.Figure optionsDownload as PowerPoint slide