- AZAINDENOISOQUINOLINE TOPOISOMERASE I INHIBITORS
-
The invention described herein pertains to substituted azaindenoisoquinoline compounds, in particular 7-, 8-, 9-, and 10-azaindenoisoquinoline compounds, which are inhibitors of topoisomerase I, processes and intermediates for their syntheses, pharmaceutical compositions of the compounds, and methods of using them in the treatment of cancer.
- -
-
Paragraph 0163
(2014/02/16)
-
- Azaindenoisoquinolines as topoisomerase i inhibitors and potential anticancer agents: A systematic study of structure-activity relationships
-
A comprehensive study of a series of azaindenoisoquinoline topoisomerase I (Top1) inhibitors is reported. The synthetic pathways have been developed to prepare 7-, 8-, 9-, and 10-azaindenoisoquinolines. The present study shows that 7-azaindenoisoquinolines possess the greatest Top1 inhibitory activity and cytotoxicity. Additionally, the introduction of a methoxy group into the D-ring of 7-azaindenoisoquinolines improved their biological activities, leading to new lead molecules for further development. A series of QM calculations were performed on the model "sandwich" complexes of azaindenoisoquinolines with flanking DNA base pairs from the Drug-Top1-DNA ternary complex. The results of these calculations demonstrate how changes in two forces contributing to the π-π stacking (dispersion and charge-transfer interactions) affect the binding of the drug to the Top1-DNA cleavage complex and thus modulate the drug's Top1 inhibitory activity.
- Kiselev, Evgeny,Agama, Keli,Pommier, Yves,Cushman, Mark
-
experimental part
p. 1682 - 1697
(2012/05/04)
-