Synthesis of resorcinylic macrocycles related to radicicol via ring-closing metathesis

Targeting the Hsp90 Chaperone: Synthesis of Novel Resorcylic Acid Macrolactone Inhibitors of Hsp90

“…Our original approach to the synthesis of radicicol analogues such as 4 was based on Danishefsky and co‐workers’ first‐generation synthesis of radicicol itself,34 employing a ring‐closing metathesis (RCM) reaction to form the macrocycle, a tactic commonly used in related syntheses 35. 44, 49, 52 We have now developed a more versatile route to the RCM precursors that is based on isocoumarin chemistry and incorporates the necessary chlorine from an early stage, thereby avoiding a late stage chlorination on every analogue. Interestingly, isocoumarins have been postulated as biosynthetic precursors to resorcylic lacones, a view supported by the recent isolation of isocoumarins from the radicicol producing fungal strain Chaetomium chiversii ,53 and were also used as intermediates in Lett’s first synthesis of radicicol 30.…”

“…Our own work in this area started with a consideration of the structure of 1 bound in the ATP pocket in the N‐terminal domain of yeast Hsp90 (Figure 2 a),25 together with published biological data on radicicol analogues,29, 45, 47–49 and resulted in the synthesis and biological evaluation of a series of novel resorcylic macrolactones of varying ring size and conformation 50. One of these analogues, NP261 ( 4 ), not only showed the established molecular signature of Hsp90 inhibitors that bind to the N ‐terminus of the protein, that is, depletion of client proteins with upregulation of Hsp70, but also bound to the protein in a similar way to the structurally more complex natural product (Figure 2 b).…”

Recent Applications Of Alkene Metathesis For Fine Chemical And Supramolecular System Synthesis

“…The RCM reaction is now currently used to improve the synthesis of known drugs and create new ones. This is the case of the synthesis of resorcinylic macrocycles with lactone or lactam functionality (Scheme 3) [19]. Thus, the dienes 10 are transformed with catalyst 1 (CH 2 Cl 2 , reflux) into 11 and the hydrogenation of the cyclized products (Pd/C) affords quantitatively the hydrogenated and deprotected macrocycles 12.…”

Propionate Analogues of Zearalenone Bind to Hsp90

“…This compound turned out to be more potent, even in vivo, than geldanamycin and is currently in clinical trials. Based on radicicol further macrocyclic compounds like 9 were designed and synthesized by McDonald et al [13] Some of them turned out to be moderate inhibitors of the ATPase activity of Hsp90. Quite recently, the natural product derrubone, an isoflavone, was identified as a Hsp90 A C H T U N G T R E N N U N G inhibitor.…”