Le carcinome hépatocellulaire (HCC) est le cancer du foie le plus répandu et représente la seconde cause de décès par cancer dans le monde. Un mauvais pronostic et l'absence de traitement efficace en font un problème majeur de santé publique dans les pays en voie de développement, notamment en Asie du Sud-Est, justifiant pleinement la recherche de molécules ou d'approches thérapeutiques nouvelles contre l'HCC. Ce travail porte sur la recherche de molécules isolées de plantes vietnamiennes actives contre l'HCC. La première approche a consisté en un criblage pharmacologique de 33 substances naturelles qui a conduit à l'identification de 7 ent-kaurane diterpénoïdes isolés de Croton kongensis Gagnep. présentant des propriétés antiprolifératives originales. La seconde approche, par criblage in silico d'une banque de 354 substances naturelles, a permis d'identifier la solasonine comme inhibiteur de l'interaction mortalin - p53 induisant l'apoptose dans la lignée cellulaire humaine HepG2. / Human hepatocellular carcinoma (HCC) is the most common type of liver cancer, the second most common cause of death from cancer worldwide. A very poor prognosis and a lack of effective treatments make liver cancer a major public health problem, notably in less developed regions, particularly in Eastern Asia. This fully justifies the search of new molecules and therapeutic strategies against HCC. The present work focused on finding bioactive compounds from Vietnamese plants against HCC. The first approach used classical screening of 33 natural compounds which resulted in the identification of 7 ent-kaurane diterpenoids isolated from Croton kongensis Gagnep. as potential agents. The second approach aimed at identifying molecules that could abrogate the interaction between Mortalin and p53 by in silico screening of a database of 354 natural compounds, which allowed the identification of Solasonine as a potent inhibitor of p53 - mortalin interactions.

Erythrina plant species, botanical family Fabaceae, are the main source for the tetracyclic erythrina-type alkaloids, and other chemical classes such as flavonoids. The Erythrina velutina Willd specie is popularly known as "Mulungu" and used by the population of the northeastern region of Brazil for its sudorific, soothing, emollient, pectoral, and local anesthetic properties. The objective of this study was to isolate and identify the constituents present in the leaves methanol extract of Erythrina velutina, and to investigate the antimicrobial activity of the crude extract and organic phases as well as contribute to the chemotaxonomy of the genus Erythrina. The leaves were collected in the city of Simão Dias, Sergipe, Brazil. The phytochemical screening performed with the crude methanol extract showed the presence of the following secondary metabolites: alkaloids, tannins, and flavonoids. The crude methanol extract was obtained by maceration and fractionated into hexane, ethyl acetate and n-butanol phase. From the crude methanol extract was extracted alkaloids that resulted on basic chloroform and nbutanol phase. Nicotinic acid was isolated from basic n-butanol phase. The structure identification involved analysis of spectral data of NMR of 1H and 13C and comparison with literature data. The behavior pharmacological screening showed that administration of the organic phases and crude extract promoted discrete behavioral changes at the level of central nervous system, suggesting that the extract of Erythrina velutina contains psychoactive compounds. In addition, antimicrobial screening showed that the crude methanol extract and hexane fraction present a weak inhibition or in part without inhibition zone defined for the fungus Trichophyton rubrum T544. / O gênero Erythrina, família Fabaceae, é muito conhecido pela presença de alcalóides tetracíclicos tipo eritrina e outras classes químicas como flavonóides. A espécie Erythrina velutina Willd, conhecida popularmente como Mulungu , é utilizada pela população do nordeste brasileiro por suas propriedades sudoríficas, calmante, emoliente, peitoral e anestésica local. O objetivo deste trabalho foi isolar e identificar os constituintes químicos presentes no extrato metanólico das folhas de Erythrina velutina, bem como investigar a atividade farmacológica e antimicrobiana do extrato bruto e das fases orgânicas, além de contribuir com a quimiotaxonomia do gênero Erythrina. As folhas foram coletadas no município de Simão Dias, Sergipe, Brasil. O extrato metanólico bruto, obtido por maceração, foi submetido a prospecção fitoquímica que indicou a presença dos seguintes metabólitos secundários: alcalóides, taninos e flavonóides. O particionamento deste extrato foi realizado com hexano, acetato de etila e n-butanol. A partir do extrato metanólico bruto foi feita uma marcha para alcalóide obtendo as fases clorofórmica e n-butanólica básica. Da fase n-butanólica básica isolou-se o ácido nicotínico. A identificação estrutural do composto foi realizada a partir dos dados espectrais de RMN de 1H e 13C e em comparação com dados da literatura. Na realização da triagem farmacológica comportamental, foi observado que administrações das fases orgânicas e do extrato bruto promoveram discretas alterações comportamentais ao nível de sistema nervoso central, sugerindo que o extrato de Erythrina velutina contém substâncias psicoativas. O extrato metanólico bruto e a fração hexânica promoveram uma inibição de crescimento fraco ou parcial, sem halo de inibição definido, para o fungo Trichophyton rubrum T544.

Les dérivés du platine (i.e. cisplatine et oxaliplatine) représentent une des classes pharmacologiques les plus utilisées en oncologie, notamment dans les cancers colorectaux. Cependant, leur efficacité est limitée par l’émergence de résistances acquises. Nous avons alors étudié in vitro dans différentes lignées cancéreuses coliques humaines (HCT116, LoVo, SW480, HT29) les conséquences à long terme des dérivés du platine lorsqu’ils sont utilisés dans des conditions tenant compte de la sensibilité cellulaire. Ils provoquent des cassures double-brin (objectivées par l’expression de -H2AX), dont le taux dépend du système p53/p21, du complexe MRN et du niveau de stabilité microsatellitaire. Ils induisent aux plus fortes concentrations ( IC50), une cytostase qui s’accompagne de la formation de cellules géantes macrocytaires et endopolyploïdes, dont certaines acquièrent un phénotype sénescent. Dans le même temps, l’activation des mécanismes de réparation des CDB varie en fonction du dérivé du Pt et de la lignée considérée. A plus long terme, des cellules « résistantes » se développent : elles ont une ploïdie normale, et se caractérisent par une plus grande résistance aux dérivés du platine et la présence de novo d’anomalies chromosomiques récurrentes leur conférant un avantage sélectif potentiel en terme de prolifération. Ces mécanismes pourraient contribuer à expliquer en clinique la survenue d’une résistance à une chimiothérapie pourtant initialement efficace. Parallèlement, nous avons évalué in vitro et in vivo de nouveaux complexes de platine obtenus par pharmacomodulation, et associant un noyau intercalant dérivé de la phénanthroline ou de l’acridine. Les résultats in vitro montrent globalement une amélioration significative de la cytotoxicité. Toutefois, un des composés les plus cytotoxiques in vitro, le [(5,6-diméthyl-1,10-phénanthroline) (S,S-diaminocyclohexane)platine(II)], n’exerce pas d’effet antitumoral dans un modèle syngénique de cancer colique chez le rat BD-IX, mais montre une néphrotoxicité marquée. Ces données soulignent l’insuffisance du criblage in vitro et la discordance in vitro/in vivo. / Platinum compounds (i.e. cisplatin and oxaliplatin) represent a class of DNA-damaging agents widely used in clinic especially in the treatment of colorectal cancer. However, their effectiveness is restricted because of emergence of acquired resistance. Therefore, long-term effects of platinum compounds, used at conditions reflecting the in vitro cellular sensibility, were assessed in vitro in several human colon cancer cell lines (HCT116, LoVo, SW480, HT29). Their cytotoxicity is related to double-strand break formation (objectived by -H2AX expression), which depends on p53/p21 status, MRN complex and microsatellite stability of the cell line. Furthermore, at the highest concentrations ( IC50), cells stopped their proliferation and exhibited phenotypic alterations resulting from progressive polyploidy and/or senescence. In the same time, DNA repair systems are activated differently according to the platinum derivate and the cell line. At later stages, cells that are more resistant to platinum compounds than their parental counterpart emerged. They have recovered their basal level of ploidy and acquired de novo recurrent chromosomal aberrations. Such mechanisms could contribute to the recurrence of clinical malignancies, even after an effective initial response to chemotherapy. On the other hand, pharmacological evaluation of new platinum compounds with phenanthroline or acridine intercalating ligand was performed in vitro and in vivo. Globally, many compounds exhibited a higher cytotoxic effect than cisplatin or oxaliplatin in all cell lines studied. Unfortunately, in vivo investigations of one of the most cytotoxic compounds ([(5,6-dimethyl-1,10-phenanthroline) (S,S-diaminocyclohexane)platinum(II)]) did not exhibit antitumor effect in BD-IX rats bearing peritoneal carcinomatosis, whatever the route of administration used (systemic or local), but it displayed nephrotoxicity. These results query the in vitro/in vivo correlation and reconsider the place of the in vivo screening.