Methyl-substituted conformationally constrained rexinoid agonists for the retinoid X receptors demonstrate improved efficacy for cancer therapy and prevention.

Academic Article

Abstract

  • (2E,4E,6Z,8Z)-8-(3',4'-Dihydro-1'(2H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,3,6-octatrienoinic acid, 9cUAB30, is a selective rexinoid for the retinoid X nuclear receptors (RXR). 9cUAB30 displays substantial chemopreventive capacity with little toxicity and is being translated to the clinic as a novel cancer prevention agent. To improve on the potency of 9cUAB30, we synthesized 4-methyl analogs of 9cUAB30, which introduced chirality at the 4-position of the tetralone ring. The syntheses and biological evaluations of the racemic homolog and enantiomers are reported. We demonstrate that the S-enantiomer is the most potent and least toxic even though these enantiomers bind in a similar conformation in the ligand binding domain of RXR.
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    Keywords

  • 2-iodoxybenzoic acid, Cancer prevention, Conformationally constrained retinoids, DMEM, Dulbecco’s modified Eagle medium, ER, GRIP-1, HMPA, IBX, KLF4, Kruppel-like factor 4, LBD, LBP, LXRs, Ligand–protein crystal structures, NR, PDB, RA, RAR, RKE, RMSD, RXR, Rexinoids, SCC, TG, THF, TLC, estrogen receptor, glucocorticoid receptor interacting protein-1, hexamethylphosphoramide, ligand binding domain, ligand binding pocket, liver X receptors, nuclear receptor, protein data bank, rat kidney epithelial, retinoic acid, retinoic acid receptor, retinoid X receptor, root mean square deviation, squamous cell carcinoma, tetrahydrofuran, thin layer chromatography, triglycerides, Humans, Ligands, Molecular Conformation, Neoplasms, Retinoid X Receptors, Retinoids
  • Digital Object Identifier (doi)

    Authorlist

  • Desphande A; Xia G; Boerma LJ; Vines KK; Atigadda VR; Lobo-Ruppert S; Grubbs CJ; Moeinpour FL; Smith CD; Christov K
  • Start Page

  • 178
  • End Page

  • 185
  • Volume

  • 22
  • Issue

  • 1