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Substituted Purine Analogues Define a Novel Structural Class of Catalytic Topoisomerase II Inhibitors

¹ Department of Pathology, Diagnostic Centre, National University Hospital; ² TopoTarget A/S; and ³ Laboratory of Experimental Medical Oncology, Finsen Centre, National University Hospital, Copenhagen, Denmark; ⁴ Science Applications International Corporation-Frederick and ⁵ Developmental Therapeutics Program, National Cancer Institute at Frederick, Frederick, Maryland

Requests for reprints: Lars H. Jensen, Department of Pathology, Diagnostic Centre, Rigshospitalet 5444, Frederik V's Vej 11, DK-2100 Copenhagen, Denmark. Phone: 45-35455488; Fax: 45-35455414; E-mail: lhjensen{at}rh.dk.

By screening 1,990 compounds from the National Cancer Institute diversity set library against human topoisomerase II, we identified a novel catalytic topoisomerase II inhibitor NSC35866 a S⁶-substituted analogue of thioguanine. In addition to inhibiting the DNA strand passage reaction of human topoisomerase II, NSC35866also inhibited its ATPase reaction. NSC35866primarily inhibited DNA-stimulated ATPase activity, whereas DNA-independent ATPase activity was less sensitive to inhibition. We compared the mode of topoisomerase II ATPase inhibition induced by NSC35866with that of 12 other substituted purine analogues of different chemical classes. The ability of thiopurines with free SH functionalities to inhibit topoisomerase II ATPase activity was completely abolished by DTT, suggesting that these thiopurines inhibit topoisomerase II ATPase activity by covalently modifying free cysteine residues. In contrast, NSC35866as well as two O⁶-substituted guanine analogues, O⁶-benzylguanine and NU2058, could inhibit topoisomerase II ATPase activity in the presence of DTT, indicating that they have a different mechanism of inhibition. NSC35866did not increase the level of topoisomerase II covalent cleavable complexes with DNA, indicating that it is a catalytic inhibitor and not a poison. NSC35866was also capable of inducing a salt-stable complex of topoisomerase II on closed circular DNA. In accordance with these biochemical data, NSC35866could antagonize etoposide-induced cytotoxicity and DNA breaks in human and murine cancer cells, confirming that NSC35866also functions as a catalytic topoisomerase II inhibitor in cells.

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