Synthesis kinases inhibitory potencies and in vitro antiproliferative activity of isoindigo and 7'-azaisoindigo derivatives substituted by Sonogashira cross-coupling

International audienceIn the course of structure–activity relationship studies we were interested in the synthesis of isoindigo and 7′-azaisoindigo derivatives substituted at the N-1 position by a 1-(2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl), at the 5′-position by various chains introduced by Sonogashira cross-coupling and substituted or not at the 5-position by a bromine atom. To get an insight into the substitution pattern required for the best biological potencies, their kinase inhibitory potencies and their in vitro antiproliferative activities were evaluated. The derivatives were tested toward four protein kinases (CDK5/p25, GSK3, CK1, Dyrk1A) and their in vitro antiproliferative activity was tested against two human myeloid leukaemia cell lines (K562 and HL60)

Synthesis of a staurosporine analogue possessing a 7-azaindole unit instead of an indole moiety

The synthesis of a new staurosporine analogue possessing a 7-azaindole unit instead of an indole moiety is described. This synthesis could be achieved by coupling a sugar moiety previously tosylated in 2′ position to the azaindolocarbazole aglycone. Nucleophilic substitution on the carbon bearing the tosyl group yielded to the key cyclization leading to a compound in which the carbohydrate part is linked to both indole and azaindole nitrogen

A three-step synthesis from rebeccamycin of an efficient checkpoint kinase 1 inhibitor.

International audienceRebeccamycin derivative 1 bearing a sugar moiety linked to both indole nitrogens and an amino substituent on the carbohydrate unit was synthesized in three steps from the bacterial metabolite. This compound was found to be a highly potent checkpoint kinase 1 inhibitor with an IC50 value of 2.8 nM

Synthesis of pyridino[3',2' :4,5]pyrrolo[3,2-g]pyrrolo-[3,4-e]indolizin-1,3-dione and pyrrolo[3,2-c]pyrazole skeletons

A three step synthesis of an isogranulatimide analogue, in which the imidazole moiety is replaced by a pyrrole unit and the indole heterocycle is replaced by a 7-azaindole moiety is described. Moreover, a novel synthetic pathway to the pyrrolo[3,2-c]pyrazole skeleton is reporte

Synthesis and antiproliferative activities of isoindigo and azaisoindigo derivatives

In the course of structure–activity relationship studies, diversely substituted 1-(β- d-acetylatedglucopyranosyl)isoindigo derivatives were prepared from indolines. New 7′-azaisoindigo analogues were also synthesized by coupling a glycosylated isatine and a 7-azaindolin-2-one derivative. Compounds containing a 7′-azaisoindigo framework have never been described before. To get an insight into the substitution pattern required for the best biological potencies, their antiproliferative activities were evaluated toward a human buccal carcinoma cell line (KB) and two human myeloid leukaemia cell lines (K562, HL60

Synthesis of bridged aza-rebeccamycin analogues

The syntheses of rebeccamycin analogues possessing a 7-azaindole moiety instead of an indole unit, and with both indole and azaindole moieties linked to the carbohydrate are described. In these bridged aza compounds, the oxygen of the pyranose heterocycle is oriented towards either the indole, or the azaindole unit. In these series, compounds bearing a free imide nitrogen were synthesized by coupling the corresponding aglycones with a sugar pre-tosylated in 2-position via a Mitsunobu reaction. To obtain a precursor for bridged aza-rebeccamycin analogues substituted in 6-position on the sugar moiety, a 2,6-ditosylated sugar was use

Synthesis of dipyrrolo [3,4-a:3,4-c]carbazole-1,3,4,6-tetraones bearing a sugar moiety.

The synthesis of a series of dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6-tetraones, structurally related to the G2 checkpoint inhibitor granulatimide and bearing a sugar moiety, is described. Substitutions were carried out at the 6-position of the glycosyl unit to lead to an amino substituent as observed in many biologically active compounds such as anthracyclins or staurosporine

Synthesis and biological activities of aminopyrimidyl-indoles structurally related to meridianins

International audienceThe synthesis of new meridianin derivatives substituted at the C-5 position of the 2-aminopyrimidine ring by various aryl groups and substituted or not by a methyl group on the indole nitrogen is described. These compounds were tested for their kinase inhibitory potencies toward five kinases (CDK5/p25, CK1δ/ε, GSK-3α/β, Dyrk1A and Erk2) 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

Synthesis of aminopyrimidylindoles structurally related to meridianins

The synthesis of new meridianin derivatives substituted at the C-5′ position of the 2-aminopyrimidine ring by various aryl groups and substituted or not by a methyl group on the indole nitrogen is described. The 2-aminopyrimidine ring was obtained via a Bredereck synthesis. Aryl groups were introduced by Suzuki cross-coupling after bromination of the 2-aminopyrimidine ring at the C-5′ positio

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

International audienceThe 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