SYNTHESIS AND ANTITUMOR-ACTIVITY OF NEW GLYCOSIDES OF EPIPODOPHYLLOTOXIN, ANALOGS 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'-demethylepipodophyllotaxin have been synthesi zed by means of an improved trimethylsilyl-iodide procedure for the po dophyllotoxin-4'-demethylepipodophyllotoxin conversion, an efficient a nd high yielding synthesis of silyl glycoside donors of 3-azido-2, 3-d ideoxy-beta-D-ribo- and beta-D-arabino-hexopyranoside's and stereosele ctive glycosylations. In vitro evaluation of cytotoxic effects against murine L1210 leukemia critically demonstrates the essential role play ed by a 4,6-acetal for biological activity. Among the most cytotoxic c ompounds, 3-amino-2,3-dideoxy- and 3-N,N-(dimethylamino)-2,3-dideoxy e toposide analogues, 17 and 27-29 are at least as potent as etoposide o n the in vivo P388 (iv/ip) murine leukemia models. However, surprising ly enough, none of these compounds inhibits the human DNA topoisomeras es I or II or binds to tubulin to prevent its polymerization and micro tubule assembly. Therefore, their mechanism of action remains to be cl eared up.