Synthesis and antitumor effect in vitro and in vivo of substituted 1,3-dihydroindole-2-ones.
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.
Christensen
Mette K
MK
TopoTarget A/S, Symbion, Fruebjergvej 3, DK-2100 Copenhagen, Denmark.
Erichsen
Kamille D
KD
Trojel-Hansen
Christina
C
Tjørnelund
Jette
J
Nielsen
Søren J
SJ
Frydenvang
Karla
K
Johansen
Tommy N
TN
Nielsen
Birgitte
B
Sehested
Maxwell
M
Jensen
Peter B
PB
Ikaunieks
Martins
M
Zaichenko
Andrei
A
Loza
Einars
E
Kalvinsh
Ivars
I
Björkling
Fredrik
F
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
C553293:3-cycloheptyl-3-(4-hydroxyphenyl)-6-methoxy-7-methylindolin-2-one; D000970:Antineoplastic Agents; D007211:Indoles