granulatimide and isogranulatimide

Granulatimide and isogranulatimide are alkaloids obtained from marine sources which have been shown to inhibit cell-cycle G2-checkpoint, targeting more particularly checkpoint 1 kinase (Chk1). At a structural level, they possess a characteristic pyrrolocarbazole framework also shared by the well-known rebeccamycin and staurosporine microbial metabolites which have been described to inhibit topoisomerase I and diverse kinases, respectively. This review reports precisely on the synthesis and kinase inhibitory activities of pyrrolocarbazole-based analogues of granulatimide.

Topics: Alkaloids; Carbazoles; Checkpoint Kinase 1; Humans; Imidazoles; Indoles; Marine Biology; Protein Kinase Inhibitors; Protein Kinases; Pyrroles

The two marine alkaloids granulatimide and isogranulatimide have been shown to inhibit the checkpoint kinase 1 (Chk1), a promising target for cancer treatment. A molecular docking study allowing the design of new potential Chk1 inhibitors based on the natural products skeleton and the synthetic work to an amino-target platform to prepare them are described.

Topics: Alkaloids; Checkpoint Kinase 1; Dose-Response Relationship, Drug; Drug Design; Imidazoles; Indoles; Models, Molecular; Molecular Structure; Protein Kinase Inhibitors; Protein Kinases; Structure-Activity Relationship

A series of pyrrolic analogs and two series of regioisomeric pyrazolic analogs of the marine alkaloids granulatimide and isogranulatimide were prepared. The synthesis of the two first ones was based on the condensation reaction of diversely 5-substituted 3-bromoindoles with pyrrole or pyrazole followed by addition of the intermediates on maleimide or dibromomaleimide, respectively, the so-obtained acyclic adducts being finally photocyclized to the desired analogs. Compounds of the last series were obtained by reacting different 5-substituted-indole-3-glyoxylates with N-Boc-pyrazole-3-acetamide and subsequent photochemical cyclization of the adducts. All the compounds were evaluated for their in vitro growth inhibitory properties toward eight cancer cell lines. Several compounds were also assayed for their ability to abrogate the G2-cell cycle checkpoint or to inhibit a panel of Ser/Thr kinases. Lastly, computer-assisted phase-contrast microscopy (quantitative videomicroscopy) revealed that the three most potent compounds (4a, 9a, 9e), with IC(50) growth inhibitory concentrations ranging between 10 and 20 μM, displayed cytostatic, not cytotoxic, anticancer effects.

Topics: Alkaloids; Animals; Antineoplastic Agents; Aquatic Organisms; Cell Line, Tumor; Cell Proliferation; Chemistry Techniques, Synthetic; G2 Phase Cell Cycle Checkpoints; Humans; Imidazoles; Indoles; M Phase Cell Cycle Checkpoints; Mice; Protein Kinase Inhibitors

The synthesis of new isogranulatimide analogues, their inhibitory activities toward the Checkpoint 1 kinase (Chk1), and their in vitro cytotoxicities toward four tumor cell lines (one murine L1210 leukemia, and three human cell lines: DU145 prostate carcinoma, A549 non-small cell lung carcinoma, and HT29 colon carcinoma) are described. The affinity for DNA of some representative compounds and their ability to induce DNA cleavage mediated by topoisomerase I have been examined. In some of the newly synthesized compounds, the imidazole heterocycle of isogranulatimide is replaced by a pyrrole and/or the indole unit is replaced by a 7-azaindole. Compounds in which a sugar part is attached to the 7-azaindole moiety have also been prepared. Some of the newly synthesized compounds are more potent Chk1 inhibitors than granulatimide. The selectivity of two potent Chk1 inhibitors 24 and 26 has been evaluated using various kinases. The strongest inhibitory properties are found toward Chk1.

Topics: Aza Compounds; Carbazoles; Cell Line, Tumor; Cell Proliferation; Checkpoint Kinase 1; DNA; DNA Topoisomerases, Type I; Humans; Imidazoles; Indoles; Magnetic Resonance Spectroscopy; Molecular Structure; Protein Kinase Inhibitors; Protein Kinases; Pyrroles; src-Family Kinases; Structure-Activity Relationship; Topoisomerase I Inhibitors

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.

Topics: Alkaloids; Animals; Cell Line, Tumor; Cell Proliferation; Checkpoint Kinase 1; Dose-Response Relationship, Drug; HCT116 Cells; HT29 Cells; Humans; Imidazoles; Indoles; Models, Molecular; Molecular Structure; Protein Kinase Inhibitors; Protein Kinases; Structure-Activity Relationship