Abstract
The methods described in this chapter concern procedures for the design, synthesis, and in vitro biological evaluation of an array of potent retinoid-X-receptor (RXR) agonists employing 6-(ethyl(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino)nicotinic acid (NEt-TMN), and recently reported NEt-TMN analogs, as a case study. These methods have been extensively applied beyond the present case study to generate several analogs of other potent RXR agonists (rexinoids), particularly the RXR agonist known as bexarotene (Bex), a Food and Drug Administration (FDA) approved drug for cutaneous T-cell lymphoma that is also often prescribed, off-label, for breast, lung, and other human cancers. Common side effects with Bex treatment include hypertriglyceridemia and hypothyroidism, because of off-target activation or inhibition of other nuclear receptor pathways impacted by RXR. Because rexinoids are often selective for RXR, versus the retinoic-acid-receptor (RAR), cutaneous toxicity is often avoided as a side effect for rexinoid treatment. Several other potent RXR agonists, and their analogs, have been reported in the literature and rigorously evaluated (often in comparison to Bex) as potential cancer therapeutics with unique activity and side-effect profiles. Some of the more prominent examples include LGD100268, CD3254, and 9-cis-UAB30, to name only a few. Hence, the methods described herein are more widely applicable to a diverse array of RXR agonists.
In terms of design, the structure-activity relationship (SAR) study is usually performed by modifying three distinct areas of the rexinoid base structure, either of the nonpolar or polar sides of the rexinoid and/or the linkage that joins them. For the synthesis of the modified base-structure analogs, often identical synthetic strategies used to access the base-structure are applied; however, reasonable alternative synthetic routes may need to be explored if the modified analog intermediates encounter bottlenecks where yields are negligible for a given step in the base-structure route. In fact, this particular problem was encountered and successfully resolved in our case study for generating an array of NEt-TMN analogs.
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Mangelsdorf DJ, Evans RM (1994) The retinoids. Academic Press, Orlando, FL
Leid M, Kastner P, Chambon P (1992) Multiplicity generates diversity in the retinoic acid signalling pathways. Trends Biochem Sci 17:427–433
Lala DS, Mukherjee R, Schulman IG, Koch SSC, Dardashti LJ, Nadzan AM et al (1996) Activation of specific RXR heterodimers by an antagonist of RXR homodimers. Nature 383:450
Mangelsdorf DJ, Ong ES, Dyck JA, Evans RM (1990) Nuclear receptor that identifies a novel retinoic acid response pathway. Nature 345:224
Jong L, Lehmann JM, Hobbs PD, Harlev E, Huffman JC, Pfahl M et al (1993) Conformational effects on retinoid receptor selectivity. 1. Effect of 9-double bond geometry on retinoid X receptor activity. J Med Chem 36:2605–2613
Dawson MI, Jong L, Hobbs PD, Cameron JF, Chao W-r, Pfahl M et al (1995) Conformational Effects on retinoid receptor selectivity. 2. Effects of retinoid bridging group on retinoid X receptor activity and selectivity. J Med Chem 38:3368–3383
Boehm MF, Zhang L, Badea BA, White SK, Mais DE, Berger E et al (1994) Synthesis and structure-activity relationships of novel retinoid X receptor-selective retinoids. J Med Chem 37:2930–2941
Yen W-C, Corpuz MR, Prudente RY, Cooke TA, Bissonnette RP, Negro-Vilar A et al (2004) A selective retinoid X receptor agonist bexarotene (targretin) prevents and overcomes acquired paclitaxel (taxol) resistance in human non–small cell lung cancer. Clin Cancer Res 10:8656
Dragnev KH, Petty WJ, Shah SJ, Lewis LD, Black CC, Memoli V et al (2007) A proof-of-principle clinical trial of bexarotene in patients with non–small cell lung cancer. Clin Cancer Res 13:1794
W-c Y, Prudente RY, Lamph WW (2004) Synergistic effect of a retinoid X receptor-selective ligand bexarotene (LGD1069, Targretin) and paclitaxel (Taxol) in mammary carcinoma. Breast Cancer Res Treat 88:141–148
Heo J-C, Jung T-H, Lee S, Kim HY, Choi G, Jung M et al (2016) Effect of bexarotene on differentiation of glioblastoma multiforme compared with ATRA. Clin Exp Metastasis 33:417–429
Cramer PE, Cirrito JR, Wesson DW, Lee CYD, Karlo JC, Zinn AE et al (2012) ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models. Science 335:1503
Tai LM, Bilousova T, Jungbauer L, Roeske SK, Youmans KL, Yu C et al (2013) Levels of soluble apolipoprotein E/amyloid-β (Aβ) complex are reduced and oligomeric Aβ increased with APOE4 and Alzheimer disease in a transgenic mouse model and human samples. J Biol Chem 288:5914–5926
McFarland K, Spalding TA, Hubbard D, Ma J-N, Olsson R, Burstein ES (2013) Low dose bexarotene treatment rescues dopamine neurons and restores behavioral function in models of parkinson’s disease. ACS Chem Nerosci 4:1430–1438
Cummings JL, Zhong K, Kinney JW, Heaney C, Moll-Tudla J, Joshi A et al (2016) Double-blind, placebo-controlled, proof-of-concept trial of bexarotene Xin moderate Alzheimer’s disease. Alzheimer’s Res Ther 8(4)
Boehm MF, Zhang L, Zhi L, McClurg MR, Berger E, Wagoner M et al (1995) Design and synthesis of potent retinoid X receptor selective ligands that induce apoptosis in leukemia cells. J Med Chem 38:3146–3155
Liby K, Rendi M, Suh N, Royce DB, Risingsong R, Williams CR et al (2006) The combination of the rexinoid, LG100268, and a selective estrogen receptor modulator, either arzoxifene or acolbifene, synergizes in the prevention and treatment of mammary tumors in an estrogen receptor–negative model of breast cancer. Clin Cancer Res 12:5902
Cao M, Royce DB, Risingsong R, Williams CR, Sporn MB, Liby KT (2016) The rexinoids LG100268 and LG101506 inhibit inflammation and suppress lung carcinogenesis in A/J mice. Cancer Prev Res 9:105
Fujii S, Ohsawa F, Yamada S, Shinozaki R, Fukai R, Makishima M et al (2010) Modification at the acidic domain of RXR agonists has little effect on permissive RXR-heterodimer activation. Bioorg Med Chem Lett 20:5139–5142
Ohsawa F, Morishita K-i, Yamada S, Makishima M, Kakuta H (2010) Modification at the lipophilic domain of RXR agonists differentially influences activation of RXR heterodimers. ACS Med Chem Lett 1:521–525
Kakuta H, Yakushiji N, Shinozaki R, Ohsawa F, Yamada S, Ohta Y et al (2012) RXR partial agonist CBt-PMN exerts therapeutic effects on type 2 diabetes without the side effects of RXR full agonists. ACS Med Chem Lett 3:427–432
Kakuta H, Ohsawa F, Yamada S, Makishima M, Tai A, Yasui H et al (2012) Feasibility of structural modification of retinoid X receptor agonists to separate blood glucose-lowering action from adverse effects: studies in KKAy type 2 diabetes model mice. Biol Pharm Bull 35:629–633
Ohsawa F, Yamada S, Yakushiji N, Shinozaki R, Nakayama M, Kawata K et al (2013) Mechanism of retinoid X receptor partial agonistic action of 1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-1H-benzotriazole-5-carboxylic acid and structural development to increase potency. J Med Chem 56:1865–1877
Heck MC, Wagner CE, Shahani PH, MacNeill M, Grozic A, Darwaiz T et al (2016) Modeling, synthesis, and biological evaluation of potential retinoid X receptor (RXR)-selective agonists: analogues of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene) and 6-(ethyl(5,5,8,8-tetrahydronaphthalen-2-yl)amino)nicotinic acid (NEt-TMN). J Med Chem 59:8924–8940
Ohta K, Tsuji M, Kawachi E, Fukasawa H, Hashimoto Y, Shudo K et al (1998) Potent retinoid synergists with a diphenylamine skeleton. Biol Pharm Bull 21:544–546
Ohta K, Kawachi E, Fukasawa H, Shudo K, Kagechika H (2011) Diphenylamine-based retinoid antagonists: regulation of RAR and RXR function depending on the N-substituent. Bioorg Med Chem 19:2501–2507
Wolfe JP, Wagaw S, Buchwald SL (1996) An improved catalyst system for aromatic carbon−nitrogen bond formation: the possible involvement of bis(phosphine) palladium complexes as key intermediates. J Am Chem Soc 118:7215–7216
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Wagner, C.E., Jurutka, P.W. (2019). Methods to Generate an Array of Novel Rexinoids by SAR on a Potent Retinoid X Receptor Agonist: A Case Study with NEt-TMN. In: Ray, S. (eds) Retinoid and Rexinoid Signaling . Methods in Molecular Biology, vol 2019. Humana, New York, NY. https://doi.org/10.1007/978-1-4939-9585-1_8
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DOI: https://doi.org/10.1007/978-1-4939-9585-1_8
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