title: Design, antiviral and cytostatic properties of isoxazolidine-containing amonafide analogues.
abstract: A novel series of 5-arylcarbamoyl- and 5-arylmethyl-2-methylisoxazolidin-3-yl-3-phosphonates have been synthesized via cycloaddition of N-methyl-C-(diethoxyphosphoryl)nitrone with N-substituted naphthalimide acrylamides and N-allylnaphthalimides. All cis- and trans-isoxazolidine phosphonates obtained herein were assessed for antiviral activity against a broad range of DNA and RNA viruses. Isoxazolidines trans-9d and trans-9f exhibited the highest activity (EC50=8.9μM) toward cytomegalovirus. Compounds cis- and trans-9d as well as cis- and trans-9f were found potent against HSV and Vaccinia viruses (EC50 in the 45-58μM range), whereas isoxazolidines 10a and 10d suppressed replication of Coxsackie B4 and Punta Toro viruses (EC50 in the 45-73μM range). Antiproliferative evaluation of all obtained isoxazolidines revealed the promising activity of cis-9b, cis-9d, trans-9d, cis-9e, trans-9e, cis-9f and trans-9f toward tested cancer cell lines with IC50 in the 1.1-19μM range.
authors.affiliation: Bioorganic Chemistry Laboratory, Faculty of Pharmacy, Medical University of Łódź, Muszyńskiego 1, 90-151 Łódź, Poland.
authors.forename: Kamil
authors.initials: K
authors.lastname: Kokosza
authors.affiliation: Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
authors.forename: Graciela
authors.initials: G
authors.lastname: Andrei
authors.affiliation: Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
authors.forename: Dominique
authors.initials: D
authors.lastname: Schols
authors.affiliation: Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
authors.forename: Robert
authors.initials: R
authors.lastname: Snoeck
authors.affiliation: Bioorganic Chemistry Laboratory, Faculty of Pharmacy, Medical University of Łódź, Muszyńskiego 1, 90-151 Łódź, Poland. Electronic address: dorota.piotrowska@umed.lodz.pl.
authors.forename: Dorota G
authors.initials: DG
authors.lastname: Piotrowska
mesh_terms: D000178:Acrylamides / Q000737:chemistry; D000225:Adenine; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D061565:Cycloaddition Reaction; D003587:Cytomegalovirus / Q000187:drug effects / Q000502:physiology; D054697:Cytostatic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D015195:Drug Design; D004770:Enterovirus / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D053644:Naphthalimides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009589:Nitrogen Oxides / Q000737:chemistry; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000494:pharmacology; D016856:Phlebovirus / Q000187:drug effects / Q000502:physiology; D018139:Simplexvirus / Q000187:drug effects / Q000502:physiology; D013329:Structure-Activity Relationship; D014616:Vaccinia virus / Q000187:drug effects / Q000502:physiology
chemical_list: D000178:Acrylamides; D000970:Antineoplastic Agents; D000998:Antiviral Agents; D054697:Cytostatic Agents; D007555:Isoxazoles; D053644:Naphthalimides; D009589:Nitrogen Oxides; D063065:Organophosphonates; C015388:nitrones; C037020:amonafide; D000225:Adenine
keywords: Antiviral; Cytostatic; Isoxazolidines; Naphthalimides; Phosphonates