Synthesis, Antitubulin, and Antiproliferative SAR of C3/C1-Substituted Tetrahydroisoquinolines

The syntheses and antiproliferative activities of novel substituted tetrahydroisoquinoline derivatives and their sulfamates are discussed. Biasing of conformational populations through substitution on the tetrahydroisoquinoline core at C1 and C3 has a profound effect on the antiproliferative activity against various cancer cell lines. The C3 methyl‐substituted sulfamate (±)‐7‐methoxy‐2‐(3‐methoxybenzyl)‐3‐methyl‐6‐sulfamoyloxy‐1,2,3,4‐tetrahydroisoquinoline (6 b), for example, was found to be ∼10‐fold more potent than the corresponding non‐methylated compound 7‐methoxy‐2‐(3‐methoxybenzyl)‐6‐sulfamoyloxy‐1,2,3,4‐tetrahydroisoquinoline (4 b) against DU‐145 prostate cancer cells (GI50 values: 220 nM and 2.1 μM, respectively). Such compounds were also found to be active against a drug‐resistant MCF breast cancer cell line. The position and nature of substitution of the N‐benzyl group in the C3‐substituted series was found to have a significant effect on activity. Whereas C1 methylation has little effect on activity, introduction of C1 phenyl and C3‐gem‐dimethyl substituents greatly decreases antiproliferative activity. The ability of these compounds to inhibit microtubule polymerisation and to bind tubulin in a competitive manner versus colchicine confirms the mechanism of action. The therapeutic potential of a representative compound was confirmed in an in vivo multiple myeloma xenograft study. The core of the matter: C3 substitution at the tetrahydroisoquinoline core has a profound effect on antiproliferative activity against various cancer cell lines. Sulfamate 6 b, for example, was found to be 10‐fold more potent than 4 b against DU‐145 prostate cancer cells. Extensive SAR studies led to compounds like 6 r with enhanced ability to inhibit microtubule polymerisation and colchicine binding to tubulin in a competitive manner, confirming the mechanism of action.