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 3 and 4 (7–11) were obtained. The absolute configuration of 4 was revised to 2Z, 4S, 5S, 6R, and 9R. 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.