Exploring the molecular mechanism of karrikins and strigolactones q Adrian Scaffidi a,⇑ , Mark T. Waters b , Charles S. Bond a , Kingsley W. Dixon c,d , Steven M. Smith a , Emilio L. Ghisalberti a , Gavin R. Flematti a a School of Chemistry and Biochemistry, The University of Western Australia, 35 Stirling Highway, Crawley, WA 6009, Australia b ARC Centre of Excellence in Plant Energy Biology, The University of Western Australia, 35 Stirling Highway, Crawley, WA 6009, Australia c School of Plant Biology, The University of Western Australia, 35 Stirling Highway, Crawley, WA 6009, Australia d King Park Botanic Garden, Fraser Avenue, West Perth, WA 6005, Australia article info Article history: Received 16 February 2012 Revised 26 March 2012 Accepted 3 April 2012 Available online 10 April 2012 Keywords: Karrikinolide Strigolactones Plant hormones Smoke Molecular mechanism abstract Karrikins and strigolactones are novel plant growth regulators that contain similar molecular features, but very little is known about how they elicit responses in plants. A tentative molecular mechanism has previously been proposed involving a Michael-type addition for both compounds. Through struc- ture–activity studies with karrikins, we now propose an alternative mechanism for karrikin and strigo- lactone mode of action that involves hydrolysis of the butenolide ring. Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved. Karrikinolide (KAR 1 ) 1 is a potent seed germination stimulant derived from burning plant material, and defines a family of related small molecules known as karrikins (Fig. 1). 1,2 These com- pounds are able to promote seed germination in numerous plant species native to both fire and non-fire prone regions around the world. 3 Recently, significant attention has been directed towards this intriguing class of small molecules due to their molecular sim- ilarity to the strigolactone group of germination and shoot-branch- ing phytohormones (Fig. 1), 4,5 and the fact that both classes of compounds act through a common cell signalling pathway. 5,6 Although the molecular architecture of strigolactones is much more complex compared to the simpler planar karrikins, both com- pounds contain substituted methyl butenolide rings and it has been shown that this functionality is essential for strigolactone receptor recognition. 7,8 Both also contain enol ethers, yet despite these structural and functional similarities, very little is known about how these molecules interact with various biomolecules to elicit a response in plants. A proposed mechanism for strigolactone activity has previously been reported based on the chemistry of the synthetic analogue GR24 2 (Fig. 2a). 7,9 It was demonstrated that GR24 2 undergoes a nucleophilic addition with thiophenol in a Michael fashion to re- lease the D-ring and yield a covalent attachment of the nucleophile to the ABC portion of the molecule. 7 Furthermore, the saturation of the enol ether double bond renders the molecule inactive provid- ing further evidence that a Michael type addition is required for bioactivity. Although various labelled derivatives have been pre- pared to explore this mechanism, no endogenous nucleophile or receptor molecule has been isolated to date. 10 Most recently, Zwa- nenburg et al. and Fukui et al. report that the enol ether moiety and ABC rings in strigolactones are not essential for activity, a conclu- sion based on active analogues lacking both these characteris- tics. 11,12 These analogues replace the enol ether and ABC rings with a leaving group suggesting that a general labile bond at C5 of the D-ring is sufficient to furnish activity. Furthermore, Zwanen- burg et al. provide an alternative Michael acceptor mechanism O O O O O O O O 1 2 A B C D Figure 1. Chemical structures of karrikinolide (KAR 1 ) 1 and the synthetic strigo- lactone (GR24) 2. 0960-894X/$ - see front matter Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bmcl.2012.04.016 q The authors would like to thank the Australian Research Council (LP0882775, DP109671) for financial support, Lucy Commander for collecting Solanum orbicul- atum seed and the Centre for Microscopy, Characterisation and Analysis at UWA. ⇑ Corresponding author. E-mail address: adrian.scaffidi@uwa.edu.au (A. Scaffidi). Bioorganic & Medicinal Chemistry Letters 22 (2012) 3743–3746 Contents lists available at SciVerse ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl