4m8h › Citations

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

Desphande A, Xia G, Boerma LJ, Vines KK, Atigadda VR, Lobo-Ruppert S, Grubbs CJ, Moeinpour FL, Smith CD, Christov K, Brouillette WJ, Muccio DD
Bioorg Med Chem 22 178-85 (2014)
Cited: 16 times
EuropePMC logo PMID: 24359708

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.

Articles - 4m8h mentioned but not cited (2)

  1. Methyl-substituted conformationally constrained rexinoid agonists for the retinoid X receptors demonstrate improved efficacy for cancer therapy and prevention. Desphande A, Xia G, Boerma LJ, Vines KK, Atigadda VR, Lobo-Ruppert S, Grubbs CJ, Moeinpour FL, Smith CD, Christov K, Brouillette WJ, Muccio DD. Bioorg Med Chem 22 178-185 (2014)
  2. A multidisciplinary approach disclosing unexplored Aflatoxin B1 roles in severe impairment of vitamin D mechanisms of action. Persico M, Sessa R, Cesaro E, Dini I, Costanzo P, Ritieni A, Fattorusso C, Grosso M. Cell Biol Toxicol 39 1275-1295 (2023)


Reviews citing this publication (2)

  1. A review of the molecular design and biological activities of RXR agonists. de Almeida NR, Conda-Sheridan M. Med Res Rev 39 1372-1397 (2019)
  2. Translation of a Tissue-Selective Rexinoid, UAB30, to the Clinic for Breast Cancer Prevention. Muccio DD, Atigadda VR, Brouillette WJ, Bland KI, Krontiras H, Grubbs CJ. Curr Top Med Chem 17 676-695 (2017)

Articles citing this publication (12)

  1. Conformationally Defined Rexinoids and Their Efficacy in the Prevention of Mammary Cancers. Atigadda VR, Xia G, Deshpande A, Wu L, Kedishvili N, Smith CD, Krontiras H, Bland KI, Grubbs CJ, Brouillette WJ, Muccio DD. J Med Chem 58 7763-7774 (2015)
  2. Retinoid X Receptor Agonists Upregulate Genes Responsible for the Biosynthesis of All-Trans-Retinoic Acid in Human Epidermis. Wu L, Chaudhary SC, Atigadda VR, Belyaeva OV, Harville SR, Elmets CA, Muccio DD, Athar M, Kedishvili NY. PLoS One 11 e0153556 (2016)
  3. Methyl substitution of a rexinoid agonist improves potency and reveals site of lipid toxicity. Atigadda VR, Xia G, Desphande A, Boerma LJ, Lobo-Ruppert S, Grubbs CJ, Smith CD, Brouillette WJ, Muccio DD. J Med Chem 57 5370-5380 (2014)
  4. TRC4, an improved triptolide derivative, specifically targets to truncated form of retinoid X receptor-alpha in cancer cells. Wang PY, Zeng WJ, Liu J, Wu YL, Ma Y, Zeng Z, Pang JY, Zhang XK, Yan X, Wong AST, Zeng JZ. Biochem Pharmacol 124 19-28 (2017)
  5. Pharmacogenomic analysis of retinoic-acid induced dyslipidemia in congenic rat model. Krupková M, Liška F, Sedová L, Křenová D, Křen V, Seda O. Lipids Health Dis 13 172 (2014)
  6. Stability of the Retinoid X Receptor-α Homodimer in the Presence and Absence of Rexinoid and Coactivator Peptide. Yang Z, Muccio DD, Melo N, Atigadda VR, Renfrow MB. Biochemistry 60 1165-1177 (2021)
  7. A Randomized, Placebo-Controlled, Double-Blind, Dose Escalation, Single Dose, and Steady-State Pharmacokinetic Study of 9cUAB30 in Healthy Volunteers. Kolesar JM, Andrews S, Green H, Havighurst TC, Wollmer BW, DeShong K, Laux DE, Krontiras H, Muccio DD, Kim K, Grubbs CJ, House MG, Parnes HL, Heckman-Stoddard BM, Bailey HH. Cancer Prev Res (Phila) 12 903-912 (2019)
  8. An Isochroman Analog of CD3254 and Allyl-, Isochroman-Analogs of NEt-TMN Prove to Be More Potent Retinoid-X-Receptor (RXR) Selective Agonists Than Bexarotene. Jurutka PW, di Martino O, Reshi S, Mallick S, Sausedo MA, Moen GA, Lee IJ, Ivan DJ, Krall TD, Peoples SJ, Perez A, Tromba L, Le A, Khadka I, Petros R, Savage BM, Salama E, Salama J, Ziller JW, Noh Y, Lee MY, Liu W, Welch JS, Marshall PA, Wagner CE. Int J Mol Sci 23 16213 (2022)
  9. Increased Molecular Flexibility Widens the Gap between K i and K d values in Screening for Retinoid X Receptor Modulators. Watanabe M, Nakamura-Nakayama M, Fujihara M, Kawasaki M, Nakano S, Kakuta H. ACS Med Chem Lett 13 211-217 (2022)
  10. Modeling, Synthesis, and Biological Evaluation of Potential Retinoid-X-Receptor (RXR) Selective Agonists: Analogs of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahyro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and 6-(Ethyl(4-isobutoxy-3-isopropylphenyl)amino)nicotinic Acid (NEt-4IB). Jurutka PW, di Martino O, Reshi S, Mallick S, Sabir ZL, Staniszewski LJP, Warda A, Maiorella EL, Minasian A, Davidson J, Ibrahim SJ, Raban S, Haddad D, Khamisi M, Suban SL, Dawson BJ, Candia R, Ziller JW, Lee MY, Liu C, Liu W, Marshall PA, Welch JS, Wagner CE. Int J Mol Sci 22 12371 (2021)
  11. Conformationally Defined Rexinoids for the Prevention of Inflammation and Nonmelanoma Skin Cancers. Atigadda VR, Kashyap MP, Yang Z, Chattopadhyay D, Melo N, Sinha R, Belyaeva OV, Chou CF, Chang PL, Kedishvili NY, Grubbs CJ, Renfrow MB, Muccio DD, Elmets CA, Athar M. J Med Chem 65 14409-14423 (2022)
  12. Next-generation retinoid X receptor agonists increase ATRA signaling in organotypic epithelium cultures and have distinct effects on receptor dynamics. Melo N, Belyaeva OV, Berger WK, Halasz L, Yu J, Pilli N, Yang Z, Klyuyeva AV, Elmets CA, Atigadda V, Muccio DD, Kane MA, Nagy L, Kedishvili NY, Renfrow MB. J Biol Chem 299 102746 (2023)


Quick links