Methyl Substitution of a Rexinoid Agonist Improves Potency and Reveals Site of Lipid Toxicity
详细信息 查看全文
- 作者：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
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：June 26, 2014
- 年：2014
- 卷：57
- 期：12
- 页码：5370-5380
- 全文大小：484K
- ISSN：1520-4804
文摘
(2E,4E,6Z,8E)-8-(3鈥?4鈥?Dihydro-1鈥?2鈥?i>H)-naphthalen-1鈥?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 hRXR伪. 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 hRXR伪-LBD, we reveal that each rexinoid, which induced hyperlipidemia, had methyl groups that interacted with helix 7 residues of the LBD.