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Novel mechanisms of DNA topoisomerase II inhibition by pyranonaphthoquinone derivatives—eleutherin, α lapachone, and β lapachone∗

2000; Elsevier BV; Volume: 60; Issue: 9 Linguagem: Inglês

10.1016/s0006-2952(00)00437-8

1873-2968

Preethi Krishnan, Kenneth F. Bastow,

Synthesis and bioactivity of alkaloids

Pyranonaphthoquinones have diverse biological activities against Gram-positive bacteria, fungi, and mycoplasms, and, recently, there has also been an increasing interest in their anti-cancer activity. This study includes three derivatives: eleutherin (compound 1), β lapachone (compound 2), and its structural isomer, α lapachone (compound 3). The mechanism of topoisomerase II inhibition by the three derivatives was examined systematically with respect to the steps of the catalytic cycle of the enzyme. Etoposide, the prototypical enzyme poison, was used as a control and in combination with compounds 1–3 to localize their mechanism of action. The study revealed that eleutherin (1) and β lapachone (2) inhibited topoisomerase II by inducing religation and dissociation of the enzyme from DNA in the presence of ATP. Whereas compound 2 was an "irreversible" inhibitor of topoisomerase II, compound 1 merely slowed the catalytic cycle of the enzyme. α Lapachone (3), on the other hand, inhibited initial non-covalent binding of topoisomerase II to DNA and, in addition, induced religation of DNA breaks (even in pre-established ternary complexes) before dissociating the enzyme from DNA. Compound 3 was an "irreversible" inhibitor of topoisomerase II. The diverse and unique mechanisms of topoisomerase II inhibition by pyranonaphthoquinone derivatives reveal novel ways to target the enzyme with potential for anti-cancer drug design.