Synthesis and structure-activity relationships among glycosidic derivatives of 4'-demethylepipodophyllotoxin and epipodophyllotoxin, showing VM26- and VP16-213-like activities.
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abstract
We have synthesized acetal and ketal derivatives of 4'-demethylepipodophyllotoxin-beta-D-glucoside (DMEPG) and epipodophyllotoxin-beta-D-glucoside (EPG) with a number of different aldehydes (viz. acetaldehyde, propionaldehyde, 2-thiophenecarboxaldehyde, 3-thiophenecarboxaldehyde, 2-furancarboxaldehyde, benzaldehyde, phenylacetaldehyde, hydrocinnamaldehyde) and acetone. The cross resistance of these compounds towards a set of Chinese hamster ovary cell mutants resistant to either podophyllotoxin (PodR mutants) or VM26 (VpmR mutants) which exhibit mutually exclusive cross-resistance patterns toward compounds that show either podophyllotoxin- or VM26-like activities have been examined. Results of our studies show that, with the exception of 2-furan derivatives, all the remaining acetals and ketals of DMEPG and EPG showed similar cross-resistance patterns towards the VpmR and the PodR mutants, as seen with VM26 and VP16-213. These results provide strong suggestive evidence that all of these derivatives (except 2-furan) possess biological activities similar to VM26 and VP16-213, and that their cellular toxicities were due to this type of activity. The VM26-like behavior of different EPG derivatives, which lack the free 4'-OH group, provide evidence that a free 4'-OH group is not essential for VM26-like activity. However, in comparison to the EPG derivatives, the corresponding DMEPG compounds showed 10- to 30-fold higher activities, indicating an enhancing effect of the free 4'-OH group on this kind of activity. Some of the newly synthesized DMEPG and EPG derivatives show higher activity in comparison to VM26 and VP16-213, and structure-activity relationship among this group of compounds is discussed.
