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.
Wagner
Carl E
CE
Division of Mathematical and Natural Sciences, New College of Interdisciplinary Arts and Sciences, Arizona State University, Glendale, Arizona 85306, USA. Carl.Wagner@asu.edu
Jurutka
Peter W
PW
Marshall
Pamela A
PA
Groy
Thomas L
TL
van der Vaart
Arjan
A
Ziller
Joseph W
JW
Furmick
Julie K
JK
Graeber
Mark E
ME
Matro
Erik
E
Miguel
Belinda V
BV
Tran
Ivy T
IT
Kwon
Jungeun
J
Tedeschi
Jamie N
JN
Moosavi
Shahram
S
Danishyar
Amina
A
Philp
Joshua S
JS
Khamees
Reina O
RO
Jackson
Jevon N
JN
Grupe
Darci K
DK
Badshah
Syed L
SL
Hart
Justin W
JW
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