Podophyllotoxin is a natural product and precursor for several antitumor drugs. Recently, we reported the synthesis of a library of aza-podophyllotoxin derivatives, close structural analogues of podophyllotoxin that displays promising competitive biological activity (Kumar, et.al.). Several compounds from this library of aza-podophyllotoxin derivatives were submitted to NCI for antitumor activity on 60 types of human cancer lines. The majority of the aza-podophyllotoxin derivatives submitted for testing were found very active at single dose (stage I) and five (5) concentrations dose studies (stage II) level, most of them entered into stage III (repetition of stage II) followed by stage IV (Hollow fiber studies on human carcinoma in mice model) protocols of NCI to evaluate anticancer activity of these new compounds. Based on these exciting anti-tumor activity results of aza-podophyllotoxin derivatives on the 60 cell line panel from NCI, it is worthwhile to investigate this new scaffold extensively for further studies.Selected aza-podophyllotoxin derivatives from this compound library were further investigated to understand their mode of action in order to establish a structure activity relationship. Two compounds (4-(2-Hydroxyethyl)-10-(3,4,5-trimethoxyphenyl)-3,4,6,7,8,10-hexahydro-1H-cyclopenta[g]furo[3,4-b]quinolin-1-one) (8a  ) and 6-(2-Hydroxyethyl)-10-(3,4,5-trimethoxyphenyl)-2,3,7,10-tetrahydro-[1,4]dioxino[2,3-g]furo[3,4-b]quinolin-9(6H)-one (9a)  were found to be very active against COLO 205 type of human colon cancer cells at NCI. The aza-podophyllotoxin derivatives 8a  and 9a  have been studied extensively in order to determine the mechanism by which compounds induces cell death i.e. apoptosis or necrosis; IC50 determination of 8a  and 9a against COLO 205 cells, activation of caspase 3 and 7 assay, and mitochondria permeability assay.Ref: Kumar A, Kumar V, Alegria A, Malhotra S. (2011). N-hydroxyethyl-4-aza- didehydropodophyllotoxin derivatives as potential antitumor agents. Eur J Pharm Sci. Sep 18;44(1-2):21-6. doi:10.1016/j.ejps.2011.04.013. Epub 2011 May 13. PubMed PMID: 21601635; PubMedCentral PMCID: PMC3278235.

Biological activity of N-Hydroxyethyl-4-aza-didehyropodophyllotoxin derivatives upon colorectal adenocarcinoma cells

247th National Meeting (2014)

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