title: Synthesis and antitumor effect in vitro and in vivo of substituted 1,3-dihydroindole-2-ones.
abstract: Optimization of the anticancer activity for a class of compounds built on a 1,3-dihydroindole-2-one scaffold was performed. In comparison with recently published derivatives of oxyphenisatin the new analogues exhibited an equally potent antiproliferative activity in vitro and improved tolerability and activity in vivo. The best compounds from this series showed low nanomolar antiproliferative activity toward a series of cancer cell lines (compound (S)-38: IC(50) of 0.48 and 2 nM in MCF-7 (breast) and PC3 (prostate), respectively) and potent antitumor effects in well tolerated doses in xenograft models. The racemic compound (RS)-38 showed complete tumor regression at a dose of 20 mg/kg administered iv on days 1 and 7 in a PC3 rat xenograft.
authors.affiliation: TopoTarget A/S, Symbion, Fruebjergvej 3, DK-2100 Copenhagen, Denmark.
authors.forename: Mette K
authors.initials: MK
authors.lastname: Christensen
authors.forename: Kamille D
authors.initials: KD
authors.lastname: Erichsen
authors.forename: Christina
authors.initials: C
authors.lastname: Trojel-Hansen
authors.forename: Jette
authors.initials: J
authors.lastname: Tjørnelund
authors.forename: Søren J
authors.initials: SJ
authors.lastname: Nielsen
authors.forename: Karla
authors.initials: K
authors.lastname: Frydenvang
authors.forename: Tommy N
authors.initials: TN
authors.lastname: Johansen
authors.forename: Birgitte
authors.initials: B
authors.lastname: Nielsen
authors.forename: Maxwell
authors.initials: M
authors.lastname: Sehested
authors.forename: Peter B
authors.initials: PB
authors.lastname: Jensen
authors.forename: Martins
authors.initials: M
authors.lastname: Ikaunieks
authors.forename: Andrei
authors.initials: A
authors.lastname: Zaichenko
authors.forename: Einars
authors.initials: E
authors.lastname: Loza
authors.forename: Ivars
authors.initials: I
authors.lastname: Kalvinsh
authors.forename: Fredrik
authors.initials: F
authors.lastname: Björkling
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
chemical_list: C553293:3-cycloheptyl-3-(4-hydroxyphenyl)-6-methoxy-7-methylindolin-2-one; D000970:Antineoplastic Agents; D007211:Indoles