ChemInform Abstract: Syntheses of Aminoalcohol‐Derived Macrocycles Leading to a Small‐Molecule Binder to and Inhibitors of Sonic Hedgehog.

Macrocyclic Hedgehog Pathway Inhibitors: Optimization of Cellular Activity and Mode of Action Studies

“…In 2009, a macrocyclic compound derived from a diversityoriented synthesis (DOS) library [robotnikinin (1)] was described that inhibits the Hh signaling pathway. 15,16 Hit compounds were identified by their interaction with Sonic Hedgehog (Shh) in a small-molecule microarray screen. We aimed to build upon this work by developing analogues with improved activity in cellular assays.…”

“…Our primary objective was thus to find analogues with improved potency and maximal inhibition in these assays. 18 The preparation of macrocyclic analogues of robotnikinin used a build/couple/pair 19 strategy related to previous reports 15,16,20 that affords rapid access to diverse analogues. Our general strategy is illustrated in Scheme 1, with only one of numerous accessible stereoisomers depicted.…”