Novel jadomycins: incorporation of non-natural and natural amino acids David L. Jakeman, a,b, * Spring Farrell, a Wendy Young, b Rene ´ J. Doucet a and Shannon C. Timmons b a College of Pharmacy, Dalhousie University, 5968 College street, Halifax, Nova Scotia, Canada B3H 3J5 b Department of Chemistry, Dalhousie University, Nova Scotia, Halifax, Canada B3H 4J3 Received 6 December 2004; revised 22 December 2004; accepted 29 December 2004 Available online 22 January 2005 Abstract—Electrospray ionization mass spectrometry of extracts from Streptomyces venezuelae ISP5230 cultures grown on chemi- cally synthesized non-natural L-amino acids, D-amino acids or any of the 20 natural amino acids demonstrated incorporation of the amino acid into a jadomycin B analogue. Ó 2005 Elsevier Ltd. All rights reserved. The need to develop new therapeutically active agents and to enlarge the reservoir of novel bioactive structural scaffolds provides impetutus to discover versatile routes to classes of secondary metabolites. Streptomycetes are soil bacteria responsible for producing a wide array of secondary metabolites, many of which have been devel- oped into therapeutically important agents to treat a wide array of diseases and health-related conditions. Jadomycin was the first secondary metabolite to be iso- lated from Streptomyces venezuelae ISP5230 cultures as a result of environmental stress (e.g., ethanol/tempera- ture/phage) 1 and a glycosylated derivative (jadomycin B) was subsequently characterized after modifying the isolation conditions (Fig. 1). 2 Jadomycins show pharma- cological activity against cancer cell lines and biological activity versus bacteria and yeast. 3 The jadomycins exhi- bit two striking structural features: the relatively rare 2,6-dideoxysugar, L-digitoxose and a five-membered oxazolone ring generated from a polyketide-derived angucycline intermediate and an amino acid required as a metabolic nitrogen source. Molecular genetic analysis of jadomycin B biosynthe- sis, 4–10 indicated the absence of candidate genes able to catalyze formation of the oxazolone ring, supporting a pathway in which L-isoleucine reacts spontaneously with an aldimine intermediate (Fig. 1). 11,12 Non-enzymic aldimine intermediates have also been postulated in the biosynthesis of betaxanthin in plants. 13 Forming the oxazolone ring non-enzymically could provide access to a wide variety of structural analogues, since the ami- no acid is used as the sole nitrogen source in the growth media, providing an amenable route to a variety of 0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2004.12.082 Keywords: Biosynthesis; Combinatorial secondary metabolites; Angu- cycline antibiotics; Aldimine intermediates. * Corresponding author. Tel.: +1 902 494 7159; fax: +1 902 494 1396; e-mail: david.jakeman@dal.ca Figure 1. Secondary metabolites produced by ethanol-shocked Strep- tomyces venezuelae ISP5230. Bioorganic & Medicinal Chemistry Letters 15 (2005) 1447–1449