Azaindenoisoquinolines and dibenzonaphthyridinediones as Topoisomerase type I inhibitors: Design, synthesis, and biological evaluation
Topoisomerase type I (Top1) is a member of a topoisomerase family, a group of ubiquitous cellular enzymes that solve DNA topological problems. Top1 plays its vital role in cell survival and replication by unwinding both negatively and positively supercoiled DNA during a range of cellular events. Top1 is inhibited by indenoisoquinolines, a growing class of potent antiproliferative compounds. Analysis of the structure of the drug-Top1-DNA ternary complex revealed that the polyaromatic core of indenoisoquinolines forms π-π stacking interactions with the flanking DNA base pairs. We proposed that an increase in the strength of π-π stacking interactions through facilitation of charge-transfer interactions could be achieved by increasing the electron affinity of the indenoisoquinoline system. This hypothesis is supported by high level ab initio calculations. Synthetic pathways have been developed to prepare target molecules that contain nitrogen in positions 7, 8, 9 and 10 of indenoisoquinoline. The present study shows that introduction of nitrogen in position 7 of indenoisoquinoline results in the highest Top1 inhibitory activity and cytotoxicity. 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 drug's Top1 inhibitory activity. The study of 7-azaindenoisoquinolines has shown that introduction of nitrogen in the aromatic system of indenoisoquinolines improved water solubility without compromising Top1 inhibitory activity of the drug. Another project described in this dissertation is associated with the exploration of dibenzonaphthyridines as indenoisoquinoline analogues. These compounds were synthesized via novel and efficient routes and evaluated in Top1-mediated DNA cleavage reactions. Despite the difference in orientation of only one amide bond of the newly formed six-membered lactam the dibenzo[ c,h][1,5]naphthyridinediones are capable of retaining the Top1 inhibitory activity of similarly substituted indenoisoquinoline. On the other hand, among the dibenzo[c,h][1,6]naphthyridinediones such activity is nearly abolished.
Cushman, Purdue University.
Chemistry|Organic chemistry|Pharmacy sciences
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