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 RARbeta-selective agonist BMS641 4 c 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, Cl) and the moderately bulky phenyl group at C8'' (in 4 b and 4 c) to achieve RARbeta 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 RARbeta subtype and antagonists of the RARalpha 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 (5 a) and BMS493 (6 a), 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 RARbeta inverse agonist (6 b) to an antagonist (6 c) or an agonist (6 d). Amazingly, 6 a-c commonly acted as inverse agonists for RARalpha, while 6 d and 6 e acted as regular RARalpha antagonists, not affecting co-repressor interaction. In the case of the mixed agonist/antagonist 5 a, C3-halogenation yields inverse RARalpha and RARbeta agonists (5 b-d) with the exception of iodinated 5 e, which is a regular antagonist for both these receptors. Because RARbeta 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.

Deregulation of the epigenome is recognized as cause of cancer and epigenetic factors are receiving major attention as therapeutic targets; yet, the molecular mode of action of existing epi-drugs is largely elusive. Here, we report on the decryption of the mechanism of action of UVI5008, a novel epigenetic modifier, that inhibits histone deacetylases, sirtuins, and DNA methyltransferases. UVI5008 highly efficiently induces cancer cell-selective death in a variety of models and exerts its activities in several human tumor xenografts and genetic mouse models of human breast cancer in vivo. Its anticancer activity involves independent activation of death receptors and reactive oxygen species production. Importantly, UVI5008 action is not critically dependent on p53, Bcl-2 modifying factor, and/or TNF-related apoptosisinducing ligand as cell death is efficiently induced in cells mutated or deficient for these factors limiting the risk of drug resistance development and maximizing its application spectrum. The simultaneous modulation of multiple (epigenetic) targets promises to open new avenues with unanticipated potential against cancer. Mol Cancer Ther; 10(12); 2394-404. Ó2011 AACR.