Designed Spiroketal Protein Modulation

Abstract

Spiroketals are structural motifs found in many biologically active natural products, which has stimulated considerable efforts toward their synthesis and interest in their use as drug lead compounds. Despite this, the use of spiroketals, and especially bisbenzanulated spiroketals, in a structure‐based drug discovery setting has not been convincingly demonstrated. Herein, we report the rational design of a bisbenzannulated spiroketal that potently binds to the retinoid X receptor (RXR) thereby inducing partial co‐activator recruitment. We solved the crystal structure of the spiroketal–hRXRα–TIF2 ternary complex, and identified a canonical allosteric mechanism as a possible explanation for the partial agonist behavior of our spiroketal. Our co‐crystal structure, the first of a designed spiroketal–protein complex, suggests that spiroketals can be designed to selectively target other nuclear receptor subtypes.

Spirocyclic Scaffolds in Medicinal Chemistry

“…Scheepstra et al synthesized a bisbenzannulated spiroketal partial agonist targeting the retinoid X receptor (RXR), a member of the gene transcription factor superfamily. 116 The spirocyclic modulator 185 bound to RXR and induced partial coactivator recruitment. The effect of spiroketal stereochemistry was evaluated in a fluorescence polarization assay with fluorescently labeled peptides as D22.…”

“…Scheepstra et al synthesized a bisbenzannulated spiroketal partial agonist targeting the retinoid X receptor (RXR), a member of the gene transcription factor superfamily . The spirocyclic modulator 185 bound to RXR and induced partial coactivator recruitment.…”

Copper(i)-catalyzed electrophilic thiocyanation/dearomatization/spirocyclization of benzofurans to synthesize benzannulated spiroketals

“…Spiroketals are important motifs in natural products, 1 biologically active molecules, 2 and chiral ligands 3 (Fig. 1).…”

Advances in the Catalytic Asymmetric Synthesis of Chiral Spiroketals

“…托格列净(Tofogliflozin)是一种新型 SGLT2 抑制 剂, 目前已经在日本批准上市, 用于治疗糖尿病, 其结 构类型属于苯并螺环缩酮类糖衍生物. 螺环缩酮化合物 除了表现出广泛的生物活性外, 由于其两个氧原子的独 特位置, 可以与金属离子螯合, 因此可以被用作化学生 物学研究中的探针 [14] .…”