Designed Spiroketal Protein Modulation

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 coactivator recruitment. We solved the crystal structure of the spiroketal-hRXR alpha-TIF2 ternary complex, and identified a canonical allosteric mechanism as a possible explanation for the partial agonist behavior of our spiroketal. Our cocrystal structure, the first of a designed spiroketal-protein complex, suggests that spiroketals can be designed to selectively target other nuclear receptor subtypes

Neutral organic super electron donors made catalytic

Neutral organic super electron donors (SEDs) display impressive reducing power but, until now, it has not been possible to use them catalytically in radical chain reactions. This is because, following electron transfer, these donors form persistent radical cations that trap substrate-derived radicals. This paper unlocks a conceptually new approach to super electron donors that overcomes this issue, leading to the first catalytic neutral organic super electron donor