(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.
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.
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