Unknown

Dataset Information

0

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).


ABSTRACT: 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.

SUBMITTER: Wagner CE 

PROVIDER: S-EPMC2765782 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

altmetric image

Publications

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).

Wagner Carl E CE   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   Badshah Syed L SL   Hart Justin W JW  

Journal of medicinal chemistry 20091001 19


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.  ...[more]

Similar Datasets

| S-EPMC3479356 | biostudies-literature
| S-EPMC3916150 | biostudies-literature
| S-EPMC8624485 | biostudies-literature
| S-EPMC4027779 | biostudies-literature
| S-EPMC3583492 | biostudies-literature
| S-EPMC7445745 | biostudies-literature
| S-EPMC4647427 | biostudies-literature
| S-EPMC3634743 | biostudies-literature
| S-EPMC4549399 | biostudies-literature
| S-EPMC1144841 | biostudies-other