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

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• 作者：Anil Desph ; e ; 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
• 关键词：RXR ; retinoid X receptor ; RAR ; retinoic acid receptor ; RA ; retinoic acid ; LBD ; ligand binding domain ; IBX ; 2-iodoxybenzoic acid ; RKE ; rat kidney epithelial ; SCC ; squamous cell carcinoma ; TG ; triglycerides ; LBP ; ligand binding pocket ; THF ; tetrahydrofuran ; HMPA ; hexamethylphosphoramide ; TLC ; thin layer chromatography ; DMEM ; Dulbecco&rsquo ; s modified Eagle medium ; ER ; estrogen receptor ; GRIP-1 ; glucocorticoid receptor interacting protein-1 ; KLF4 ; Kruppel-like factor 4 ; LXRs ; liver X receptors ; NR
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：1 January, 2014
• 年：2014
• 卷：22
• 期：1
• 页码：178-185
• 全文大小：1453 K

文摘

(2E,4E,6Z,8Z)-8-(3鈥?4鈥?Dihydro-1鈥?2H)-naphthalen-1鈥?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.