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

Academic Article

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.
  • Published In

    Keywords

  • Animals, Anticarcinogenic Agents, Apoptosis, Bexarotene, Binding Sites, Cell Line, Cell Proliferation, Cell Transformation, Neoplastic, Crystallography, X-Ray, Fatty Acids, Unsaturated, Female, Humans, Hyperlipidemias, Mammary Neoplasms, Experimental, Models, Molecular, Molecular Structure, Naphthalenes, Rats, Retinoid X Receptor alpha, Stereoisomerism, Structure-Activity Relationship, Tetrahydronaphthalenes, Transcriptional Activation
  • Digital Object Identifier (doi)

    Authorlist

  • Atigadda VR; Xia G; Desphande A; Boerma LJ; Lobo-Ruppert S; Grubbs CJ; Smith CD; Brouillette WJ; Muccio DD
  • Start Page

  • 5370
  • End Page

  • 5380
  • Volume

  • 57
  • Issue

  • 12