Methyl-substituted conformationally constrained rexinoid agonists for the retinoid X receptors demonstrate improved efficacy for cancer therapy and prevention |
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| Institution: | 1. Department of Chemistry, University of Alabama at Birmingham, Birmingham, AL 35294, USA;2. Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA;3. Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA;4. Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA;5. Department of Vision Sciences, University of Alabama at Birmingham, Birmingham, AL 35294, USA;6. Department of Surgical Oncology, University of Illinois, Chicago, IL 60612, USA;1. NeuroGate Therapeutics, Inc., 150 Fayetteville Street, Suite 2300, Raleigh, NC 27601, United States;2. Department of Pharmacology and Neuroscience Graduate Interdisciplinary Program, College of Medicine, University of Arizona, Tucson, AZ 85742, United States;3. Program in Medical Neuroscience, Paul and Carole Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, United States;4. Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, United States;5. Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, United States;6. Department of Chemistry, University of North Carolina, Chapel Hill, NC 27599, United States;1. Molecular Sciences and Candidate Optimization, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, United States;2. Neuroscience Discovery Biology, Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, United States;1. School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, PR China;2. School of Medicine, Nankai University, Tianjin 300072, PR China;3. Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100094, PR China;4. Jiangxi University of Traditional Chinese Medicine, No. 56 Yangmin Road, Nanchang 330006, PR China |
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| 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. |
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| Keywords: | Conformationally constrained retinoids Rexinoids Cancer prevention Ligand–protein crystal structures |
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