Inhibitors
of LeishmaniaN-myristoyltransferase
(NMT), a potential target for the
treatment of leishmaniasis, obtained from a high-throughput screen,
were resynthesized to validate activity. Crystal structures bound
to Leishmania major NMT were obtained,
and the active diastereoisomer of one of the inhibitors was identified.
On the basis of structural insights, enzyme inhibition was increased
40-fold through hybridization of two distinct binding modes, resulting
in novel, highly potent Leishmania donovani NMT inhibitors with good selectivity over the human enzyme.
The monocyclic 1,4-benzoquinone, HU-331, the direct oxidation product of cannabidiol, inhibits the catalytic activity of topoisomerase II but without inducing DNA strand breaks or generating free radicals, and unlike many fused-ring quinones exhibits minimal cardiotoxicity. Thus, monocyclic quinones have potential as anti-cancer agents, and investigation of the structural origins of their biological activity is warranted. New syntheses of cannabidiol and (±)-HU-331 are here reported. Integrated synthetic protocols afforded a wide range of polysubstituted resorcinol derivatives; many of the corresponding novel 2-hydroxy-1,4-benzoquinone derivatives are potent inhibitors of the catalytic activity of topoisomerase II, some more so than HU-331, whose monoterpene unit replaced by a 3-cycloalkyl unit conferred increased anti-proliferative properties in cell lines with IC50 values extending below 1 mM, and greater stability in solution than HU-331. The principal pharmacophore of quinones related to HU-331 was identified. Selected monocyclic quinones show potential for the development of new anticancer agents. Financial support from the Engineering and Physical Sciences Research Council for a PhD studentship to T. D.W. is gratefully acknowledged.
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