title: Discovery of Quinoline-Derived Trifluoromethyl Alcohols, Determination of Their in vivo Toxicity and Anticancer Activity in a Zebrafish Embryo Model.
abstract: In this study the rational design, synthesis, and anticancer activity of quinoline-derived trifluoromethyl alcohols were evaluated. Members of this novel class of trifluoromethyl alcohols were identified as potent growth inhibitors in a zebrafish embryo model. Synthesis of these compounds was carried out with an sp(3) -C-H functionalization strategy of methyl quinolines with trifluoromethyl ketones. A zebrafish embryo model was also used to explore the toxicity of ethyl 4,4,4-trifluoro-3-hydroxy-3-(quinolin-2-ylmethyl)butanoate (1), 2-benzyl-1,1,1-trifluoro-3-(quinolin-2-yl)propan-2-ol (2), and trifluoro-3-(isoquinolin-1-yl)-2-(thiophen-2-yl)propan-2-ol (3). Compounds 2 and 3 were found to be more toxic than compound 1; apoptotic staining assays indicated that compound 3 causes increased cell death. In vitro cell proliferation assays showed that compound 2, with an LC50 value of 14.14 μm, has more potent anticancer activity than cisplatin. This novel class of inhibitors provides a new direction in the discovery of effective anticancer agents.
authors.affiliation: Department of Biology, Georgia Southern University, 1332 Southern Drive, Statesboro, GA, 30460-8042, USA. vsittaramane@georgiasouthern.edu.
authors.forename: Vinoth
authors.initials: V
authors.lastname: Sittaramane
authors.affiliation: Department of Biology, Georgia Southern University, 1332 Southern Drive, Statesboro, GA, 30460-8042, USA.
authors.forename: Jihan
authors.initials: J
authors.lastname: Padgett
authors.affiliation: Department of Biology, Georgia Southern University, 1332 Southern Drive, Statesboro, GA, 30460-8042, USA.
authors.forename: Philip
authors.initials: P
authors.lastname: Salter
authors.affiliation: Department of Biology, Georgia Southern University, 1332 Southern Drive, Statesboro, GA, 30460-8042, USA.
authors.forename: Ashley
authors.initials: A
authors.lastname: Williams
authors.affiliation: Department of Biology, Georgia Southern University, 1332 Southern Drive, Statesboro, GA, 30460-8042, USA.
authors.forename: Shauntelle
authors.initials: S
authors.lastname: Luke
authors.affiliation: Department of Chemistry, Georgia Southern University, 521 College of Education Drive, Statesboro, GA, 30460-8064, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: McCall
authors.affiliation: Department of Chemistry, Georgia Southern University, 521 College of Education Drive, Statesboro, GA, 30460-8064, USA.
authors.forename: Jonathan F
authors.initials: JF
authors.lastname: Arambula
authors.affiliation: Department of Chemistry, Georgia Southern University, 521 College of Education Drive, Statesboro, GA, 30460-8064, USA.
authors.forename: Vincent B
authors.initials: VB
authors.lastname: Graves
authors.affiliation: Department of Chemistry, Georgia Southern University, 521 College of Education Drive, Statesboro, GA, 30460-8064, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Blocker
authors.affiliation: Department of Chemistry, Georgia Southern University, 521 College of Education Drive, Statesboro, GA, 30460-8064, USA.
authors.forename: David
authors.initials: D
authors.lastname: Van Leuven
authors.affiliation: Department of Chemistry, Georgia Southern University, 521 College of Education Drive, Statesboro, GA, 30460-8064, USA.
authors.forename: Keturah
authors.initials: K
authors.lastname: Bowe
authors.affiliation: Department of Chemistry, Georgia Southern University, 521 College of Education Drive, Statesboro, GA, 30460-8064, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Heimberger
authors.affiliation: Department of Chemistry, Georgia Southern University, 521 College of Education Drive, Statesboro, GA, 30460-8064, USA.
authors.forename: Hannah C
authors.initials: HC
authors.lastname: Cade
authors.affiliation: Department of Chemistry, Georgia Southern University, 521 College of Education Drive, Statesboro, GA, 30460-8064, USA.
authors.forename: Supriya
authors.initials: S
authors.lastname: Immaneni
authors.affiliation: Department of Chemistry, Georgia Southern University, 521 College of Education Drive, Statesboro, GA, 30460-8064, USA. malnu@georgiasouthern.edu.
authors.forename: Abid
authors.initials: A
authors.lastname: Shaikh
mesh_terms: D000438:Alcohols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D023421:Models, Animal; D015394:Molecular Structure; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity*; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays; D015027:Zebrafish / Q000196:embryology*
chemical_list: D000438:Alcohols; D000970:Antineoplastic Agents; D006845:Hydrocarbons, Fluorinated; D011804:Quinolines; C037219:quinoline
keywords: anticancer activity; cytotoxicity; organofluorine compounds; synthesis design; zebrafish