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 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 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 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

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 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 of glycosyl-isoindigo derivatives

The synthesis of 1-(β--glucopyranosyl)-isoindigo from commercially available indoline is described. The synthetic pathway used allowed the substitution of the aromatic moiety by either electron donor or acceptor substituent

Impact of short term HAART initiated during the acute or chronic stage on SIV infection of the male genital tract

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Pim-selective inhibitor DHPCC-9 reveals Pim kinases as potent stimulators of cancer cell migration and invasion

<p>Abstract</p> <p>Background</p> <p>Pim family kinases are small constitutively active serine/threonine-specific kinases, elevated levels of which have been detected in human hematopoietic malignancies as well as in solid tumours. While we and others have previously shown that the oncogenic Pim kinases stimulate survival of hematopoietic cells, we now examined their putative role in regulating motility of adherent cancer cells. For this purpose, we inhibited Pim kinase activity using a small molecule compound, 1,10-dihydropyrrolo[2,3-<it>a</it>]carbazole-3-carbaldehyde (DHPCC-9), which we had recently identified as a potent and selective inhibitor for all Pim family members.</p> <p>Results</p> <p>We now demonstrate that the Pim kinase inhibitor DHPCC-9 is very effective also in cell-based assays. DHPCC-9 impairs the anti-apoptotic effects of Pim-1 in cytokine-deprived myeloid cells and inhibits intracellular phosphorylation of Pim substrates such as Bad. Moreover, DHPCC-9 slows down migration and invasion of cancer cells derived from either prostate cancer or squamocellular carcinoma patients. Silencing of Pim expression reduces cell motility, while Pim overexpression enhances it, strongly suggesting that the observed effects of DHPCC-9 are dependent on Pim kinase activity. Interestingly, DHPCC-9 also abrogates NFATc-dependent migration of cancer cells, implying that NFATc factors mediate at least part of the pro-migratory effects of Pim kinases.</p> <p>Conclusions</p> <p>Altogether, our data indicate that DHPCC-9 is not only a powerful tool to investigate physiological effects of the oncogenic Pim family kinases, but also an attractive molecule for drug development to inhibit invasiveness of Pim-overexpressing cancer cells.</p