Synthesis and biological activity of sulfonamide derivatives of epipodophyllotoxin.
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.
Guianvarc'h
Dominique
D
Laboratoire de Biophysique, CNRS UMR 5153-MNHN USM 0503, INSERM UR 565, 43 rue Cuvier, 75231 Paris Cedex 05, France.
Duca
Maria
M
Boukarim
Chawki
C
Kraus-Berthier
Laurence
L
Léonce
Stéphane
S
Pierré
Alain
A
Pfeiffer
Bruno
B
Renard
Pierre
P
Arimondo
Paola B
PB
Monneret
Claude
C
Dauzonne
Daniel
D
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
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