Synthesis and biological study of 4-aminopyrimidine-5-carboxaldehyde oximes as antiproliferative VEGFR-2 inhibitors.
A novel 4-aminopyrimidine-5-carboxaldehyde oxime scaffold with inhibitory activity against VEGFR-2 kinase has been identified. With a 4-fluoro-2-methylindol-5-yloxy group at the 6-position and alkyl groups as the oxime side chains, many analogues showed good potency for VEGFR-2. This series also exhibited antiproliferative activity against cancer cells, causing cell accumulation at the G2/M phase of the cell cycle and preventing cells from entering mitosis. Described here are the chemistry, structure-activity relationships (SAR), and biological testing for this series.
Huang
Shenlin
S
Johnson and Johnson Pharmaceutical Research and Development, L.L.C, 1000 Route 202, Raritan, NJ 08869, USA. shenlinhuang@hotmail.com <shenlinhuang@hotmail.com>
Li
Ronghua
R
Connolly
Peter J
PJ
Xu
Guozhang
G
Gaul
Michael D
MD
Emanuel
Stuart L
SL
Lamontagne
Kenneth R
KR
Greenberger
Lee M
LM
D049109:Cell Proliferation / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D015394:Molecular Structure; D010091:Oximes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
D010091:Oximes; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D040301:Vascular Endothelial Growth Factor Receptor-2