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.
Synthesis and Antitumor Activity of New Glycosides of Epipodophyllotoxin, Analogues of Etoposide, and NK 611.-The synthesis of a series of title compounds, e.g. (X)-(XII), includes improved trimethylsilyl iodide procedure for epimerization, an efficient preparation of silyl glycoside donors such as (VI) and (VII) in high yield, and stereoselective glycosylation to give the corresponding β-D-glycosyl derivatives [cf.(IX)]. In comparison with the reference compound etoposide, (X), (XI), and (XIIa) show equipotent activity during in vitro evaluation against murine L1210 leukemia. Derivative (XIIb) exhibits ten-fold activity against topoisomerase II enzyme, but during in vivo evaluation against P388 murine leukemia (XI) reveal potent and (X) even equipotent activity, whereas (XII) are completely inactive. -(DALEY,
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A One-Pot, Efficient Synthesis of the Potent Cytotoxic Podophyllotoxin Derivative NPF.-In continuation of a medical chemistry program concerning the podophyllotoxin area, an improved preparation for 4'-demethylepipodophyllotoxin (III) and a one-pot synthesis of NPF (V) are reported. Both procedures are based on the application of trimethylsilyl iodide which causes both C-4 epimerization and 4'-O-demethylation of (I).- (DALEY, L.; MERESSE, P.; BERTOUNESQUE, E.; MONNERET, C.; Tetrahedron Lett. 38 (1997) 15, 2673-2676 Inst. Curie, CNRS, F-75248 Paris, Fr.; EN)
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