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Methyl substitution of a rexinoid agonist improves potency and reveals site of lipid toxicity.

Atigadda VR, Xia G, Desphande A, Boerma LJ, Lobo-Ruppert S, Grubbs CJ, Smith CD, Brouillette WJ, Muccio DD - J. Med. Chem. (2014)

Bottom Line: To evaluate how methyl substitution influenced potency and lipid biosynthesis, we synthesized four 9cUAB30 homologues with methyl substitutions at the 5-, 6-, 7-, or 8-position of the tetralone ring.The syntheses and biological evaluations of these new analogues are reported here along with the X-ray crystal structures of each homologue bound to the ligand binding domain of hRXRα.On the basis of the X-ray crystal structures of these new rexinoids and bexarotene (Targretin) bound to hRXRα-LBD, we reveal that each rexinoid, which induced hyperlipidemia, had methyl groups that interacted with helix 7 residues of the LBD.

View Article: PubMed Central - PubMed

Affiliation: Departments of †Chemistry, ‡Biochemistry and Molecular Genetics, §Medicine, and ∥Vision Sciences, University of Alabama at Birmingham , Birmingham, Alabama 35294, United States.

ABSTRACT
(2E,4E,6Z,8E)-8-(3',4'-Dihydro-1'(2'H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,4,6-octatrienoic acid, 9cUAB30, is a selective rexinoid that displays substantial chemopreventive capacity with little toxicity. 4-Methyl-UAB30, an analogue of 9cUAB30, is a potent RXR agonist but caused increased lipid biosynthesis unlike 9cUAB30. To evaluate how methyl substitution influenced potency and lipid biosynthesis, we synthesized four 9cUAB30 homologues with methyl substitutions at the 5-, 6-, 7-, or 8-position of the tetralone ring. The syntheses and biological evaluations of these new analogues are reported here along with the X-ray crystal structures of each homologue bound to the ligand binding domain of hRXRα. We demonstrate that each homologue of 9cUAB30 is a more potent agonist, but only the 7-methyl-9cUAB30 caused severe hyperlipidemia in rats. On the basis of the X-ray crystal structures of these new rexinoids and bexarotene (Targretin) bound to hRXRα-LBD, we reveal that each rexinoid, which induced hyperlipidemia, had methyl groups that interacted with helix 7 residues of the LBD.

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Structuresof 9-cis-retinoic acid, bexarotene(Targretin), 9-cis-UAB30, and four methyl homologuesof 9-cis-UAB30 (1–4). The position of the methyl group substitution on 9-cis-UAB30 uses the tetralone ring numbering scheme.
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fig1: Structuresof 9-cis-retinoic acid, bexarotene(Targretin), 9-cis-UAB30, and four methyl homologuesof 9-cis-UAB30 (1–4). The position of the methyl group substitution on 9-cis-UAB30 uses the tetralone ring numbering scheme.

Mentions: 9cUAB30 is a rexinoid containing a tetralonering rather than thetetramethyltetrahydronapthelene ring of bexarotene or the trimethylcyclohexenylring of 9cRA (Figure 1).4,5 9cUAB30,bexarotene, and 9cRA each reduce proliferation, enhance apoptosisin mammary tumors, and efficiently prevent mammary cancers in rodentmodels.6 We reported 9cRA, 9cUAB30, andbexarotene each bind to hRXRα-LBD in an L-shaped geometry, andbinding of these agonists causes a nearly identical set of conformationalchanges on the ligand binding domain of human RXRα (hRXRα-LBD)to recruit a coactivator peptide to the surface of the domain.7,8 There were small differences in these structures localized to theligand binding pocket. Both 9cRA and bexarotene occupy more volumein this pocket, and each interacts with helices 3 and 7 more than9cUAB30. These conformational changes and interactions were also presentin the 9cUAB30 homologue with a methyl group at the 4-position ofthe tetralone ring.9 This homologue of9cUAB30, 4-methyl-9cUAB30, is more potent than 9cUAB30, but it enhanceslipid biosynthesis to an extent exhibited by bexarotene rather thanits parent compound. When the gene arrays were analyzed from rat liversobtained from treatment of bexarotene, 4-methyl-9cUAB30, and 9cUAB30,both bexarotene and 4-methyl-9cUAB30 induce signaling through theRXR:LXR heterodimers and the levels of mRNA of key enzymes involvedin lipogenesis increase.10 In contrast,the levels of these key lipogenic liver enzymes of 9cUAB30 treatedrats are nearly identical to those from untreated rats, suggestingthat this rexinoid is not an agonist in liver tissues (tissue selective).


Methyl substitution of a rexinoid agonist improves potency and reveals site of lipid toxicity.

Atigadda VR, Xia G, Desphande A, Boerma LJ, Lobo-Ruppert S, Grubbs CJ, Smith CD, Brouillette WJ, Muccio DD - J. Med. Chem. (2014)

Structuresof 9-cis-retinoic acid, bexarotene(Targretin), 9-cis-UAB30, and four methyl homologuesof 9-cis-UAB30 (1–4). The position of the methyl group substitution on 9-cis-UAB30 uses the tetralone ring numbering scheme.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4216212&req=5

fig1: Structuresof 9-cis-retinoic acid, bexarotene(Targretin), 9-cis-UAB30, and four methyl homologuesof 9-cis-UAB30 (1–4). The position of the methyl group substitution on 9-cis-UAB30 uses the tetralone ring numbering scheme.
Mentions: 9cUAB30 is a rexinoid containing a tetralonering rather than thetetramethyltetrahydronapthelene ring of bexarotene or the trimethylcyclohexenylring of 9cRA (Figure 1).4,5 9cUAB30,bexarotene, and 9cRA each reduce proliferation, enhance apoptosisin mammary tumors, and efficiently prevent mammary cancers in rodentmodels.6 We reported 9cRA, 9cUAB30, andbexarotene each bind to hRXRα-LBD in an L-shaped geometry, andbinding of these agonists causes a nearly identical set of conformationalchanges on the ligand binding domain of human RXRα (hRXRα-LBD)to recruit a coactivator peptide to the surface of the domain.7,8 There were small differences in these structures localized to theligand binding pocket. Both 9cRA and bexarotene occupy more volumein this pocket, and each interacts with helices 3 and 7 more than9cUAB30. These conformational changes and interactions were also presentin the 9cUAB30 homologue with a methyl group at the 4-position ofthe tetralone ring.9 This homologue of9cUAB30, 4-methyl-9cUAB30, is more potent than 9cUAB30, but it enhanceslipid biosynthesis to an extent exhibited by bexarotene rather thanits parent compound. When the gene arrays were analyzed from rat liversobtained from treatment of bexarotene, 4-methyl-9cUAB30, and 9cUAB30,both bexarotene and 4-methyl-9cUAB30 induce signaling through theRXR:LXR heterodimers and the levels of mRNA of key enzymes involvedin lipogenesis increase.10 In contrast,the levels of these key lipogenic liver enzymes of 9cUAB30 treatedrats are nearly identical to those from untreated rats, suggestingthat this rexinoid is not an agonist in liver tissues (tissue selective).

Bottom Line: To evaluate how methyl substitution influenced potency and lipid biosynthesis, we synthesized four 9cUAB30 homologues with methyl substitutions at the 5-, 6-, 7-, or 8-position of the tetralone ring.The syntheses and biological evaluations of these new analogues are reported here along with the X-ray crystal structures of each homologue bound to the ligand binding domain of hRXRα.On the basis of the X-ray crystal structures of these new rexinoids and bexarotene (Targretin) bound to hRXRα-LBD, we reveal that each rexinoid, which induced hyperlipidemia, had methyl groups that interacted with helix 7 residues of the LBD.

View Article: PubMed Central - PubMed

Affiliation: Departments of †Chemistry, ‡Biochemistry and Molecular Genetics, §Medicine, and ∥Vision Sciences, University of Alabama at Birmingham , Birmingham, Alabama 35294, United States.

ABSTRACT
(2E,4E,6Z,8E)-8-(3',4'-Dihydro-1'(2'H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,4,6-octatrienoic acid, 9cUAB30, is a selective rexinoid that displays substantial chemopreventive capacity with little toxicity. 4-Methyl-UAB30, an analogue of 9cUAB30, is a potent RXR agonist but caused increased lipid biosynthesis unlike 9cUAB30. To evaluate how methyl substitution influenced potency and lipid biosynthesis, we synthesized four 9cUAB30 homologues with methyl substitutions at the 5-, 6-, 7-, or 8-position of the tetralone ring. The syntheses and biological evaluations of these new analogues are reported here along with the X-ray crystal structures of each homologue bound to the ligand binding domain of hRXRα. We demonstrate that each homologue of 9cUAB30 is a more potent agonist, but only the 7-methyl-9cUAB30 caused severe hyperlipidemia in rats. On the basis of the X-ray crystal structures of these new rexinoids and bexarotene (Targretin) bound to hRXRα-LBD, we reveal that each rexinoid, which induced hyperlipidemia, had methyl groups that interacted with helix 7 residues of the LBD.

Show MeSH
Related in: MedlinePlus