Abstract A67: Syntheses and antitumor activities on NCI-60 human tumor cell line protocol of novel N-hydroxyethyl-4-aza-didehyropodophyllotoxin derivatives with halo substitutions on ring-E

Abstract

Abstract Podophyllotoxin is a natural product obtained from endangered Berberidaceae family species. Derivatives namely etoposide, etopophos and teniposide have been developed from podophyllotoxin and are currently used in clinic for the treatment of a variety of malignancies since five decades. Synthesis of podophyllotoxin is not feasible so far and due to this reason structural modification of podophyllotoxin could not be explored very well. 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. In past we have developed synthetic analogues of podophyllotoxin i.e. aza-podophyllotoxin derivatives an important scaffold to address this chemistry. We have developed some heterocyclic analogues of podophyllotoxin i.e. N-hydroxyethyl-4-aza-podophyllotoxin derivatives. Owing to their promising activity against 60 cell lines at NCI, we further developed a novel library of N-hydroxyethyl-4-aza-didehyropodophyllotoxin derivatives substituted at ring-E by halogens. 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. These new compounds shows comparatively good activity against ovarian and melanoma cancer lines. Citation Format: Ajay Kumar, Vineet Kumar, Antonio E. Alegria, Malhotra V. Sanjay. Syntheses and antitumor activities on NCI-60 human tumor cell line protocol of novel N-hydroxyethyl-4-aza-didehyropodophyllotoxin derivatives with halo substitutions on ring-E. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A67.