title: Tetrahydroisoquinolinone-based steroidomimetic and chimeric microtubule disruptors.
abstract: 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.
authors.affiliation: Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY (UK).
authors.forename: Mathew P
authors.initials: MP
authors.lastname: Leese
authors.forename: Fabrice L
authors.initials: FL
authors.lastname: Jourdan
authors.forename: Meriel R
authors.initials: MR
authors.lastname: Major
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Dohle
authors.forename: Ernest
authors.initials: E
authors.lastname: Hamel
authors.forename: Eric
authors.initials: E
authors.lastname: Ferrandis
authors.forename: Ann
authors.initials: A
authors.lastname: Fiore
authors.forename: Philip G
authors.initials: PG
authors.lastname: Kasprzyk
authors.forename: Barry V L
authors.initials: BV
authors.lastname: Potter
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D001593:Benzyl Compounds / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D008870:Microtubules / Q000737:chemistry / Q000378:metabolism*; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000737:chemistry*; D014183:Transplantation, Heterologous; D050257:Tubulin Modulators / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C000590351:7-methoxy-2-(3-methoxybenzyl)-6-sulfamoyloxy-1,2,3,4-tetrahydroisoquinoline; D000970:Antineoplastic Agents; D001593:Benzyl Compounds; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D050257:Tubulin Modulators
keywords: colchicine binding; microtubule disruptors; tetrahydroisoquinolines; tubulin assembly