Structure-Activity Relationship of Phytotoxic Natural 10-Membered Lactones and Their Semisynthetic Derivatives.

Anna Dalinova,Vsevolod Dubovik,Alexander Berestetskiy,Dmitry Kochura,Elena Tyutereva,Olga Voitsekhovskaja,Anatoly Fedorov,Sergey Smirnov,Leonid Chisty,Igor Senderskiy

doi:10.3390/jof7100829

Abstract

Ten-membered lactones (nonenolides) demonstrate phytotoxic, antimicrobial, and fungicidal activity promising for the development of natural product-derived pesticides. The fungus Stagonospora cirsii is able to produce phytotoxic stagonolides A (1), J (2), K (3) and herbarumin I (4) with high yield. The aim of this study was to create a set of structurally related nonenolides and to reveal the structural features that affect their biological activity. Stagonolide A (1) and C-7 oxidized stagonolide K (11) showed the highest phytotoxicity in leaf puncture assay and agar seedlings assay. The oxidation of C-7 hydroxyl group (as in 1, acetylstagonolide A (10) and (11) led to the manifestation of toxicity to microalgae, Bacillus subtilis and Sf9 cells regardless of the configuration of C-9 propyl chains (R in 1 and 10, S in 11). C-7 non-oxidized nonenolides displayed none or little non-target activity. Notably, 7S compounds were more phytotoxic than their 7R analogues. Due to the high inhibitory activity against seedling growth and the lack of side toxicity, mono- and bis(acetyl)- derivatives of herbarumin I were shown to be potent for the development of pre-emergent herbicides. The identified structural features can be used for the rational design of new herbicides.

Highlights

Secondary metabolites of microorganisms are structurally “optimized” by evolution to serve particular biological functions, including competition with other organisms.characterization of these natural products can provide new scaffolds for the development of pesticides
Stagonolide K (3) acetylation was well performed using a large excess of acylating reagent with 91% yield (Figure 2)
In our previous studies we have shown that the phytopathogenic pycnidial fungus Stagonospora cirsii Davis is a “biofactory” for nonenolides production with diverse structures and biological activities including stagonolides A−K, herbarumin I and modiolide

Summary

Introduction

Secondary metabolites of microorganisms are structurally “optimized” by evolution to serve particular biological functions, including competition with other organisms. Characterization of these natural products can provide new scaffolds for the development of pesticides. Many active ingredients of conventional pesticides (i.e., kresoximmethyl, azoxystrobin, kasugamycin and others) are the examples of such natural productderived molecules [1]. It is necessary to screen natural product libraries for the compounds that possess promising activity against weeds and pests. Detailed investigation of their biological properties and structure–activity relationships (SAR) is necessary for the screening of target-specific toxins for the development of natural product-derived pesticides

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