Methods to Generate an Array of Novel Rexinoids by SAR on a Potent Retinoid X Receptor Agonist

A Case Study with NEt-TMN

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

The methods described in this chapter concern procedures for the design, synthesis, and in vitro biological evaluation of an array of potent retinoid-X-receptor (RXR) agonists employing 6-(ethyl(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino)nicotinic acid (NEt-TMN), and recently reported NEt-TMN analogs, as a case study. These methods have been extensively applied beyond the present case study to generate several analogs of other potent RXR agonists (rexinoids), particularly the RXR agonist known as bexarotene (Bex), a Food and Drug Administration (FDA) approved drug for cutaneous T-cell lymphoma that is also often prescribed, off-label, for breast, lung, and other human cancers. Common side effects with Bex treatment include hypertriglyceridemia and hypothyroidism, because of off-target activation or inhibition of other nuclear receptor pathways impacted by RXR. Because rexinoids are often selective for RXR, versus the retinoic-acid-receptor (RAR), cutaneous toxicity is often avoided as a side effect for rexinoid treatment. Several other potent RXR agonists, and their analogs, have been reported in the literature and rigorously evaluated (often in comparison to Bex) as potential cancer therapeutics with unique activity and side-effect profiles. Some of the more prominent examples include LGD100268, CD3254, and 9-cis-UAB30, to name only a few. Hence, the methods described herein are more widely applicable to a diverse array of RXR agonists. In terms of design, the structure-activity relationship (SAR) study is usually performed by modifying three distinct areas of the rexinoid base structure, either of the nonpolar or polar sides of the rexinoid and/or the linkage that joins them. For the synthesis of the modified base-structure analogs, often identical synthetic strategies used to access the base-structure are applied; however, reasonable alternative synthetic routes may need to be explored if the modified analog intermediates encounter bottlenecks where yields are negligible for a given step in the base-structure route. In fact, this particular problem was encountered and successfully resolved in our case study for generating an array of NEt-TMN analogs.

Original languageEnglish (US)
Title of host publicationMethods in Molecular Biology
PublisherHumana Press Inc.
Pages109-121
Number of pages13
DOIs
StatePublished - Jan 1 2019

Publication series

NameMethods in Molecular Biology
Volume2019
ISSN (Print)1064-3745
ISSN (Electronic)1940-6029

Fingerprint

Retinoid X Receptors
Structure-Activity Relationship
Cutaneous T-Cell Lymphoma
Retinoic Acid Receptors
Hypertriglyceridemia
Niacin
United States Food and Drug Administration
Cytoplasmic and Nuclear Receptors
Hypothyroidism
Names
Neoplasms
Breast
Lung
Skin
Pharmaceutical Preparations

Keywords

  • Cutaneous T-cell lymphoma
  • Luciferase assay
  • Mammalian two hybrid assay
  • Nuclear receptor
  • Retinoid X receptor
  • Rexinoid
  • Synthetic methods

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics

Cite this

Methods to Generate an Array of Novel Rexinoids by SAR on a Potent Retinoid X Receptor Agonist : A Case Study with NEt-TMN. / Wagner, Carl; Jurutka, Peter.

Methods in Molecular Biology. Humana Press Inc., 2019. p. 109-121 (Methods in Molecular Biology; Vol. 2019).

Research output: Chapter in Book/Report/Conference proceedingChapter

Wagner, Carl ; Jurutka, Peter. / Methods to Generate an Array of Novel Rexinoids by SAR on a Potent Retinoid X Receptor Agonist : A Case Study with NEt-TMN. Methods in Molecular Biology. Humana Press Inc., 2019. pp. 109-121 (Methods in Molecular Biology).
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