Modeling, Synthesis and Biological Evaluation of Potential Retinoid X Receptor‐Selective Agonists: Novel Halogenated Analogues of 4‐[1‐(3,5,5,8,8‐Pentamethyl‐5,6,7,8‐tetrahydro‐2‐naphthyl)ethynyl]benzoic Acid (Bexarotene)

Abstract

The synthesis of halogenated analogs of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (1), known commonly as bexarotene, and their evaluation for retinoid-X-receptor (RXR)-specific agonist performance is described. Compound 1 is FDA approved to treat cutaneous T-cell lymphoma (CTCL); however, bexarotene treatment can induce hypothyroidism and elevated triglyceride levels, presumably by disrupting RXR heterodimer pathways for other nuclear receptors. The novel halogenated analogs in this study were modeled and assessed for their ability to bind to RXR and stimulate RXR homodimerization in an RXRE-mediated transcriptional assay as well as an RXR mammalian-2-hybrid assay. In an array of 8 novel compounds, 4 analogs were discovered to promote RXR-mediated transcription with comparable EC50 values as 1 and are selective RXR agonists. Our approach also uncovered a periodic trend of increased binding and homodimerization of RXR when substituting a halogen atom for a proton ortho to the carboxylic acid on 1.

Modeling, Synthesis, and Biological Evaluation of Potential Retinoid X Receptor (RXR) Selective Agonists: Novel Analogues of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and (E)-3-(3-(1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalen-7-yl)-4-hydroxyphenyl)acrylic Acid (CD3254)

“…Docks were performed with both the Autodock and OpenBabel charges; the latter tend to show less overpolarization. 35 All compounds were predicted to bind nearly as well or better than 1 , with predicted binding affinities generally within 0.5 kcal/mol of 1 . Overlays of docking poses in the L-shaped binding pocket showed that the phenyl ring was held in nearly identical position for most ligands, while small adjustments were observed in the position of the double ring system.…”

A review of the molecular design and biological activities of RXR agonists

“…The addition of two fluorine atoms to 2 gave the RXR agonist 19 . This molecule presented an EC 50 value of 34 nM in HCT‐116 colon cancer cells, which is superior to the EC 50 value for 2 , 55 nM . The acrylic acid analogue CD3254 ( 20 ) was also reported as a potent and selective RXR agonist (EC 50 = 13 ± 3 nM in HCT‐116 cells) .…”

“…This fact has limited the use of 1 as a therapeutic agent. Molecule 1 is currently used only for Kaposi's sarcoma of the skin when applied as gel (Toctino or Panretin) and for chronichand eczema …”

Triggering of Suicidal Erythrocyte Death by Bexarotene

“…Bexarotene, a synthetic analog (4-[1- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid) of retinoids [1,2], selectively binds to and activates the retinoid X receptor (RXRs) subfamilies [1][2][3][4][5][6][7][8], thus inhibiting tumor growth both, in vitro and in vivo [1]. The substance is used for the treatment of cutaneous T-cell lymphoma (CTCL) [3,5,6,, and has been shown to be effective in other malignancies, such as non-small cell lung cancer [16,29,30], breast cancer [16,[31][32][33], and -in animals -colon cancer [34], breast cancer [35,36] and lung cancer [37].…”