title: Synthesis, antitumor activity, and mechanism of action of benzo[b]chromeno[6,5-g][1,8]naphthyridin-7-one analogs of acronycine.
abstract: A series of 6-methoxy-3,3,14-trimethyl-3,14-dihydro-7H-benzo[b]chromeno[6,5-g][1,8]naphthyridin-7-one (4), 13-aza derivatives of benzo[b]acronycine, the isomeric 5-methoxy-2,2,13-trimethyl-2,13-dihydro-6H-benzo[b]chromeno[7,6-g][1,8]naphthyridin-6-one (5), and related cis-diols mono- and diesters were designed and synthesized. Their in vitro and in vivo 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 21 showed a strong activity against KB-3-1 cell lines and was selected for in vivo evaluation and proved to be active, inhibiting tumor growth by more than 80%. After separation of the two enantiomers, compounds 21a and 21b were also evaluated against C38 colon adenocarcinoma; their activities were found to be significantly different.
authors.affiliation: Laboratoire de Pharmacognosie, Université Paris Descartes , U.M.R./C.N.R.S. n° 8638, Faculté des Sciences Pharmaceutiques et Biologiques, 4 Avenue de l'Observatoire, 75006 Paris, France.
authors.forename: Wen
authors.initials: W
authors.lastname: Tian
authors.forename: Rodrigue
authors.initials: R
authors.lastname: Yougnia
authors.forename: Sabine
authors.initials: S
authors.lastname: Depauw
authors.forename: Amélie
authors.initials: A
authors.lastname: Lansiaux
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: David-Cordonnier
authors.forename: Bruno
authors.initials: B
authors.lastname: Pfeiffer
authors.forename: Laurence
authors.initials: L
authors.lastname: Kraus-Berthier
authors.forename: Stéphane
authors.initials: S
authors.lastname: Léonce
authors.forename: Alain
authors.initials: A
authors.lastname: Pierré
authors.forename: Hanh
authors.initials: H
authors.lastname: Dufat
authors.forename: Sylvie
authors.initials: S
authors.lastname: Michel
mesh_terms: D000175:Acronine / Q000737:chemistry*; D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D024202:Electrophoretic Mobility Shift Assay; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D015394:Molecular Structure; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C000595867:1,2-diacetoxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo(b)chromeno(6,5-g)(1,8)naphthyridin-7-one; D000970:Antineoplastic Agents; D006576:Heterocyclic Compounds, 4 or More Rings; D009287:Naphthyridines; D000175:Acronine