Abstract 2476: Synthesis of novel aza-podophyllotoxins derivatives substituted at ring-A and their activities on NCI-60 human tumor cell line.

Abstract

Abstract Podophyllotoxin is a major cytotoxic constituent of several members of Podophyllum peltatum species. The semisynthetic derivatives namely etoposide, etopophos and teniposide have been developed from podophyllotoxin and are currently used in clinic for the treatment of several human tumors 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 various heterocyclic analogues of podophyllotoxin derivatives. Owing to their promising activity against 60 cell lines at NCI, we are actively engaged in developing new library of N-hydroxyethyl-4-aza-didehyropodophyllotoxin derivatives. A new library of aza-podophyllotoxin derivatives substituted at ring-A has been developed and 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 found to have comparatively good activity against colon and cancer lines. Citation Format: Ajay Kumar, Vineet Kumar, Sanjay V. Malhotra, Alegria E. Antonio. Synthesis of novel aza-podophyllotoxins derivatives substituted at ring-A and their activities on NCI-60 human tumor cell line. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2476. doi:10.1158/1538-7445.AM2013-2476 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.