Conception, synthèse et évaluation biologique de nouveaux antitumoraux en séries benzo[b]acridone et benzo[b]acronycine

L acronycine est un alcaloïde antitumoral à large spectre dont l évaluation clinique a été limitée en raison de sa faible puissance et de son insolubilité dans les solvants biocompatibles. Les diesters de série 1,2-dihydro-1,2-dihydroxybenzo[b]acronycine se sont révélés particulièrement intéressants, notamment le diacétate S-23906-1 qui fait l objet d études cliniques. De nombreux dérivés de série benzo[b]acronycine, porteurs de groupements très partants (type carbamate) et des dérivés plus stables (esters cinnamiques) ont été synthétisés. Leur cytotoxicité a été évaluée sur cellules L-1210 et KB-3-1. Les plus actifs ont été testés in vivo sur le carcinome du colon C-38 de la Souris. Ils agissent par alkylation de l ADN. La préparation d analogues simplifiés, ne comportant pas de cycle pyrane a été réalisée en séries N-méthylacridone et N-méthylbenzo[b]acronycine. Le méthoxyle en position 1 est essentiel pour observer une bonne activité dans ces séries.The pyranoacridone alkaloid acronycine exhibits antitumor properties against a large panel of tumor models. Its clinical evaluation was hampered by its the moderate potency and extremely low water-solubility. Esters in the 1,2-dihydro-1,2-dihydroxybenzo[b]acronycine series proved much more promising, particularly diacetate S-23906-1 currently under clinical trials. Numerous new derivatives were prepared in the benzo[b]acronycine series either including good leaving groups (carbamate type), or presenting increased stability (cinnamic esters). Their cytotoxic activity was determined on L-1210 and KB-3-1 cells. The most active compounds were also tested in vivo against C-38 carcinoma in Mice. Their mechanism of action involves DNA alkylation. Simplified analogues were synthesized in the N-méthylacridone and N-méthylbenzo[b]acronycine series. The methoxy group at position 1 appears as an essential structural requirement to observe biological activity in these latter series.PARIS-BIUP (751062107) / SudocSudocFranceF

Chiroptical study and absolute configuration of securinine oxidation products

<div><p>Time-dependant density functional theory–electronic circular dichroism spectra prediction was carried out to study the absolute configuration of phyllanthidine-type derivatives <b>5</b> and <b>6</b>, derived from securinine (<b>1</b>) and its enantiomer virosecurinine (<b>2</b>), respectively. This method demonstrated to be very reliable in this alkaloid series. Thus, <b>5</b> and <b>6</b> shared the same stereochemistry as their parent precursors, confirming the retentive nature of the oxidation sequence. In addition, this study highlighted the key role of the methylene bridge (BC ring) in the chiroptical activity of these compounds. These results fully clarified the stereochemical relationships between the phyllanthidine and the securinine subgroups.</p></div