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

Abstract

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.

Retinoid-independent motor neurogenesis from human embryonic stem cells reveals a medial columnar ground state

“…2e–g, 11.2±0.9%). To further confirm retinoid-independent MN specification, we next differentiated hESCs in the presence of the RAR and RXR retinoid receptor antagonists UVI2024 and UVI3003 (refs 28, 29). The efficacy of these compounds was confirmed by demonstrating inhibition of RA-induced HOXB4 and HOXC5 gene expression in control cultures (Supplementary Fig.…”

“…The synthesis of UVI2024, also called BMS493, follows the methodology described recently for the preparation of the halogenated derivatives28. A description of the synthetic method and the characterization data is described in the Supplementary Methods.…”

Dual RXR Agonists and RAR Antagonists Based on the Stilbene Retinoid Scaffold

“…31 Reduction of naphthoate 14 with DIBAL H NMR spectra) of stilbenoids 22a,b,d in good yield. These esters were used in the next saponification step without further purification, due to their ease of isomerization to the Z isomers, and furnished the final arotinoids 11a,b,d (67−73%).…”

“…31 The resulting model showed the two phenyl moieties at C5 and C8 positions running almost perpendicular to the ethenylbenzoic acid buried in a predominantly hydrophobic pocket (Figure 4). Unrestrained molecular dynamics simulations 31 showed a notably stable behavior reflecting that the overall architecture of the protein was preserved for the whole length of the simulation, including the ionic bridge anchor. The evolution of the root-mean-square deviation (rmsd) of 11a with respect to the initial structure shows rmsd lower than 0.5 Å (see Supporting Information) and maintains the ionic bridge of the carboxylate to Arg276 ( Figure 4).…”

Retinoid Receptors and Therapeutic Applications of RAR/RXR Modulators

“…Stilbene arotinoids 7.3-7.4 exhibited in general inverse agonistic profiles with RAR / subtype selectivity and RAR antagonism. Halogens at C3 in this series convert the parent RAR / weak antagonist (7.4b) into a potent RAR / inverse agonist and RAR antagonist (compound 7.4c) [57].…”