Nortriketones: antimicrobial trimethylated acylphloroglucinols from manuka (Leptospermum scoparium)

Authors: KILLEEN, DANIEL - University Of Otago; LARSEN, LESLEY - University Of Otago; Dayan, Franck; GORDON, KEITH - University Of Otago; PERRY, NIGEL - University Of Otago; VAN KLINK, JOHN - University Of Otago

Submitted to: Journal of Natural Products
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/28/2015
Publication Date: 1/5/2016
Citation: Killeen, D.P., Larsen, L., Dayan, F.E., Gordon, K.C., Perry, N.B., Van Klink, J.W. 2016. Nortriketones: antimicrobial trimethylated acylphloroglucinols from manuka (Leptospermum scoparium). Journal of Natural Products. doi: 10.1021/acs.jnatprod.5b00968.

Interpretive Summary: Triketones are important bioactive plant secondary metabolites from which the newest class of commercial herbicides have been derived. This collaboration with scientists from the University of Otago (New Zealand) had led to the identification of analogues belonging to the nortriketone group. Nortriketones are structurally similar to the bioactive ß-triketones from manuka, but have one less ring methyl group. These molecules had some antimicrobial activity against Gram-positive bacteria. In spite of their structural similarity with other triketone natural products, the nortriketones were inactive against the herbicide target enzyme p-hydroxyphenylpyruvate dioxygenase, highlighting the importance of the missing methyl group in providing herbicidal activity.

Technical Abstract: Four trimethylated acylphloroglucinols (5-8) have been isolated from manuka (Leptospermum scoparium) foliage. Apart from myrigalone A (8), which has previously been isolated from European bog myrtle (Myrica gale), these compounds have not been characterized before. The nortriketones are structurally similar to the bioactive tetramethylated ß-triketones from ma¯nuka, but have one less ring methyl group. Two oxidized trimethylated compounds, 9 and 10, were also isolated, but these are likely isolation artifacts. When evaluated for antibacterial activity against Gram-positive bacteria, myrigalone A (8) was slightly less potent (MIC 64 µg/mL) than the corresponding tetramethylated compound, grandiflorone (4) (MIC 16-32 µg/mL). Unlike their tetramethylated analogues, the nortriketones were inactive against the herbicide target enzyme p-hydroxyphenylpyruvate dioxygenase. The Raman spectra of leaf oil glands in different manuka varieties can be used to distinguish plants that contain nortriketones from those that accumulate triketones.