P. Krishnan et Kf. Bastow, Novel mechanisms of DNA topoisomerase II inhibition by pyranonaphthoquinone derivatives - Eleutherin, alpha lapachone, and beta lapachone, BIOCH PHARM, 60(9), 2000, pp. 1367-1379
Pyranonaphthoquinones have diverse biological activities against Gram posit
ive bacteria, fungi and mycoplasms, and, recently, there has also been an i
ncreasing interest in their anti-cancer activity. This study includes three
derivatives: eleutherin (compound 1), beta lapachone (compound 2), and its
structural isomer, alpha lapachone (compound 3). The mechanism of topoisom
erase II inhibition by the three derivatives was examined systematically wi
th respect to the steps of the catalytic cycle of the enzyme. Etoposide, th
e prototypical enzyme poison, was used as a control and in combination with
compounds 1-3 to localize their mechanism of action. The study revealed th
at eleutherin (1) and beta lapachone (2) inhibited topoisomerase II by indu
cing 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. alpha Lapacho
ne (3), on the other hand, inhibited initial non-covalent binding of topois
omerase II to DNA and, in addition, induced religation of DNA breaks (even
in pre-established ternary complexes) before dissociating the enzyme from D
NA. Compound 3 was an "irreversible" inhibitor of topoisomerase II. The div
erse and unique mechanisms of topoisomerase II inhibition by pyranonaphthoq
uinone derivatives reveal novel ways to target the enzyme with potential fo
r anti cancer drug design. (C) 2000 Elsevier Science Inc.