Synthetic approaches to indolo[6,7-a]pyrrolo[3,4-c]carbazoles: potent cyclin D1/CDK4 inhibitors.
Synthesis of indolo[6,7-a]pyrrolo[3,4-c]carbazoles 1, a new class of cyclin D1/CDK4 inhibitors, by oxidation of the corresponding aryl indolylmaleimides 2, will be described. Two approaches to the synthesis of 2 were identified that required new methods for the synthesis of 7-substituted indole acetamides 3 and N-methyl (indol-7-yl)oxoacetates 6. The chemistry developed enabled introduction of functionality (-OR, NR(2)) at C(12) and N(13) facilitating structure-activity relationship (SAR) evaluation of this indolocarbazole platform.
Faul
Margaret M
MM
Global Chemical Process Research and Development, Indianapolis, Indiana 46285, USA. mfaul@amgen.com
Engler
Thomas A
TA
Sullivan
Kevin A
KA
Grutsch
John L
JL
Clayton
Marcella T
MT
Martinelli
Michael J
MJ
Pawlak
Joseph M
JM
LeTourneau
Michael
M
Coffey
D Scott
DS
Pedersen
Steven W
SW
Kolis
Stanley P
SP
Furness
Kelly
K
Malhotra
Sushant
S
Al-awar
Rima S
RS
Ray
James E
JE
D000081:Acetamides / Q000737:chemistry; D000085:Acetates / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D002227:Carbazoles / Q000138:chemical synthesis*; D019938:Cyclin D1 / Q000037:antagonists & inhibitors*; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D006801:Humans; D007211:Indoles / Q000737:chemistry*; D008301:Maleimides / Q000737:chemistry; D016877:Oxidants / Q000737:chemistry; D010777:Photochemistry; D011518:Proto-Oncogene Proteins; D011758:Pyrroles / Q000737:chemistry*; D013329:Structure-Activity Relationship
D000081:Acetamides; D000085:Acetates; D000970:Antineoplastic Agents; D002227:Carbazoles; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D016877:Oxidants; D011518:Proto-Oncogene Proteins; D011758:Pyrroles; D019938:Cyclin D1; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases