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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). 2009
Carl E Wagner, and
Peter W Jurutka, and
Pamela A Marshall, and
Thomas L Groy, and
Arjan van der Vaart, and
Joseph W Ziller, and
Julie K Furmick, and
Mark E Graeber, and
Erik Matro, and
Belinda V Miguel, and
Ivy T Tran, and
Jungeun Kwon, and
Jamie N Tedeschi, and
Shahram Moosavi, and
Amina Danishyar, and
Joshua S Philp, and
Reina O Khamees, and
Jevon N Jackson, and
Darci K Grupe, and
Syed L Badshah, and
Justin W Hart
Division of Mathematical and Natural Sciences, New College of Interdisciplinary Arts and Sciences, Arizona State University, Glendale, Arizona 85306, USA. Carl.Wagner@asu.edu
This report describes the synthesis of analogues of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (1), commonly known as bexarotene, and their analysis in acting as retinoid X receptor (RXR)-specific agonists. Compound 1 has FDA approval to treat cutaneous T-cell lymphoma (CTCL); however, its use can cause side effects such as hypothyroidism and increased triglyceride concentrations, presumably by disruption of RXR heterodimerization with other nuclear receptors. The novel analogues in the present study have been evaluated for RXR activation in an RXR mammalian-2-hybrid assay as well as an RXRE-mediated transcriptional assay and for their ability to induce apoptosis as well as for their mutagenicity and cytotoxicity. Analysis of 11 novel compounds revealed the discovery of three analogues that best induce RXR-mediated transcriptional activity, stimulate apoptosis, have comparable K(i) and EC(50) values to 1, and are selective RXR agonists. Our experimental approach suggests that rational drug design can develop new rexinoids with improved biological properties.
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