title: Synthesis and biological study of a new series of 4'-demethylepipodophyllotoxin derivatives.
abstract: Etoposide (VP-16) is a potent human DNA topoisomerase II poison, derived from 4'-demethylepipodophyllotoxin, widely used in cancer chemotherapy. Continuous efforts have driven to synthesize new related compounds, presenting decreased toxic side effects, metabolic inactivation, drug resistance, and increased water solubility. Identified structure-activity relationships have pointed out the importance of the 4beta-substitution and of the configuration of the D ring. Here we report the synthesis of two novel series of derivatives of 4'-demethylepipodophyllotoxin. The first bears a carbamate chain in the 4 position (13a-f), whereas, in the second series, in addition to this chain, the lactone ring has been modified by shifting the carbonyl from position 13 to position 11 (27a-f). Moreover, an analogue of TOP-53 having this lactone modification has also been prepared (32). From this study, structure-activity relationships were established. Compounds 13a and 27a displayed potent cytotoxic activity against the L1210 cell line (10 to 20-fold higher than VP-16) and proved to be strong topoisomerase II poisons more potent than VP-16. From preliminary in vivo investigation of both compounds against P388 leukemia and orthotopically grafted human A549 lung carcinoma, it appeared that 13a and 27a constitute promising leads for a new class of antitumor agents.
authors.affiliation: Laboratoire de Biophysique, UMR 5153 CNRS, Muséum National d'Histoire Naturelle, USM 0503, INSERM UR565, 43 rue Cuvier, 75231 Paris Cedex 05, France.
authors.forename: Maria
authors.initials: M
authors.lastname: Duca
authors.forename: Dominique
authors.initials: D
authors.lastname: Guianvarc'h
authors.forename: Philippe
authors.initials: P
authors.lastname: Meresse
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Bertounesque
authors.forename: Daniel
authors.initials: D
authors.lastname: Dauzonne
authors.forename: Laurence
authors.initials: L
authors.lastname: Kraus-Berthier
authors.forename: Sylvie
authors.initials: S
authors.lastname: Thirot
authors.forename: Stéphane
authors.initials: S
authors.lastname: Léonce
authors.forename: Alain
authors.initials: A
authors.lastname: Pierré
authors.forename: Bruno
authors.initials: B
authors.lastname: Pfeiffer
authors.forename: Pierre
authors.initials: P
authors.lastname: Renard
authors.forename: Paola B
authors.initials: PB
authors.lastname: Arimondo
authors.forename: Claude
authors.initials: C
authors.lastname: Monneret
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007783:Lactones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors; D014183:Transplantation, Heterologous
chemical_list: C496959:11-oxo-13-deoxo-4'-demethylepipodophyllotoxin 4-(N-(2-(N',N'-dimethylaminoethyl)))carbamate; C496958:4'-demethylepipodophyllotoxin 4-(N-(2-(N',N'-dimethylaminoethyl)))carbamate; D000970:Antineoplastic Agents; D002219:Carbamates; D007783:Lactones; D059005:Topoisomerase II Inhibitors; D011034:Podophyllotoxin; C072088:4'-demethylepipodophyllotoxin