New compounds related to podophyllotoxin and congeners: synthesis, structure elucidation and biological testing.
4-Azido, 4-amino, 4-amido and 4-alkoxy compounds related to the lignans podophyllotoxin and 4'-demethylepipodophyllotoxin have been synthesized, and their structures elucidated. The Ritter reaction was shown to be useful in the preparation of the 4-amido compounds with the required stereochemistry. A preparative method for 4-chloro-4-deoxypicrophyllotoxin, for which all earlier synthetic attempts resulted in the two dehydrated compounds, alpha- and beta-apopicropodophyllotoxin, was developed. 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 cells 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 to the cells.
Hansen
H F
HF
Research Center for Medical Biotechnology, H. C. Orsted Institute, University of Copenhagen, Denmark.
Jensen
R B
RB
Willumsen
A M
AM
Nørskov-Lauritsen
N
N
Ebbesen
P
P
Nielsen
P E
PE
Buchardt
O
O
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003114:Colony-Forming Units Assay; D003587:Cytomegalovirus / Q000187:drug effects; D005260:Female; D006678:HIV / Q000187:drug effects; D018258:Herpesvirus 2, Human / Q000187:drug effects; D006801:Humans; D051379:Mice; D011034:Podophyllotoxin / Q000031:analogs & derivatives / Q000032:analysis* / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D011034:Podophyllotoxin