77820-96-3Relevant academic research and scientific papers
Optimisation of tetrahydroisoquinoline-based chimeric microtubule disruptors
Dohle, Wolfgang,Leese, Mathew P.,Jourdan, Fabrice L.,Chapman, Christopher J.,Hamel, Ernest,Ferrandis, Eric,Potter, Barry V. L.
, p. 1783 - 1793 (2014/08/18)
Tetrahydroisoquinoline (THIQ)-based chimeric microtubule disruptors were optimised through modification of the N-benzyl motif, in concert with changes at C3 and C7, resulting in the identification of compounds with improved in vitro antiproliferative activities (e.g. 15: GI50 20 nM in DU-145). The broad anticancer activity of these novel structures was confirmed in the NCI 60-cell line assay, with 12 e,f displaying MGM values in the 40 nM region. In addition, their profiles as inhibitors of tubulin polymerisation and colchicine binding to tubulin were confirmed. Compound 15, for example, inhibited tubulin polymerisation with an IC50 of 1.8 μM, close to that of the clinical drug combretastatin A-4, and also proved effective at blocking colchicine binding. Additionally, compound 20 b was identified as the only phenol in the series to date showing both better in vitro antiproliferative properties than its corresponding sulfamate and excellent antitubulin data (IC50=1.6 μM). Compound 12 f was selected for in vivo evaluation at the NCI in the hollow fibre assay and showed very good activity and wide tissue distribution, illustrating the value of this template for further development.
Tetrahydroisoquinolinone-based steroidomimetic and chimeric microtubule disruptors
Leese, Mathew P.,Jourdan, Fabrice L.,Major, Meriel R.,Dohle, Wolfgang,Hamel, Ernest,Ferrandis, Eric,Fiore, Ann,Kasprzyk, Philip G.,Potter, Barry V. L.
, p. 85 - 108 (2014/01/17)
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 Copyright
A NOVEL SYNTHESIS OF DIBENZO-1-AZABICYCLONONANES
Hara, Hiroshi,Hoshino, Osamu,Umezawa, Bunsuke
, p. 907 - 910 (2007/10/02)
Treatment of the N-benzylated p-quinol acetates (1a and 1b) with trifluoroacetic acid gave (+/-)-3-hydroxydibenzoazabicyclononanes (5a and 5c) in good yields.On the other hand, lead tetraacetate oxidation of 2-benzyl-6-hydroxy-7-methoxy-1,2,3,4-tetrahydro
