Studies on cyclin-dependent kinase inhibitors: indolo-[2,3-a]pyrrolo[3,4-c]carbazoles versus bis-indolylmaleimides.
A series of indolo[2,3-a]pyrrolo[3,4-c]carbazoles and their bis-indolylmaleimides precursors have been prepared in order to compare their activity as D1-CDK4 inhibitors. Both enzymatic and antiproliferative assays have shown that the structurally more constrained indolo[2,3-a]pyrrolo[3,4-c]carbazoles are consistently more active (8-42-fold) in head-to-head comparison with their bis-indolylmaleimides counterparts. Cell-cycle analysis using flow cytometry have also shown that the indolocarbazoles are selective G1 blockers while the bis-indolylmaleimides arrest cells in the G2/M phase.
Sanchez-Martinez
Concha
C
DCR&T, Lilly Spain S.A., Avda de la Industria 30, 28108 Alcobendas, Madrid, Spain. sanchez-martinez_concepcion@lilly.com
Shih
Chuan
C
Zhu
Guoxin
G
Li
Tiechao
T
Brooks
Harold B
HB
Patel
Bharvin K R
BK
Schultz
Richard M
RM
DeHahn
Tammy B
TB
Spencer
Charles D
CD
Watkins
Scott A
SA
Ogg
Catherine A
CA
Considine
Eileen
E
Dempsey
Jack A
JA
Zhang
Faming
F
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002227:Carbazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D008968:Molecular Conformation; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D002227:Carbazoles; D004791:Enzyme Inhibitors; D011758:Pyrroles; D018844:Cyclin-Dependent Kinases