Hf. Hansen et al., NEW COMPOUNDS RELATED TO PODOPHYLLOTOXIN AND CONGENERS - SYNTHESIS, STRUCTURE ELUCIDATION AND BIOLOGICAL TESTING, Acta chemica Scandinavica, 47(12), 1993, pp. 1190-1200
4-Azido, 4-amino, 4-amido and 4-alkoxy compounds related to the lignan
s podophyllotoxin and 4'-demethylepipodophyllotoxin have been synthesi
zed, and their structures elucidated. The Ritter reaction was shown to
be useful in the preparation of the 4-amido compounds with the requir
ed stereochemistry. A preparative method for 4-chloro-4-deoxypicrophyl
lotoxin, for which all earlier synthetic attempts resulted in the two
dehydrated compounds, alpha- and beta-apopicropodophyllotoxin, was dev
eloped. Supplementary preliminary studies of the biological activities
of some of the compounds were performed. All compounds had pronounced
inhibitory effect on the in vitro growth of human cervical cancer cel
ls and TC-mouse cells with 4-amino-4-deoxypodophyllotoxin and 4-azido-
4-deoxypodophyllotoxin showing the highest activity. Alkaline elution
studies indicate that the toxicity of the 4'-demethoxy derivatives is
due to protein-mediated DNA nicking. None of the compounds were found
to have antiviral effect against herpes simplex type 2 (HSV-2), human
immunodeficiency (HIV), and cytomegalovirus (CMV) in doses not toxic t
o the cells.