Highly Potent Naphthofuran‐Based Retinoic Acid Receptor Agonists

Abstract

A collection of arotinoids with a central benzofuran or naphthofuran ring structure was efficiently synthesized by a three-step process that comprises a Sonogashira coupling, an iodine-induced 5-endo-dig cyclization of the o-methoxyphenyl- or naphthyl-ethynyl benzoates, and finally a Suzuki/Sonogashira coupling of the corresponding 3-iodobenzo- or naphthofurans. Most of these 3-substituted naphthofuran arotinoids (but not the 5,7-di-tert-butylbenzofurans with the same substitution pattern at the C2 and C3 positions) are potent agonists of the retinoic acid receptor (RAR) subtypes, with activities in the nanomolar range.

Adamantyl Arotinoids That Inhibit IκB Kinase α and IκB Kinase β

“…Generation of the alkynyl anion of 18 [30] obtained upon treatment with LDA at -78 °C followed by addition of aldehyde 17 [14] afforded the propargylic alcohol 19 , which underwent oxidation using CrO 3 and pyridine in CH 2 Cl 2 at 25 °C to provide propargylic ketone 20 in 89% yield. [31] Selective deprotection of the less hindered MEM acetal ortho to the ketone [32] led to phenol 21 in 69% yield.…”

Synthesis of 2,3‐Disubstituted Benzofurans by the Palladium‐Catalyzed Coupling of 2‐Iodoanisoles and Terminal Alkynes, Followed by Electrophilic Cyclization: 3‐Iodo‐2‐phenylbenzofuran

“…Since this process was first communicated in 2005, it has been subsequently employed in the synthesis of coumestans, 7 permethylated anigopreissin A 8 and XH-14 9 derivatives, inhibitors of mycobacterium protein tyrosine phosphatase B, 10 and retinoic acid receptor agonists. 11 This approach to 2,3-disubstituted benzofurans is very versatile. The substituents attached to the triple bond can be vinylic groups or aromatic rings bearing certain types of functionality.…”

Syntheses of 2‐Aroyl 3‐Aryl Benzofuran and Benzothiophenes

“…Benzofuran and benzothiophene derivatives are an important class of heterocyclic compounds that exhibit biological activity on a wide range of targets . Recently, benzofurans have been identified as selective adenosine A 2A receptor antagonists for a novel non dopaminergic approach to PD therapy, nonacidic benzofuran EP1 receptor antagonists for the treatment of inflammatory pain , kinase CK2 inhibitors as antitumor agents , antagonists of the CXCR2 receptor as potential use for the treatment of inflammatory and related diseases , uric acid transporter 1 (hURAT1) inhibitors with uricosuric activity , and agonists of the retinoic acid receptor (RAR) subtypes for cancer therapy and prevention . They are found as a key structural unit in many natural products, and pharmaceuticals, such as, for example, amiodarone, befunolol, or bergapten.…”