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).
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.
Division of Mathematical and Natural Sciences, New College of Interdisciplinary Arts and Sciences, Arizona State University, Glendale, Arizona 85306, USA. Carl.Wagner@asu.edu
Carl E
CE
Wagner
Peter W
PW
Jurutka
Pamela A
PA
Marshall
Thomas L
TL
Groy
Arjan
A
van der Vaart
Joseph W
JW
Ziller
Julie K
JK
Furmick
Mark E
ME
Graeber
Erik
E
Matro
Belinda V
BV
Miguel
Ivy T
IT
Tran
Jungeun
J
Kwon
Jamie N
JN
Tedeschi
Shahram
S
Moosavi
Amina
A
Danishyar
Joshua S
JS
Philp
Reina O
RO
Khamees
Jevon N
JN
Jackson
Darci K
DK
Grupe
Syed L
SL
Badshah
Justin W
JW
Hart
D017209:Apoptosis / Q000187:drug effects; D000077610:Bexarotene; D045744:Cell Line, Tumor; D006801:Humans; D047488:Retinoid X Receptors / Q000819:agonists*; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis* / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; D000077610:Bexarotene