Structure–Activity Relationships of Natural C-9-Methyl-Substituted 10-Membered Lactones and Their Semisynthetic Derivatives

Fungal 10-membered lactones (TMLs), such as stagonolide A, herbarumin I, pinolidoxin, and putaminoxin, are promising candidates for the development of nature-derived herbicides. The aim of this study was to analyze the structure–activity relationships (SAR) of C-9-methyl-substituted TMLs with a multitarget bioassay approach to reveal compounds with useful (phytotoxic, entomotoxic, antimicrobial) or undesirable (cytotoxic) bioactivities. A new TML, stagonolide L (1), along with five known compounds (stagonolides D (2) and E (3), curvulides A (4) and B1/B2(5a,b), and pyrenolide C (6)), were purified from cultures of the phytopathogenic fungus Stagonospora cirsii, and five semisynthetic derivatives of 3and 4(7–11) were obtained. The absolute configuration of 4was revised to 2Z, 4S, 5S, 6R, and 9R.The identity of 5a,band stagonolide H is discussed. The phytotoxicity of compound 4, the entomotoxicity of 5a,b, and nonselective toxicity of compound 6are demonstrated. The latter confirms the hypothesis that the a,ß-unsaturated carbonyl group is associated with the high general toxicity of TML, regardless of its position in the ring and other substituents. The epoxide in compound 4is important for phytotoxicity. The revealed SAR patterns will be useful for further rational design of TML-based herbicides including curvulide A analogs with a 4,5-epoxy group.