Synthesis of quinolinyl/isoquinolinyl[a]pyrrolo [3,4-c] carbazoles as cyclin D1/CDK4 inhibitors.
A novel series of pyrrolo[3,4-c] carbazoles fused with a quinolinyl/isoquinolinyl moiety were synthesized and their D1/CDK4 inhibitory and antiproliferative activity were evaluated. Compound 8H, 14H-isoquinolinyl[6,5-a]-pyrrolo[3,4-c]carbazole-7,9-dione (1d) was found to be a highly potent D1/CDK4 inhibitor with an IC(50) of 69 nM. Compound 1d also inhibited tumor cell growth, arrested tumor cells in G1 phase and inhibited pRb phosphorylation.
Zhu
Guoxin
G
Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. zhu_guoxin@lilly.com
Conner
Scott
S
Zhou
Xun
X
Shih
Chuan
C
Brooks
Harold B
HB
Considine
Eileen
E
Dempsey
Jack A
JA
Ogg
Cathy
C
Patel
Bharvin
B
Schultz
Richard M
RM
Spencer
Charles D
CD
Teicher
Beverly
B
Watkins
Scott A
SA
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002227:Carbazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D002453:Cell Cycle; D018360:Crystallography, X-Ray; D019938:Cyclin D1 / Q000037:antagonists & inhibitors*; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D003500:Cyclization; D004121:Dimethyl Sulfoxide; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D002227:Carbazoles; D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D019938:Cyclin D1; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D004121:Dimethyl Sulfoxide