Chiral Dihydrobenzofuran Acids Show Potent Retinoid X Receptor–Nuclear Receptor Related 1 Protein Dimer Activation

Sundén, Henrik; Schäfer, Anja; Scheepstra, Marcel; Leysen, S.; Malo, Marcus; Ma, Jian‐Nong; Burstein, Ethan S.; Ottmann, C.; Brunsveld, Luc; Olsson, Roger

doi:10.1021/acs.jmedchem.5b01702

Cited by 15 publications

(23 citation statements)

References 37 publications

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“…Molecule 2 also activated RXR/Nurr1 heterodimers and restored behavioral function in a rat model of PD . Nurr1 is essential for both development and maintenance of dopamine neurons and a reduction of its expression is associated with PD in humans.…”

Section: Rxr Agonistsmentioning

confidence: 96%

“…The group of Zhang has identified a link between RXRα and the activation of the PI3K/AKT pathway . Further, RXR has been associated with other diseases including leukemia, AD, schizophrenia, and multiple sclerosis (MS) . Because of its role in gene control and non‐genomic functions, the development of RXR ligands is a blossoming area of medicinal chemistry research.…”

Section: The Retinoid X Receptormentioning

confidence: 99%

“…Because of its good overlay with 2 , it was hypothesized the dihydrobenzofuran scaffold could be a promising starting point for the synthesis of RXR and RXR/Nurr1 ligands. The dihydrobenzufuran acid enantiomer ( 40 , Figure ) was found to be a full RXR agonist with pEC 50 (negative logarithm of EC 50 , in mols) of 8.2 and an efficacy of 119% (when compared to 2 , which was equal to 100%), and a RXR/Nurr1 pEC 50 of 7.9 and efficacy of 111% . The X‐ray structure of 40 showed hydrophobic interactions with Val 342, Val 349, Ile 310, Ile 268, and Leu 436, and H‐bond interactions of the carboxylic acid group with Arg 316 and Ala 327 (Figure ).…”

Section: Rxr Agonistsmentioning

confidence: 99%

“…The ent ‐ 40 derivative displayed a steric clash (Figure B) with Ala 272 and failed to make H bond contacts with Ala 327 and Arg 316, which may explain why the molecule is 100‐fold less potent in the biological assays. The sterically constricted dihydrobenzofuran scaffold presented exactly the right molecular topology to activate RXRα, providing a new platform to further RXR/Nurr1 exploration …”

Section: Rxr Agonistsmentioning

confidence: 99%

“…The arrow indicates how the enantiomer would sterically clash with RXR residue A272 (PDB 5EC9). Used, and modified, with permission from Ref …”

Section: Rxr Agonistsmentioning

confidence: 99%

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A review of the molecular design and biological activities of RXR agonists

Almeida

Conda‐Sheridan

2019

Medicinal Research Reviews

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An attractive approach to combat disease is to target theregulation of cell function. At the heart of this task are nuclear receptors (NRs); which control functions such as gene transcription. Arguably, the key player in this regulatory machinery is the retinoid X receptor (RXR). This NR associates with a third of the NRs found in humans. Scientists have hypothesized that controlling the activity of RXR is an attractive approach to control cellular functions that modulate diseases such as cancer, diabetes, Alzheimer's disease and Parkinson's disease. In this review, we will describe the key features of the RXR, present a historic perspective of the first RXR agonists, and discuss various templates that have been reported to activate RXR with a focus on their molecular structure, biological activity, and limitations. Finally, we will present an outlook of the field and future directions and considerations to synthesize or modulate RXR agonists to make these compounds a clinical reality.

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Section: Rxr Agonistsmentioning

confidence: 96%

Section: The Retinoid X Receptormentioning

confidence: 99%

Section: Rxr Agonistsmentioning

confidence: 99%

Section: Rxr Agonistsmentioning

confidence: 99%

“…The arrow indicates how the enantiomer would sterically clash with RXR residue A272 (PDB 5EC9). Used, and modified, with permission from Ref …”

Section: Rxr Agonistsmentioning

confidence: 99%

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A review of the molecular design and biological activities of RXR agonists

Almeida

Conda‐Sheridan

2019

Medicinal Research Reviews

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Photocatalytic Dearomative Intermolecular Seven‐Membered Ring Construction of Benzofurans

Harada,

Yamamoto,

Okabe

et al. 2023

Asian J Org Chem

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We report the synthesis of seven‐membered carbocycles through the dearomative intermolecular reaction of benzofurans with vinylcyclopropanes. The significant feature of this method involves activating benzofurans through energy transfer from an activated photocatalyst. Substituent effects were investigated for each substrate, and hydrocyclohepta[b]benzofurans with a tetrasubstituted carbon were obtained as a single diastereomer. This synthetic approach compliments the reported methodologies for synthesizing this type of skeleton and introduces a new feedstock for this skeleton with a different substitution pattern. Computational studies of the reaction mechanism suggested that the reaction proceeds stepwise through addition, small ring opening, and re‐cyclization. This novel synthetic approach opens up new possibilities for efficiently constructing seven‐membered carbocycles. Moreover, it provides a valuable platform for discovering unique molecules with diverse substitution patterns.

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