Synthesis and antitumor activity of new glycosides of epipodophyllotoxin, analogues of etoposide, and NK 611.
A series of 3-amino- and 3-alkylamino-2-deoxy-beta-D-ribo- and beta-D-arabino-glycosides of 4'-demethylepipodophyllotoxin have been synthesized by means of an improved trimethylsilyliodide procedure for the podophyllotoxin-4'-demethylepipodophyllotoxin conversion, an efficient and high yielding synthesis of silyl glycoside donors of 3-azido-2,3-dideoxy-beta-D-ribo- and beta-D-arabino-hexopyranosides and stereoselective glycosylations. In vitro evaluation of cytotoxic effects against murine L1210 leukemia critically demonstrates the essential role played by a 4,6-acetal for biological activity. Among the most cytotoxic compounds, 3-amino-2,3-dideoxy- and 3-N, N-(dimethylamino)-2,3-dideoxy etoposide analogues, 17 and 27-29 are at least as potent as etoposide on the in vivo P388 (iv/ip) murine leukemia models. However, surprisingly enough, none of these compounds inhibits the human DNA topoisomerases I or II or binds to tubulin to prevent its polymerization and microtubule assembly. Therefore, their mechanism of action remains to be cleared up.
Daley
L
L
UMR 176 CNRS/Institut Curie, Section Recherche, 26 rue d'Ulm, F-75248 Paris Cedex 05, France.
Guminski
Y
Y
Demerseman
P
P
Kruczynski
A
A
Etiévant
C
C
Imbert
T
T
Hill
B T
BT
Monneret
C
C
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001704:Biopolymers; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006027:Glycosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006031:Glycosylation; D006801:Humans; D020128:Inhibitory Concentration 50; D007939:Leukemia L1210 / Q000473:pathology; D007941:Leukemia P388 / Q000473:pathology; D051379:Mice; D008811:Mice, Inbred DBA; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D014183:Transplantation, Heterologous; D014404:Tubulin / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001704:Biopolymers; D006027:Glycosides; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D014404:Tubulin; C080080:NK 611; D011034:Podophyllotoxin