Podophyllotoxin (PPT) has been known to possess anti-tumor activity. Derivatives of podophyllotoxin, namely etoposide, etopophos and teniposide have been developed for the treatment of a variety of malignancies. However, due to the drug resistance developed by cancer cells as well as side effects associated with the use of these agents in clinic, the search for new effective anticancer analogues of podophyllotoxin remains an intense area of research. The structural complexity of podophyllotoxin, arising from the presence of four stereogenic carbons in ring C has restricted most of the structural activity relationship (SAR) studied by derivatization of the parent natural product rather than by de novo multi-step chemical synthesis. Our endeavor in this field lead to synthesis of a library of N-hydroxy aza-podophyllotoxin derivatives, which were screened for their antitumor activity using the National Cancer Institute's 60 human tumor cell line screen. This was followed by a screen of in vivo activity using a panel of tumor hollow-grafts implanted in mice consisting of breast (MDA-MB-231), non-small lung (NCI-H23 and NCI-H522), colon (SW-620 and COLO 205), melanoma (UACC-62, MDA-MB-435 and LOXIMVI), ovarian (OVCAR-5 and OVCAR-3) and CNS (U251 and SF-295) cell lines. This is the first report of aza-podophyllotoxins anticancer activity evaluation on such a broad panel of cancer cell lines. The toxicity of all the active compounds was low, while their antiproliferative activity was high, providing a wide therapeutic window for their potential application as anticancer drugs.Acknowledgement: This Project has been funded with federal funds from the National Cancer Institute, NIH under contract No. HSN261200800001E

Syntheses and antitumor activity of <i>N</i>-hydroxyethyl-4-aza-didehyropodophyllotoxin derivatives

242nd National Meeting (2011)

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Syntheses and antitumor activity of N-hydroxyethyl-4-aza-didehyropodophyllotoxin derivatives