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31.
Voldoire A Moreau P Sancelme M Matulova M Léonce S Pierré A Hickman J Pfeiffer B Renard P Dias N Bailly C Prudhomme M 《Bioorganic & medicinal chemistry》2004,12(8):1955-1962
Analogues of antifungal tjipanazoles were obtained by semi-synthesis from rebeccamycin, an antitumor antibiotic isolated from cultures of Saccharothrix aerocolonigenes. The antiproliferative activities of the new compounds were evaluated in vitro against nine tumor cell lines. The effect on the cell cycle of murine leukemia L1210 cells was examined and the antimicrobial activities against two Gram positive bacteria, a Gram negative bacterium and a yeast were determined. The inhibitory properties toward four kinases and toward topoisomerase I were evaluated. The most cytotoxic compound in the series was a dinitro derivative characterized as a potent topoisomerase I inhibitor. 相似文献
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Serena Cervantes Evelien M Bunnik Anita Saraf Christopher M Conner Aster Escalante Mihaela E Sardiu Nadia Ponts Jacques Prudhomme Laurence Florens Karine G Le Roch 《Autophagy》2014,10(1):80-92
Autophagy is a catabolic pathway typically induced by nutrient starvation to recycle amino acids, but can also function in removing damaged organelles. In addition, this pathway plays a key role in eukaryotic development. To date, not much is known about the role of autophagy in apicomplexan parasites and more specifically in the human malaria parasite Plasmodium falciparum. Comparative genomic analysis has uncovered some, but not all, orthologs of autophagy-related (ATG) genes in the malaria parasite genome. Here, using a genome-wide in silico analysis, we confirmed that ATG genes whose products are required for vesicle expansion and completion are present, while genes involved in induction of autophagy and cargo packaging are mostly absent. We subsequently focused on the molecular and cellular function of P. falciparum ATG8 (PfATG8), an autophagosome membrane marker and key component of the autophagy pathway, throughout the parasite asexual and sexual erythrocytic stages. In this context, we showed that PfATG8 has a distinct and atypical role in parasite development. PfATG8 localized in the apicoplast and in vesicles throughout the cytosol during parasite development. Immunofluorescence assays of PfATG8 in apicoplast-minus parasites suggest that PfATG8 is involved in apicoplast biogenesis. Furthermore, treatment of parasite cultures with bafilomycin A1 and chloroquine, both lysosomotropic agents that inhibit autophagosome and lysosome fusion, resulted in dramatic morphological changes of the apicoplast, and parasite death. Furthermore, deep proteomic analysis of components associated with PfATG8 indicated that it may possibly be involved in ribophagy and piecemeal microautophagy of the nucleus. Collectively, our data revealed the importance and specificity of the autophagy pathway in the malaria parasite and offer potential novel therapeutic strategies. 相似文献
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Swati Agrawal Duk-Won D. Chung Nadia Ponts Giel G. van Dooren Jacques Prudhomme Carrie F. Brooks Elisadra M. Rodrigues John C. Tan Michael T. Ferdig Boris Striepen Karine G. Le Roch 《PLoS pathogens》2013,9(6)
Apicomplexan parasites are responsible for numerous important human diseases including toxoplasmosis, cryptosporidiosis, and most importantly malaria. There is a constant need for new antimalarials, and one of most keenly pursued drug targets is an ancient algal endosymbiont, the apicoplast. The apicoplast is essential for parasite survival, and several aspects of its metabolism and maintenance have been validated as targets of anti-parasitic drug treatment. Most apicoplast proteins are nuclear encoded and have to be imported into the organelle. Recently, a protein translocon typically required for endoplasmic reticulum associated protein degradation (ERAD) has been proposed to act in apicoplast protein import. Here, we show ubiquitylation to be a conserved and essential component of this process. We identify apicoplast localized ubiquitin activating, conjugating and ligating enzymes in Toxoplasma gondii and Plasmodium falciparum and observe biochemical activity by in vitro reconstitution. Using conditional gene ablation and complementation analysis we link this activity to apicoplast protein import and parasite survival. Our studies suggest ubiquitylation to be a mechanistic requirement of apicoplast protein import independent to the proteasomal degradation pathway. 相似文献
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Hugon B Anizon F Bailly C Golsteyn RM Pierré A Léonce S Hickman J Pfeiffer B Prudhomme M 《Bioorganic & medicinal chemistry》2007,15(17):5965-5980
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. 相似文献
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Serena Cervantes Jacques Prudhomme David Carter Krishna G Gopi Qian Li Young-Tae Chang Karine G Le Roch 《BMC cell biology》2009,10(1):45-10
Background
Malaria, a major public health issue in developing nations, is responsible for more than one million deaths a year. The most lethal species, Plasmodium falciparum, causes up to 90% of fatalities. Drug resistant strains to common therapies have emerged worldwide and recent artemisinin-based combination therapy failures hasten the need for new antimalarial drugs. Discovering novel compounds to be used as antimalarials is expedited by the use of a high-throughput screen (HTS) to detect parasite growth and proliferation. Fluorescent dyes that bind to DNA have replaced expensive traditional radioisotope incorporation for HTS growth assays, but do not give additional information regarding the parasite stage affected by the drug and a better indication of the drug's mode of action. Live cell imaging with RNA dyes, which correlates with cell growth and proliferation, has been limited by the availability of successful commercial dyes. 相似文献40.
Conchon E Anizon F Aboab B Golsteyn RM Léonce S Pfeiffer B Prudhomme M 《Bioorganic & medicinal chemistry》2008,16(8):4419-4430
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. 相似文献