C3 Halogen and C8 Substituents on Stilbene Arotinoids Modulate Retinoic Acid Receptor Subtype Function

The synthesis and biological evaluation of the entire series of C3-halogenated derivatives and bulkier substituents at the C8 '' position of the parent stilbene-based RAR beta-selective agonist BMS641 4c was undertaken. The synthesis uses an E-selective Horner-Wadsworth-Emmons (HWE) condensation of C8-substituted C5-dimethyl dihydronaphthaldehyde and the benzylic phosphonates derived from the C3-halogenated benzoates to construct the stilbene skeleton. Transactivation studies revealed the synergistic effect of small halogen atoms at C3 (F, CI) and the moderately bulky phenyl group at C8 '' (in 4 b and 4 c) to achieve RAR beta selectivity. Our results, supported by computational studies, provide a structural rationale for the mixed agonist-antagonist activities of these arotinoids, which are potent agonists of the RAR beta subtype and antagonists of the RAR alpha paralogue. Moreover, transitions from partial agonists to inverse agonists and antagonists can be accomplished with the incorporation of the same halogen atoms into the structures of known modulators BMS701 (5a) and BMS493 (6a), which have bulkier substituents than phenyl (p-tolyl and phenylethynyl, respectively) at C8 ''. Conversely, incorporation of halogen atoms in 6 a converted the ligand from an RAR beta inverse agonist (6 b) to an antagonist (6 c) or an agonist (6 d). Amazingly, 6 a-c commonly acted as inverse agonists for RARa, while 6 d and 6 e acted as regular RAR alpha antagonists, not affecting co-repressor interaction. In the case of the mixed agonist/antagonist 5a, C3-halogenation yields inverse RAR alpha and RAR beta agonists (5 b-d) with the exception of iodinated 5 e, which is a regular antagonist for both these receptors. Because RAR beta gene expression is frequently deleted or epigenetically silenced in several tumor cells, the novel repertoire of receptor and function-selective RAR agonists, mixed agonist/antagonists, regular antagonists, and inverse agonists will be useful in the elucidation of the mechanism of tumor suppression by retinoids.