Synthesis and cytostatic activity of geiparvarin analogues

In an attempt to determine some of the structural features of geiparvarin (1) that account for its cytostatic activity in vitro, a series of geiparvarin analogues (4a-g) modified in the 3(2H)-furanone moiety have been designed and synthesized. The preparation of 4a-g was achieved through a new approach to the 3(2H)-furanone ring based on the elaboration of isoxazole derivatives. Among these synthetic analogues, 4b, the 5-methyl-5-ethyl derivative, proved as active as 1 in inhibiting the proliferation of murine and human tumor cell lines in vitro. As a rule, substitutions at the C5 atom of the 3(2H)-furanone moiety of 1 slightly decreased the cytostatic activity of geiparvarin. Several geiparvarin analogues described in this study (i.e. the 5-methyl-5-ethyl derivative 4b, 3(2H)-furanimine 4c, 5-methyl derivative 4f, and 5-ethyl derivative 4g) showed such activity in vitro and deserve further investigation for their antitumor potentials in vivo.