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 B 1 /B 2 ( 5a , b ), and pyrenolide C ( 6 )), were purified from cultures of the phytopathogenic fungus Stagonospora cirsii , and five semisynthetic derivatives of 3 and 4 ( 7 - 11 ) were obtained. The absolute configuration of 4 was revised to 2 Z , 4 S , 5 S , 6 R , and 9 R. The identity of 5a , b and stagonolide H is discussed. The phytotoxicity of compound 4 , the entomotoxicity of 5a , b , and nonselective toxicity of compound 6 are demonstrated. The latter confirms the hypothesis that the α,β-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 4 is 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.