Steroidomimetic Tetrahydroisoquinolines for the Design of New Microtubule Disruptors

Structure–activity relationship translation offers an expeditious means for discovery of new active series. This approach was applied to discover tetrahydroisoquinoline (THIQ)-based steroidomimetic microtubule disruptors. The two A-ring elements of a three-point steroidal pharmacophore were incorporated into a THIQ-based A,B-ring mimic to which an H-bond acceptor was attached as the third motif. Optimization of the representative<b> 6c</b> through conformational biasing delivered a 10-fold gain in activity and a new series of microtubule disruptors (e.g., <b>9c</b>) with antiproliferative activity in the nanomolar range. The THIQ derivatives match, or surpass, the activities of the steroidal series and exhibit improved physicochemical properties