Indenoisoquinolines

COMPARE analysis can also be used to identify de novo new classes of compounds directed against known targets. For many yearS/ the camptothecin class of compounds was the only explored class of inhibitors of topoisomerase 1, an enzyme responsible for DNA single-strand breaks and religation. COMPARE analysis/ however/ showed a high correlation between camptothecins and a previously unexplored class of compounds known as indenoisoquinolin.es. Confirmatory testing revealed that the hide no isoquinolines did in fact inhibit topoisomerase I (22). 

In 1978, the synthesis of the indenoisoquinoline NSC 314622 (Figure 6.16) was reported as the result of an unexpected transformation during a synthesis of nitidine chloride. Given its weak antitumor activity, it was not investigated further. 

FIGURE 6.16 The indenoisoquinoline NSC 314622 resurfaced 20 years after its first testing as a top 1 inhibitor. ... 

Particularly, isoquinolonic acids are useful precursors for the total synthesis of naturally occurring phenanthridine alkaloids such as corynoUne, oxocorynoline, and epicorynoline as well as indenoisoquinolines possessing sigiuflcant antitumor activity. 

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