Synthesis and mixed lineage kinase activity of pyrrolocarbazole and isoindolone analogs of (+)K-252a.
Structural modification of the indolecarbazole natural product (+)K-252a identified structural requirements for MLK activity and a novel series of potent fused pyrrolocarbazole MLK1/3 inhibitors. The SAR revealed that the lactam regiochemistry, the shape of the heterocycle, and aryl rings B and F are important to MLK activity. Heteroatom and alkyl replacement of the N-12 and/or N-13 indole nitrogen atoms identified the nonplanar dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-7-one (8) and corresponding 5,7-dione (7) as potent cell-permeable MLK1/3 family-selective leads with in vitro activity comparable to that of (+)K-252a and determined them to be 2- to 3-fold more potent than the aglycone natural product K-252c.
Hudkins
Robert L
RL
Cephalon, Inc., 145 Brandywine Parkway, West Chester, Pennsylvania 19380, USA. rhudkins@ cephalon.com
Johnson
Neil W
NW
Angeles
Thelma S
TS
Gessner
George W
GW
Mallamo
John P
JP
D000818:Animals; D016466:CHO Cells; D002227:Carbazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D026121:Indole Alkaloids; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C517642:12,13-dihydro-5H,6H,14H-naphthyl(3,4-a)pyrrolo(3,4-c)carbazole-7(7H)-one; C517643:12,13-dihydro-6H,14H-naphthyl(3,4-a)pyrrolo(3,4-c)carbazole-5,7(5H,7H)-dione; D002227:Carbazoles; D006576:Heterocyclic Compounds, 4 or More Rings; D026121:Indole Alkaloids; D007211:Indoles; D011758:Pyrroles; C049985:staurosporine aglycone; D020930:MAP Kinase Kinase Kinases