Synthesis and biological activity of isogranulatimide analogues

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 Chk

Synthèse de nouveaux analogues originaux des granulatimide et isogranulatimides à visée antitumorale

CLERMONT FD-BCIU Sci.et Tech. (630142101) / SudocSudocFranceF

Synthèse d'analogues de la granulatimide possédant un maléimide à la place de l'hétérocycle imidazole

Poste

Pyrrolocarbazoles as Checkpoint 1 kinase inhibitors

International audienceThe 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

New highly sensitive rodent and human tests for soluble amyloid precursor protein alpha quantification: preclinical and clinical applications in Alzheimer’s disease

<p>Abstract</p> <p>Background</p> <p>Amyloid precursor protein (APP), a key molecule in Alzheimer’s disease (AD), is metabolized in two alternative cleavages, generating either the amyloidogenic peptides involved in AD pathology or the soluble form of APP (sAPPα). The level of amyloidogenic peptides in human cerebrospinal fluid (CSF) is considered to be a biomarker of AD, whereas the level of sAPPα in CSF as a biomarker has not been clearly established. sAPPα has neurotrophic and neuroprotective properties. Stimulating its formation and secretion is a promising therapeutic target in AD research. To this end, very sensitive tests for preclinical and clinical research are required.</p> <p>Methods</p> <p>The tests are based on homogenous time-resolved fluorescence and require no washing steps.</p> <p>Results</p> <p>We describe two new rapid and sensitive tests for quantifying mouse and human sAPPα. These 20 μl-volume tests quantify the levels of: i) endogenous mouse sAPPα in the conditioned medium of mouse neuron primary cultures, as well as in the CSF of wild-type mice, ii) human sAPPα in the CSF of AD mouse models, and iii) human sAPPα in the CSF of AD and non-AD patients. These tests require only 5 μl of conditioned medium from 5 × 10⁴ mouse primary neurons, 1 μl of CSF from wild-type and transgenic mice, and 0.5 μl of human CSF.</p> <p>Conclusions</p> <p>The high sensitivity of the mouse sAPPα test will allow high-throughput investigations of molecules capable of increasing the secretion of endogenous sAPPα in primary neurons, as well as the <it>in vivo</it> validation of molecules of interest through the quantification of sAPPα in the CSF of treated wild-type mice. Active molecules could then be tested in the AD mouse models by quantifying human sAPPα in the CSF through the progression of the disease. Finally, the human sAPPα test could strengthen the biological diagnosis of AD in large clinical investigations. Taken together, these new tests have a wide field of applications in preclinical and clinical studies.</p