title: Synthesis of C-glycosyl pyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones as a scaffold for check point kinase 1 inhibitors.
abstract: Indolocarbazole natural products are known to possess a variety of biological activities that hold promise as cancer chemotherapeutic agents. We newly designed C-glycosyl pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione derivatives 7 and 8, which are natural-product-like scaffolds. Compounds 7 and 8 were stereoselectively and efficiently synthesized using β-selective C-allylation, Heck reaction, and thermal 6π-electron cyclization/oxidative aromatization. Their potential as Chk1 inhibitors was investigated, and 7 and 8 exhibited an inhibitory activity with IC50 values of 0.5-9.5 μM, which is good activity for scaffolds. The key intermediate 23 was obtained by five steps from d-ribose in 33% overall yield by this synthetic route, which would enable us to prepare a range of analogues in order to investigate further structure-activity relationship studies in the optimization process.
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University , Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ichikawa
authors.forename: Nana
authors.initials: N
authors.lastname: Tatebayashi
authors.forename: Akira
authors.initials: A
authors.lastname: Matsuda
mesh_terms: D002227:Carbazoles / Q000138:chemical synthesis* / Q000737:chemistry; D000071877:Checkpoint Kinase 1; D004305:Dose-Response Relationship, Drug; D005960:Glucosides / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism*; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: C000592251:C-glycosyl pyrrolo(3,4-c)carbazole-1,3(2H,6H)-dione; D002227:Carbazoles; D005960:Glucosides; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1