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

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.

• Authors: Venkatram R Atigadda, Gang Xia, Anil Desphande, LeeAnn J Boerma, Susan Lobo-Ruppert, Clinton J Grubbs, Craig D Smith, Wayne J Brouillette, Donald D Muccio
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 57 Issue 12 Pg. 5370-80 (Jun 26 2014) ISSN: 1520-4804 [Electronic] United States
• PMID: 24801499 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anticarcinogenic Agents
• Fatty Acids, Unsaturated
• Naphthalenes
• Retinoid X Receptor alpha
• Tetrahydronaphthalenes
• Bexarotene
• UAB 30

Topics

• Animals
• Anticarcinogenic Agents (chemistry, pharmacology, toxicity)
• Apoptosis (drug effects)
• Bexarotene
• Binding Sites
• Cell Line
• Cell Proliferation (drug effects)
• Cell Transformation, Neoplastic (drug effects)
• Crystallography, X-Ray
• Fatty Acids, Unsaturated (chemistry, pharmacology, toxicity)
• Female
• Humans
• Hyperlipidemias (chemically induced)
• Mammary Neoplasms, Experimental (pathology, prevention & control)
• Models, Molecular
• Molecular Structure
• Naphthalenes (chemistry, pharmacology, toxicity)
• Rats
• Retinoid X Receptor alpha (agonists, genetics)
• Stereoisomerism
• Structure-Activity Relationship
• Tetrahydronaphthalenes (pharmacology, toxicity)
• Transcriptional Activation