Synthesis, checkpoint kinase 1 inhibitory properties and in vitro antiproliferative activities of new pyrrolocarbazoles.

In the course of structure-activity relationship studies on granulatimide analogues, new pyrrolo[3,4-c]carbazoles have been synthesized in which the imidazole heterocycle was replaced by a five-membered ring lactam system or a dimethylcyclopentanedione. Moreover, the synthesis of an original structure in which a sugar moiety is attached to the indole nitrogen and to a six-membered D ring via an oxygen is reported. The inhibitory activities of the newly synthesized compounds toward checkpoint kinase 1 and their in vitro antiproliferative activities toward three tumor cell lines: murine leukemia L1210, and human colon carcinoma HT29 and HCT116 are described.

Synthesis, in vitro antiproliferative activities, and Chk1 inhibitory properties of pyrrolo[3,4-a]carbazole-1,3-diones, pyrrolo[3,4-c]carbazole-1,3-diones, and 2-aminopyridazino[3,4-a]pyrrolo[3,4-c]carbazole-1,3,4,7-tetraone.

The synthesis of substituted pyrrolo[3,4-a]carbazole-1,3-diones, pyrrolo[3,4-c]carbazole-1,3-diones, and 2-aminopyridazino[3,4-a]pyrrolo[3,4-c]carbazole-1,3,4,7-tetraone is reported. Their inhibitory properties toward Checkpoint 1 kinase (Chk1) have been evaluated and their in vitro antiproliferative activities toward three tumor cell lines: murine leukemia L1210, human colon carcinoma HT29 and HCT116 have been determined. From the biological results, it appears that, in contrast with the upper E heterocycle, the lower D heterocycle is not absolutely required for Chk1 inhibition. The ATP binding pocket of Chk1 seems to be adaptable to substitution of the nitrogen of the imide E heterocycle with a hydroxymethyl group, allowing the fundamental hydrogen bond with the Glu(85) residue of the enzyme.

Synthesis and biological evaluation of diversely substituted indolin-2-ones.

The synthesis of indolin-2-one derivatives substituted in the 3-position by an aminomethylene group bearing either an ornithine or a lysine residue is described. The inhibitory activities of these compounds toward a panel of eight kinases were examined. Furthermore, the antibacterial activities of the prepared compounds were tested against two Gram-positive bacteria Bacillus cereus and Streptomyces chartreusis, a Gram-negative bacterium Escherichia coli and a yeast Candida albicans.

Synthesis and biological activities of new checkpoint kinase 1 inhibitors structurally related to granulatimide.

In the course of structure-activity relationship studies on granulatimide analogues, new pyrrolo[3,4-c]carbazoles in which the imidazole heterocycle has been replaced by a five- or a six-membered ring bearing one or two carbonyl functions have been synthesized. Their checkpoint kinase 1 (Chk1) inhibitory properties and their in vitro antiproliferative activities toward three tumor cell lines-murine leukemia L1210 and human colon carcinoma HT29 and HCT116 have been determined. The results of molecular modeling in the ATP binding pocket of Chk1 are described. Among the newly synthesized compounds, compounds 13 and 16, in which the imidazole was replaced by a quinone and a hydroquinone and which bear a hydroxy group on the indole moiety, are the most potent Chk1 inhibitors in this series with IC50 values of 27 and 23 nM, respectively.

Bis-imide granulatimide analogues as potent Checkpoint 1 kinase 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.

Synthesis and antiproliferative activities of indolin-2-one derivatives bearing amino acid moieties.

A convenient synthesis of indolin-2-ones substituted in the 3 position by an aminomethylene group bearing different amino acid moieties is described. Their antiproliferative activities were evaluated toward a panel of human solid tumor cell lines (PC 3, DLD-1, MCF-7, M4 Beu, A549, PA 1) and healthy cell lines (a murine fibroblast L929 and a human fibroblast primary culture).

Synthesis, in vitro antiproliferative activities, and Chk1 inhibitory properties of indolylpyrazolones and indolylpyridazinedione.

The synthesis of 5-indolylpyrazol-3-one, 4-indolylpyrazol-3-one and 4-indolyl-pyridazin-3,6-dione is reported. Their Chk1 inhibitory properties have been evaluated and their in vitro antiproliferative activities toward three tumor cell lines: murine leukemia L1210, human colon carcinoma HT29 and HCT116 have been determined. 4-Indolyl-pyridazin-3,6-dione is inactive against Chk1 and exhibits weak cytotoxicities toward the tumor cell lines tested. The IC(50) values toward Chk1 of the two indolylpyrazolones are identical and are in the micromolar range, but the cytotoxicities of 4-indolylpyrazol-3-one are significantly stronger than those of 5-indolylpyrazol-3-one. Since 4-indolylpyrazol-3-one and 5-indolylpyrazol-3-one can present several conformers and tautomeric forms, molecular modelling in the ATP binding site of Chk1 has been carried out to investigate which form could induce the best stabilization in the active site of the enzyme. To get an insight into the kinase selectivity of these compounds, their inhibitory activities toward Src kinase were evaluated.

Synthesis and biological evaluation of oxindoles and benzimidazolinones derivatives.

The synthesis of new oxindoles and benzimidazolinones derivatives bearing a sugar residue on the aromatic nitrogen is described. The presence of the glycoside moiety should enhance the solubility of these heterocyclic compounds and/or improve the interaction with the active site of the biological targets. The inhibitory activities of these new compounds toward five kinases were examined: KDR (VEGFR-2), FGFR-1, PDGFR-beta, EGFR and Tie 2. Furthermore, the antibacterial activities of the prepared compounds were tested against two Gram-positive bacteria Bacillus cereus and Streptomyces chartreusis, a Gram-negative bacterium Escherichia coli and a yeast Candida albicans.

Synthesis and in vitro antiproliferative activities of quinoline derivatives.

The synthesis of new di- and trimeric quinoline derivatives is described as well as their in vitro antiproliferative activities toward a human fibroblast primary culture and two human solid cancer cell lines (MCF-7 and PA 1).

In-vitro antiproliferative activities and kinase inhibitory potencies of glycosyl-isoindigo derivatives.

In the course of studies on the preparation of potential kinase inhibitors, we were interested in the synthesis of diversely substituted glycosyl-isoindigo derivatives. To get an insight into the effect of the substitution pattern of the isoindigo aromatic and carbohydrate moieties on the biological activities and to identify the cellular target(s) involved in the in-vitro antiproliferative activity of these derivatives, their inhibitory activities toward a panel of 10 different kinases were examined. The best inhibitory activities were found toward cyclin-dependent kinase 2/cyclin A. Molecular modelling experiments were carried out to investigate the binding interactions between the active site of cyclin-dependent kinase 2 and the lead compound of this series.

Photochemistry of the three carboxypyridines in water: a pH dependent reaction.

The photochemistry of ortho, meta and para-carboxypyridines (pK(a)(1)= 1.0-2.1 and pK(a)(2)= 4.7-5.3) in aqueous medium was studied by laser-flash photolysis and product studies. At pH < pK(a)(1), hydroxylated compounds are produced with low quantum yields. Within the pH range 4-7, ortho and meta isomers undergo dimerization together with decarboxylation with a quantum yield showing a very sharp maximum around pK(a)(2)([small phi](max)= 0.09 and 0.01, respectively) while the para isomer is photostable. End-of-pulse transients assigned to triplet states were detected by laser-flash photolysis at pH < pK(a)(1) and pH > 4. Additionally, the carboxypyridinyl radicals were detected as secondary intermediates at pH < pK(a)(1) and 4 < pH < 7 and the OH-adduct radicals at pH < pK(a)(1). This is in favour of an electron transfer reaction between triplet and starting compound producing a charge transfer species. The radical anion would escape as carboxypyridinyl radical while the radical cation may add water at pH < pK(a)(1) yielding the OH-adduct radical or may undergo decarboxylation at pH > 4. The high quantum yield of phototransformation of the ortho isomer at pH > 4 is due to an easy decarboxylation process. A reaction scheme is proposed accounting for the dependences of [small phi] on both the pH and the carboxypyridines concentration. This study points out the distinct pattern of reactivity of carboxypyridines depending on the ionisation state of starting compounds and isomeric substitution.