Azaindenoisoquinolines as Topoisomerase I Inhibitors and Potential Anticancer Agents: A Systematic Study of Structure–Activity Relationships

Abstract

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.

One‐Step Synthetic Access to Isosteric and Potent Anticancer Nitrogen Heterocycles with the Benzo[c]phenanthridine Scaffold

“…[14] Thiss trategy has been successful for the development of new topoisomerase I( To pI)i nhibitors as potential an-ticancera gentsb yo ptimization of the binding to the TopI-DNA covalent complex, as well as form arketed drugs, for example,identification of Vardenafil by scaffold hopping from Sildenafil. [15][16][17] One of the most-popular isostericp airs, especially in compounds that possess ah eterocyclic scaffold, are CH and N. [15,16,18] This replacement is often linked to improved solubility and reduced lipophilicity,w hich we have already shown for the pyrido [3,4-c] [1,9]phenanthrolines 8. [12,19] Additionally,p yridine andp yrimidine rings are common motifs in the structures of approved drugs.…”

“…One possibility to realize the change required in the scaffold is isosteric replacement of certain atoms in the structural core . This strategy has been successful for the development of new topoisomerase I (Top I) inhibitors as potential anticancer agents by optimization of the binding to the Top I–DNA covalent complex, as well as for marketed drugs, for example, identification of Vardenafil by scaffold hopping from Sildenafil . One of the most‐popular isosteric pairs, especially in compounds that possess a heterocyclic scaffold, are CH and N .…”

Topoisomerase 1B poisons: Over a half‐century of drug leads, clinical candidates, and serendipitous discoveries

“…The azaindenoisoquinolines were therefore synthesized. 7‐Azaindenoisoquinolines (represented by 54 ) are the most potent of the aza‐analogs of the indenone ring, and original derivatives did not decrease Top1 inhibition or cytotoxicity while improving water solubility . Morpholine and imidazole derivatives (as in the clinical candidates) were excellent Top1 poisons that induced γ‐H2AX formation in cells and were not transported by the ABC1 transporter .…”

Design, Synthesis, and Biological Evaluation of Potential Prodrugs Related to the Experimental Anticancer Agent Indotecan (LMP400)

“…30, 42, 47, 48, 56, 57, 59, 60 However, previous investigations of indenoisoquinoline prodrugs are limited to a study of dihydroindenoisoquinoline prodrugs of indenoisoquinolines, 61 and no work on ester prodrugs has previously been reported.…”