DOI: 10.1002/chem.200601236 Kibdelones: Novel Anticancer Polyketides from a Rare Australian Actinomycete Ranjala Ratnayake, [a] Ernest Lacey, [b] Shaun Tennant, [b] Jennifer H. Gill, [b] and Robert J. Capon* [a] Introduction During our investigations into bioactive metabolites from Australian microorganisms we examined an isolate of a rare actinomycete genus, Kibdelosporangium sp. (MST-108465). Bioassay profiling of a methanolic extract derived from a culture of MST-108465 uncovered an unusual combination of potent antibacterial, nematocidal, and cytotoxic activities. HPLC-DAD-ELSD (DAD = diode array detector; ELSD = evaporative light scattering detector) analysis of the secon- dary metabolites present drew attention to a family of non- polar metabolites displaying distinctive UV-visible spectra. An electronic search of an in-house database (MST, COMET) [1] comprising HPLC-DAD-ELSD profiles from over 1500 natural products, and extracts from 6000 annotat- ed microorganisms (a comprehensive library of microbes that produce microbial metabolites from across the spec- trum of known structure classes), failed to identify these nonpolar metabolites. A further search against a larger COMET data set comprising HPLC-DAD-ELSD profiles from 50000 microbes selected for their capacity to yield novel secondary metabolites also failed to return a match. Taken together, these searches suggested that Kibdelo- sporangium sp. (MST-108465) and its metabolites were re- markably rare. Scaled up solid and liquid-phase fermenta- tion of the Kibdelosporangium sp. optimized for production of cytotoxic metabolites yielded a family of new heterocyclic polyketides exemplified by kibdelone A (1). In this report we describe the isolation, characterization, structure elucida- tion, and biological evaluation of kibdelones A–C (1–3), kibdelone B rhamnoside (5), 13-oxokibdelone A (7), and 25-methoxy-24-oxokibdelone C (8). Results and Discussion Fermentation and isolation : Having established that the MeOH extract obtained from a solid-phase microfermenta- Abstract: The kibdelones are a novel family of bioactive heterocyclic poly- ketides produced by a rare soil actino- mycete, Kibdelosporangium sp. (MST- 108465). Complete relative stereostruc- tures were assigned to kibdelones A–C (1–3), kibdelone B rhamnoside (5), 13- oxokibdelone A (7), and 25-methoxy- 24-oxokibdelone C (8) on the basis of detailed spectroscopic analysis and chemical interconversion, as well as mechanistic and biosynthetic consider- ations. Under mild conditions, kibde- lones B (2) and C (3) undergo a facile equilibration to kibdelones A–C (1–3), while kibdelone B rhamnoside (5) equilibrates to a mixture of kibdelone A–C rhamnosides (4–6). A plausible mechanism for this equilibration is pro- posed and involves air oxidation, qui- none/hydroquinone redox transforma- tions, and a choreographed sequence of keto/enol tautomerizations that aroma- tize ring C via a quinone methide inter- mediate. Kibdelones exhibit potent and selective cytotoxicity against a panel of human tumor cell lines and display sig- nificant antibacterial and nematocidal activity. Keywords: actinomycete · anti- tumor agents · natural products · NMR spectroscopy · polyketides [a] R. Ratnayake, Prof. R. J. Capon Centre for Molecular Biodiversity Institute for Molecular Bioscience University of Queensland, St. Lucia QLD, 4072 (Australia) Fax: (+ 94)7-3346-2090 E-mail: r.capon@imb.uq.edu.au [b] Dr. E. Lacey, Dr. S. Tennant, Dr. J.H. Gill Microbial Screening Technologies Pty. Ltd. Building A, 28–54 Percival Road, Smithfield NSW, 2164 (Australia) Supporting information for this article (NMR assignments for com- pounds 2–8 and 10, fermentation media treatment/extraction meth- ods, and kibdelones A–C equilibration studies) is available on the WWW under http://www.chemeurj.org/or from the author. # 2007 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim Chem. Eur. J. 2007, 13, 1610–1619 1610