Synthesis of 3-desoxycollinoketone B and its ability to reduce Alzheimer-associated misfolded proteins.

Abstract

Collinolactone, featuring a 7/10/6 tricyclic core, has been proposed to be biosynthesized via a transannular [6 + 4] cycloaddition reaction. Besides its intriguing architecture, collinolactone holds pharmaceutical promises due to its ability to disrupt amyloid-β (Aβ) and tau aggregation, which are specifically found as disease culprits in the brains of Alzheimer's disease (AD) patients and are key targets in current drug discovery efforts. However, challenges associated with its acquisition from a natural source and limited pharmacokinetic properties have hampered its further studies. Herein, we report the design, synthesis, and biological evaluation of 3-desoxycollinoketone B, a collinolactone derivative with improved pharmacokinetics for AD treatment. A stereoselective transannular [6 + 4] cycloaddition efficiently constructs the tricyclic core, allowing its scalable synthesis. AI-assisted binding prediction and simulations not only indicate superior binding of 3-desoxycollinoketone B to Aβ and tau aggregates to collinolactone, but also suggest a mechanistic basis for fibril destabilization. In vitro studies confirm its inhibition and dissociation of Aβ and tau fibrils, while in vivo experiments in AD mouse models show substantial amelioration of cognitive functions and Aβ/tau-associated pathology.