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 relative to a benchmark steroidal bis- sulfamate in an in vivo model of multiple myeloma.
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colchicine binding, microtubule disruptors, tetrahydroisoquinolines, tubulin assembly, Animals, Antineoplastic Agents, Benzyl Compounds, Cell Line, Tumor, Cell Proliferation, Humans, Isoquinolines, Mice, Mice, Nude, Microtubules, Multiple Myeloma, Stereoisomerism, Structure-Activity Relationship, Tetrahydroisoquinolines, Transplantation, Heterologous, Tubulin Modulators