Conception, synthèse et évaluation biologique de nouveaux ligands alkylants de l'ADN à visée anticancéreuse en séries pyrano[2',3':7,8]quino[2,3-b]quinoxalin-12(5H)-one et pyrano[2,3-h]pyrazino[2,3-b]quinolin-10(5h)-one

L objet de ce travail est l obtention d aza-analogues de séries acronycine ou benzo[b]acronycine. Ces composés présentent deux azotes en para introduits soit sur le cycle A de l acronycine ou sur le cycle B de la benzo[b]acronycine. Une série pyrano[2 ,3 :7,8]quino[2,3-b]quinoxalin-12(5H)-one et une série pyrano[2,3-h]pyrazino[2,3-b]quinolin-10(5H)-one ont ainsi été préparées. L activité cytotoxique, in vitro des différents composés ainsi préparés a été évaluée sur cellules leucémiques murines L1210 et tumeur solide humaine (carcinome épidermoïde buccal KB-3-1). Certains composés se sont révélés particulièrement prometteurs et les plus actifs ont été sélectionnés pour faire l objet d essais in vivo chez la souris. C est notamment le cas de la (+-)-cis-1,2-diacétoxy-6-méthoxy-3,3,14-triméthyl-1,2,3,14-tétrahydro-7H-pyrano[2 ,3':7,8]quino[2,3-b]quinoxalin-7-one qui présente une cytotoxicité tout à fait comparable à celle du S23906-1 qui a fait l objet d un essai clinique de phase I.The purpose of this work is the synthesis of aza-analogues in the acronycine and benzo[b]acronycine series. Two nitrogen atoms in para positions are located in the A cycle of acronycine or in the B cycle of the benzo[b]acronycine. Accordingly, various compounds belonging to the pyrano[2',3':7,8]quino[2,3-b]quinoxalin-12(5H)-one and pyrano[2,3-h]pyrazino[2,3-b]quinolin-10(5H)-one were prepared. The cytotoxic activity of the novel compounds was evaluated against murine leukemic L1210 and human carcinoma KB-3-1 cells in vitro. The most active compounds were selected for in vivo trials. The cytotoxic and antitumor properties of (+-)-cis-1,2-diacetoxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-pyrano[2',3':7,8]quino[2,3-b]quinoxalin-7-one were similar to those of S23906-1 which recently underwent phase I clinical trials.PARIS-BIUP (751062107) / SudocSudocFranceF

One-pot synthesis of novel poly-substituted phenanthrenes

International audienceA one-pot synthesis of novel poly-substituted phenanthrenes is described in this article through a Suzuki–Miyaura cross-coupling followed by a Dieckmann–Thorpe ring closure under microwave irradiation. The selection of the appropriate starting materials allowed us to introduce diversity on various positions of the phenanthrene ring syste

One-pot synthesis of new aza- and diaza-aminopenanthrenes

International audienceThe synthesis of a series of benzo(iso)quinoline and phenanthroline derivatives has been achieved using an efficient one-pot procedure. It proceeds through a Suzuki–Miyaura cross-coupling followed by a Dieckmann–Thorpe ring closure under microwave irradiation and provides easy access to building blocks not readily available through other method

Synthesis, Antitumor Activity, and Mechanism of Action of Benzo[<i>b</i>]chromeno[6,5‑<i>g</i>][1,8]naphthyridin-7-one Analogs of Acronycine

A series of 6-methoxy-3,3,14-trimethyl-3,14-dihydro-<i>7H</i>-benzo­[<i>b</i>]­chromeno­[6,5<i>-g</i>]­[1,8]­naphthyridin-7-one (<b>4</b>), 13-aza derivatives of benzo­[<i>b</i>]­acronycine, the isomeric 5-methoxy-2,2,13-trimethyl-2,13-dihydro-<i>6H-</i>benzo­[<i>b</i>]­chromeno­[7,6<i>-g</i>]­[1,8]­naphthyridin-6-one (<b>5</b>), and related <i>cis</i>-diols mono- and diesters were designed and synthesized. Their <i>in vitro</i> and <i>in vivo</i> biological activities were evaluated. As previously observed in the acronycine series, esters were the most potent derivatives exhibiting submicromolar activities; among them monoesters are particularly active. Racemic diacetate <b>21</b> showed a strong activity against KB-3-1 cell lines and was selected for <i>in vivo</i> evaluation and proved to be active, inhibiting tumor growth by more than 80%. After separation of the two enantiomers, compounds <b>21a</b> and <b>21b</b> were also evaluated against C38 colon adenocarcinoma; their activities were found to be significantly different