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

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.

• Authors: Anil Desphande, Gang Xia, LeeAnn J Boerma, Kimberly K Vines, Venkatram R Atigadda, Susan Lobo-Ruppert, Clinton J Grubbs, Fariba L Moeinpour, Craig D Smith, Konstantin Christov, Wayne J Brouillette, Donald D Muccio
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 22 Issue 1 Pg. 178-85 (Jan 01 2014) ISSN: 1464-3391 [Electronic] England
• PMID: 24359708 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Ltd. All rights reserved.

Chemical References

• KLF4 protein, human
• Klf4 protein, rat
• Kruppel-Like Factor 4
• Ligands
• Retinoid X Receptors
• Retinoids

Topics

• Humans
• Kruppel-Like Factor 4
• Ligands
• Molecular Conformation
• Neoplasms (prevention & control, therapy)
• Retinoid X Receptors (metabolism)
• Retinoids (chemistry, metabolism)