title: Solid-phase synthesis of libraries of ethynylated aminosteroid derivatives as potential antileukemic agents.
abstract: Steroids possessing an ethynyl group at position 17α (tertiary alcohols) are well known to be more stable than their non-ethynyl analogs (secondary alcohols). To facilitate the development of new drugs with better metabolic stability, we developed a new diethylsilyl acetylenic linker allowing us to rapidly synthesize libraries of ethynylated steroid derivatives using a solid-phase strategy. To illustrate its usefulness, this linker was used to expand the molecular diversity of a lead compound having a hydroxy acetylenic pattern and to potentially find new compounds with interesting cytotoxic activity against leukemia cell lines. Herein, we report the chemical synthesis and the characterization of three libraries of ethynylated aminosteroid derivatives using the diethylacetylenic linker. We discuss their antiproliferative activities obtained in 2 leukemia cell lines (HL-60 and Jurkat), which results provided new structure-activity relationships. We also identified a new promising aminosteroid derivative with an azetidine moiety (compound B1) inhibiting 60% and 75% of HL-60 and Jurkat cell proliferation, respectively, at 1 μM. More generally, these results validate the use of a diethylsilyl acetylenic linker for researchers interested in generating libraries of alcohol derivatives with better stability and drug profile.
authors.affiliation: Laboratory of Medicinal Chemistry, CHU de Québec - Research Center (CHUL, T4-42) and Université Laval (Faculty of Medicine), Québec, QC, Canada.
authors.forename: Amélie
authors.initials: A
authors.lastname: Talbot
authors.affiliation: Laboratory of Medicinal Chemistry, CHU de Québec - Research Center (CHUL, T4-42) and Université Laval (Faculty of Medicine), Québec, QC, Canada.
authors.forename: René
authors.initials: R
authors.lastname: Maltais
authors.affiliation: Laboratory of Medicinal Chemistry, CHU de Québec - Research Center (CHUL, T4-42) and Université Laval (Faculty of Medicine), Québec, QC, Canada.
authors.forename: Lucie Carolle
authors.initials: LC
authors.lastname: Kenmogne
authors.affiliation: Laboratory of Medicinal Chemistry, CHU de Québec - Research Center (CHUL, T4-42) and Université Laval (Faculty of Medicine), Québec, QC, Canada.
authors.forename: Jenny
authors.initials: J
authors.lastname: Roy
authors.affiliation: Laboratory of Medicinal Chemistry, CHU de Québec - Research Center (CHUL, T4-42) and Université Laval (Faculty of Medicine), Québec, QC, Canada. Electronic address: donald.poirier@crchul.ulaval.ca.
authors.forename: Donald
authors.initials: D
authors.lastname: Poirier
mesh_terms: D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects*; D018922:HL-60 Cells; D006801:Humans; D019169:Jurkat Cells; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013256:Steroids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000588:Amines; D000970:Antineoplastic Agents; D013256:Steroids
keywords: Acetylenic compound; Antiproliferative activity; Cancer; Linker; Solid-phase synthesis; Steroid