ABSTRACT
The copper-catalyzed conjugate addition of various Grignard reagents to polyconjugated enones (dienone and enynone derivatives) is reported. The catalyst system, composed of copper triflate and an NHC ligand, led to the unusual selective formation of the 1,4-addition products. This reaction allows for the creation of all-carbon chiral quaternary centers with enantiomeric excesses up to 99%. The remaining unsaturation on the 1,4 adducts give access to valuable synthetic transformations.
ABSTRACT
The synthesis of non-peptidic helix mimetics based on a trimeric quinoline scaffold is described. The ability of these new compounds, as well as their synthetic dimeric intermediates, to bind to various members of the Bcl-2 protein anti-apoptotic group is also evaluated. The most interesting derivative of this new series (compound A) inhibited Bcl-x(L)/Bak, Bcl-x(L)/Bax and Bcl-x(L)/Bid interactions with IC(50) values around 25 µM.
Subject(s)
Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors , Quinolines/chemical synthesis , Quinolines/pharmacology , bcl-X Protein/antagonists & inhibitors , Apoptosis , Binding Sites , Dimerization , Dose-Response Relationship, Drug , Drug Discovery , Models, Molecular , Molecular Structure , Proto-Oncogene Proteins c-bcl-2/chemistry , Quinolines/chemistry , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/chemistry , Stereoisomerism , Structure-Activity Relationship , bcl-X Protein/chemistryABSTRACT
The carbazole framework is found in many natural compounds of biological interest. Indolocarbazoles such as rebeccamycin and staurosporine which are either a topoisomerase I inhibitor (rebeccamycin) or a non selective kinase inhibitor (staurosporine) are bacterial metabolites. In the search for new antitumor agents, DNA damage checkpoint kinases, in particular Checkpoint kinase 1, have recently emerged as attractive targets for cancer therapy. This review reports the synthesis and Chk1 inhibitory activities of pyrrolocarbazole compounds bearing four or five fused rings.
Subject(s)
Carbazoles/pharmacology , Protein Kinase Inhibitors/pharmacology , Protein Kinases/metabolism , Checkpoint Kinase 1 , Cyclization , Humans , Imidazoles/chemical synthesis , Imidazoles/chemistry , Models, Biological , Models, Molecular , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyrroles/chemical synthesis , Pyrroles/chemistry , Pyrroles/pharmacologyABSTRACT
Granulatimide and isogranulatimide, natural products isolated from an ascidian, were found to be abrogators of the cell cycle G2-M phase checkpoint by inhibition of Checkpoint 1 kinase (Chk1). In the course of structure-activity relationship studies on granulatimide analogues, we have synthesized a series of bis-imides, in which the imidazole moiety was replaced by an imide heterocycle. Various modifications have been introduced on one or both imide heterocycles, on the benzene ring, and on the indole nitrogen. Moreover, aza bis-imide analogues were synthesized in which the indole moiety was replaced by a 7-azaindole. Compared to those of granulatimide and isogranulatimide, the Chk1 inhibitory activities of some of the bis-imide carbazoles were stronger. In particular, 1,3,4,6-tetrahydro-10-hydroxy-7H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6-tetraone 11 exhibited an IC(50) value on purified full length Chk1 of 2 nM, which makes it a more potent Chk1 inhibitor than granulatimide and isogranulatimide. To get an insight into the selectivity of this new family of compounds, the inhibitory activities of 1,3,4,6-tetrahydro-7H-dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6-tetraone A have been evaluated on a panel of 15 kinases, the strongest inhibitory potency was found for Chk1. The inhibitory activities of compounds A, 5 and 11 toward Src tyrosine kinase and the cytotoxicity of various tumor cell lines were also evaluated.
Subject(s)
Alkaloids/pharmacology , Protein Kinase Inhibitors/pharmacology , Protein Kinases/metabolism , Alkaloids/chemistry , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Checkpoint Kinase 1 , Dose-Response Relationship, Drug , HCT116 Cells , HT29 Cells , Humans , Imidazoles/chemistry , Imidazoles/pharmacology , Indoles/chemistry , Indoles/pharmacology , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
The syntheses of a series of dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6-tetraones, substituted in 10-position with saturated and unsaturated side chains, via palladium catalyzed cross-coupling reactions, are described. These compounds can be considered as granulatimide bis-imide analogues. Their inhibitory activity toward Chk1 kinase and their antiproliferative activities in vitro in four tumor cell lines are reported.