Design, Synthesis, and Structure−Activity Analysis of Isoform-Selective Retinoic Acid Receptor β Ligands

Lund, Birgitte W.; Knapp, Anne E.; Piu, Fabrice; Gauthier, Natalie K; Begtrup, Mikael; Hacksell, Uli; Olsson, Roger

doi:10.1021/jm801532e

Cited by 29 publications

(24 citation statements)

References 23 publications

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“…[29] RARb-selective agonists have been described, [23] including a potent and selective agonist of the RARb2 isoform (one of the four isoforms originated by differential use of two promoters and alternative splicing) [1] with druglike properties and good oral bioavailability in rats. [53,54] RARb subtype-selective antagonists and inverse agonists are, however, unknown.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2009

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2009

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“…Comparison of 10 with the selective RARβ agonist AC-261066 8 showed that in our hands, 10 is a more potent and selective RARβ agonist (Table 4). Whilst compound 10 is marginally less potent than CD 2019, it has a better selectivity for RARβ over RARα and RARγ and is over two orders of magnitude less lipophilic.…”

mentioning

confidence: 69%

Discovery and lead optimisation of a potent, selective and orally bioavailable RARβ agonist for the potential treatment of nerve injury

Goncalves

Clarke

Jarvis

et al. 2019

Bioorganic & Medicinal Chemistry Letters

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“…The lower EC 50 (0.03 µM) value observed for 9‐cis RA suggests that it is a more efficient ligand than retinal for the RARs. Although it is possible that retinal directly binds to the RARs, albeit at a lower affinity, this possibility is unlikely as retinaldehyde lacks the critical carboxylic acid moiety that hydrogen bonds with Arg278 and Ser289 residues of the RAR (Lund et al, 2005, 2009). These data suggest that retinaldehyde is being oxidized by RALDH enzyme(s) to retinoic acid, which in turn is driving expression from the RARE‐promoter complex (Duester et al, 2003).…”

Section: Resultsmentioning

confidence: 99%

Nitrofen induces apoptosis independently of retinaldehyde dehydrogenase (RALDH) inhibition

Kling

Cavicchio

Sollinger

et al. 2010

Birth Defects Research Pt B

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Design, Synthesis, and Structure−Activity Analysis of Isoform-Selective Retinoic Acid Receptor β Ligands

Cited by 29 publications

References 23 publications

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

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

Discovery and lead optimisation of a potent, selective and orally bioavailable RARβ agonist for the potential treatment of nerve injury

Nitrofen induces apoptosis independently of retinaldehyde dehydrogenase (RALDH) inhibition

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