title: Synthesis, antitumor activity, and mechanism of action of benzo[a]pyrano[3,2-h]acridin-7-one analogues of acronycine.
abstract: Twenty-two derivatives belonging to the cis-1,2-diacyloxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[a]pyrano[3,2-h]acridin-7-one series were synthesized in nine steps starting from 3,5-dimethoxyacetanilide (5) and 2-methoxy-1-naphthalenecarboxylic acid (7). Most of them exhibited submicromolar cytotoxicity when tested against murine leukemia (L1210) and human epidermoid carcinoma (KB-3-1) cell lines. The cytotoxic activity correlated strongly with the ability of the compounds to form covalent adducts with purified DNA. Among the most active compounds, 25, with IC50 values of 0.7 and 0.15 microM against L1210 and KB-3-1, respectively, was selected for evaluation in vivo against Colon 38 adenocarcinoma implanted in mice. This compound was active at 3 mg/kg i.v. (day 12 and 24) with 3/7 tumor free mice by day 80.
authors.affiliation: Laboratoire de Pharmacognosie de l'Université René Descartes, U.M.R./C.N.R.S. No. 8638, Faculté des Sciences Pharmaceutiques et Biologiques, 4 Avenue de l'Observatoire, 75006 Paris, France.
authors.forename: Tuan Minh
authors.initials: TM
authors.lastname: Nguyen
authors.forename: Chavalit
authors.initials: C
authors.lastname: Sittisombut
authors.forename: Sabrina
authors.initials: S
authors.lastname: Boutefnouchet
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Lallemand
authors.forename: Sylvie
authors.initials: S
authors.lastname: Michel
authors.forename: Michel
authors.initials: M
authors.lastname: Koch
authors.forename: François
authors.initials: F
authors.lastname: Tillequin
authors.forename: Romain
authors.initials: R
authors.lastname: Mazinghien
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
mesh_terms: D000166:Acridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000175:Acronine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D004952:Esters / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009368:Neoplasm Transplantation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
chemical_list: C511640:1,2-diacetoxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo(a)pyrano(3,2-h)acridin-7-one; D000166:Acridines; D000970:Antineoplastic Agents; D001578:Benzopyrans; D004952:Esters; D000175:Acronine