Synthesis and biological study of a new series of 4'-demethylepipodophyllotoxin derivatives.
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.
Duca
Maria
M
Laboratoire de Biophysique, UMR 5153 CNRS, Muséum National d'Histoire Naturelle, USM 0503, INSERM UR565, 43 rue Cuvier, 75231 Paris Cedex 05, France.
Guianvarc'h
Dominique
D
Meresse
Philippe
P
Bertounesque
Emmanuel
E
Dauzonne
Daniel
D
Kraus-Berthier
Laurence
L
Thirot
Sylvie
S
Léonce
Stéphane
S
Pierré
Alain
A
Pfeiffer
Bruno
B
Renard
Pierre
P
Arimondo
Paola B
PB
Monneret
Claude
C
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
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