Tetrahydroisoquinolinone‐Based Steroidomimetic and Chimeric Microtubule Disruptors

Abstract

A 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 methoxy aryl D-ring ring mimics through methylene, carbonyl and sulfonyl linkers to afford a number of steroidomimetic hits (e.g. 20c 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 trimethoxy aryl motif prevalent in colchicine site binding microtubule disruptors delivered a series of chimeric molecules whose activity (to GI50 40 nM) surpasses that of the parent steroid derivatives. Validation of this strategy was obtained from the excellent oral activity of 20z relative to a benchmark steroidal bis-sulfamate in an in vivo model of multiple myeloma.

Optimisation of Tetrahydroisoquinoline‐Based Chimeric Microtubule Disruptors

“…[3] The major modification over foregoing work was introduction of an appropriately substituted benzyl motif at N2, followed by sequential deprotection and sulfamoylation of the 6-hydroxy group. This was achieved by transforming THIQs 5 [3] and 6a,b [12, 13] into the corresponding functionalised N-benzylated compounds 8a–d [12] and 10a–f using various direct N-benzylation methods or N ′-(3-dimethylaminopropyl)- N -ethylcarbodiimide (EDCI) coupling with the corresponding benzoic acids and subsequent reduction of product with lithium aluminium hydride (LiAlH 4 ). The protected phenols were either treated with hydrogen and palladium on carbon (Pd/C; for 8a – d ) or tetra- n -butylammonium fluoride (TBAF; for 10a – f ), furnishing phenols 11a – j in good yields.…”

“…As reported previously, in both the trimethoxybenzyl phenol 3a and 11a–c and sulfamate series 4a and 12a–c , the 3′,4′,5′-trimethoxy system proves optimal ( 4a GI 50 =297 nm), although the 2′,4′,5′-trimethoxy sulfamate 12b also displays good activity (GI 50 =660 nm). [12] Deletion of the 5′-methoxy group of 4a to give the 3′,4′-dimethoxy compound 12d results in a near 30-fold reduction in activity, thus illustrating the highly preferred status of trisubstitution in this series of chimeras. [12] Replacement of the 5′-methoxy with either chlorine in 12e , or bromine in 12f , however, delivers a dramatic 8- to 10-fold increase in antiproliferative activity, with the corresponding phenols 11e,f also exhibiting significant activity.…”

“…[12] Deletion of the 5′-methoxy group of 4a to give the 3′,4′-dimethoxy compound 12d results in a near 30-fold reduction in activity, thus illustrating the highly preferred status of trisubstitution in this series of chimeras. [12] Replacement of the 5′-methoxy with either chlorine in 12e , or bromine in 12f , however, delivers a dramatic 8- to 10-fold increase in antiproliferative activity, with the corresponding phenols 11e,f also exhibiting significant activity. The 3′,4′-dimethoxy-5′-bromo derivatives 11f and 12f are exceptionally active.…”

“…Substitution of the 4′-methoxy of 4a with an ethoxy group also delivers improved activity for phenol 11g and sulfamate 12g , revealing a degree of steric flexibility at this position in the chimeric series in strong contrast to the steroidomimetic series. [12, 13] Replacement of the 3′,4′,5′-trimethoxybenzyl group with a 3′,4′,5′-triethoxybenzyl group results in a >20-fold reduction in activity. Similarly, the 3′,4′,5′-triethyl compounds 11i and 12i are significantly less active than 3a and 4a , respectively.…”

“…Data for 1a , 3a , 4a , 11a–d and 12a–d for comparison are taken from the literature [3, 8, 12]. N/A: not applicable.…”