Pyranonaphthoquinone derivatives of eleutherin, ventiloquinone L, thysanone and nanaomycin A possessing a diverse topoisomerase II inhibition and cytotoxicity spectrum.
A series of pyranonaphthoquinone derivatives related to the known topoisomerase II inhibitor eleutherin 1 have been shown to act as specific topoisomerase II catalytic inhibitors, with several analogues displaying greater potency than the natural product itself. Amongst the compounds tested were the natural products ventiloquinone L 4 and thysanone 8 with a diverse range of topoisomerase II inhibition properties being observed. Interestingly, the natural products are generally weaker inhibitors than their synthetic counterparts, emphasising that subtle changes in the basic molecular structure of a natural product led to significant changes in the inhibition profile. It has also been demonstrated for the first time that analogues related to nanaomycin A and cardinalin-type dimeric pyranonaphthoquinones exhibit potent topoisomerase II inhibitory properties. With respect to structural features, it appears that the nature of the substituents at C1 on the pyran ring and oxygenated substituents on the aryl ring are critical for anti-topoII activity. Importantly, the topoisomerase II inhibition strength does not correlate well with the measured cytotoxicity against yeast, indicating that other molecular features in the pyranonaphthoquinone family must be considered for the design and use of this structural class as highly specific topoisomerase II inhibitors.
Department of Chemistry, University of Auckland, 23 Symonds Street, Auckland, New Zealand.
Jonathan
J
Sperry
Isabel
I
Lorenzo-Castrillejo
Margaret A
MA
Brimble
Felix
F
Machín
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D009285:Naphthoquinones / Q000737:chemistry* / Q000494:pharmacology; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000254:growth & development; D059005:Topoisomerase II Inhibitors
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009285:Naphthoquinones; D059005:Topoisomerase II Inhibitors; C415044:eleutherin