Tetrahydroisoquinolinone-Based Steroidomimetic and Chimeric Microtubule Disruptors

A structure–activity relationship (SAR) translation strategy was used for the discovery of tetrahydroisoquinoline (THIQ)‐based steroidomimetic and chimeric microtubule disruptors based upon a steroidal starting point. A steroid A,B‐ring‐mimicking THIQ core was connected to methoxyaryl D‐ring ring mimics through methylene, carbonyl and sulfonyl linkers to afford a number of steroidomimetic hits (e.g., 7‐methoxy‐2‐(3‐ methoxybenzyl)‐6‐sulfamoyloxy‐1,2,3,4‐tetrahydroisoquinoline (20 c) GI50=2.1 μM). Optimisation and control experiments demonstrate the complementary SAR of this series and the steroid derivatives that inspired its design. Linkage of the THIQ‐based A,B‐mimic with the trimethoxyaryl motif prevalent in colchicine site binding microtubule disruptors delivered a series of chimeric molecules whose activity (GI50=40 nM) surpasses that of the parent steroid derivatives. Validation of this strategy was obtained from the excellent oral activity of 7‐methoxy‐6‐sulfamoyloxy‐2‐(3,4,5‐trimethoxybenzyl)‐1,2,3,4‐tetrahydroisoquinoline (20 z) relative to a benchmark steroidal bis‐ sulfamate in an in vivo model of multiple myeloma. Found in translation! Tetrahydroisoquinoline (THIQ)‐based steroidomimetic and chimeric microtubule disruptors (e.g., 20 c) have been identified. Control experiments demonstrate the complementary SAR of this series and the steroidal compounds that inspired its design. A series of chimeric molecules whose activity (GI50=40 nM) surpasses that of the parent steroid derivatives and a compound that shows excellent oral activity in an in vivo model of multiple myeloma were also identified.