The present invention relates to novel antitumor compounds, their use in inhibiting tumor growth, and pharmaceutical compositions containing them. More particularly, the novel compounds are derivatives of 4'-demethylepipodophyllotoxin glucoside.
Etoposide and teniposide are two derivatives of 4'-demethylepipodophyllotoxin glucoside. The clinical efficacy of etoposide and teniposide in the treatment of a variety of cancers has been well documented and etoposide is currently approved in the United States for the treatment of small cell lung cancer and testicular cancer. The favorable therapeutic and pharmacological profiles of etoposide and teniposide have encouraged much activity in the search for other active analogs within the same class.
Most of the reported analogs and derivatives of etoposide and teniposide contain a D-glucose moiety, although a few derivatives having a different sugar are also known. For example, three D-galactopyranosides were reported in J. Med. Chem., 1971, 10:936-40 and several L-glucopyranosides have been described in Chem. Lett., 1987, 799-802. It is thus apparent that the effect of different sugar substituent on the activity of epipodophyllotoxin derivatives has not been fully explored.
Research effort by the present inventors in this area has led to the novel analogs disclosed and claimed herein. These new derivatives are distinguished over known 4'-demethylepipodophyllotoxin glycosides in having a mannose or an allose moiety. The novel compounds exhibit good activity against experimental leukemia in animal test models.