title: Synthesis and biological activity of sulfonamide derivatives of epipodophyllotoxin.
abstract: A series of novel 4beta-substituted sulfonamide derivatives of 4'-O-demethyl-4-desoxypodophyllotoxin has been synthesized. Their effects on human DNA topoisomerase II and, in some cases, on tubulin polymerization were evaluated. Compounds 8a, 8c, 8f, 8g, 8n, 8q, 8r, and 8s and the synthetic precursor 4 are potent topoisomerase II poisons that induce double-stranded breaks in DNA, with either improved or similar activity compared to etoposide. Only the amino precursor, compound 5, was slightly active in tubulin polymerization inhibition assays. We observed that the derivatives bearing an aromatic ring on the 4beta-sulfonamide substituent were either less cytotoxic or equivalent to the parent drug, while the sulfonamides containing an aliphatic side chain and the amino-sulfonamide derivatives, except 8d and 8g, exhibited increased cytoxicity compared to etoposide. In vivo, against the P388 leukemia and the A-549 orthotopic model of lung carcinoma, the most promising compounds were the morpholino- and the piperazino-containing sulfonamides derivatives 8r and 8s.
authors.affiliation: Laboratoire de Biophysique, CNRS UMR 5153-MNHN USM 0503, INSERM UR 565, 43 rue Cuvier, 75231 Paris Cedex 05, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Guianvarc'h
authors.forename: Maria
authors.initials: M
authors.lastname: Duca
authors.forename: Chawki
authors.initials: C
authors.lastname: Boukarim
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: 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
authors.forename: Daniel
authors.initials: D
authors.lastname: Dauzonne
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004250:DNA Topoisomerases, Type II / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors; D014183:Transplantation, Heterologous
chemical_list: C485236:4-(4-methylpiperazinyl)sulfonamido-4'-O-demethyl-4-desoxypodophyllotoxin; C485235:4-morpholinosulfonamido-4'-O-demethyl-4-desoxypodophyllotoxin; D000970:Antineoplastic Agents; D013449:Sulfonamides; D059005:Topoisomerase II Inhibitors; D004250:DNA Topoisomerases, Type II; D011034:Podophyllotoxin