The Phytotoxin Myrigalone A Triggers a Phased Detoxification Programme and Inhibits Lepidium sativum Seed Germination via Multiple Mechanisms including Interference with Auxin Homeostasis.

Molecular responses of plants to natural phytotoxins comprise more general and compound-specific mechanisms. How phytotoxic chalcones and other flavonoids inhibit seedling growth was widely studied, but how they interfere with seed germination is largely unknown. The dihydrochalcone and putative allelochemical myrigalone A (MyA) inhibits seed germination and seedling growth. Transcriptome (RNAseq) and hormone analyses of Lepidium sativum seed responses to MyA were compared to other bioactive and inactive compounds. MyA treatment of imbibed seeds triggered the phased induction of a detoxification programme, altered gibberellin, cis-(+)-12-oxophytodienoic acid and jasmonate metabolism, and affected the expression of hormone transporter genes. The MyA-mediated inhibition involved interference with the antioxidant system, oxidative signalling, aquaporins and water uptake, but not uncoupling of oxidative phosphorylation or p-hydroxyphenylpyruvate dioxygenase expression/activity. MyA specifically affected the expression of auxin-related signalling genes, and various transporter genes, including for auxin transport (PIN7, ABCG37, ABCG4, WAT1). Responses to auxin-specific inhibitors further supported the conclusion that MyA interferes with auxin homeostasis during seed germination. Comparative analysis of MyA and other phytotoxins revealed differences in the specific regulatory mechanisms and auxin transporter genes targeted to interfere with auxin homestasis. We conclude that MyA exerts its phytotoxic activity by multiple auxin-dependent and independent molecular mechanisms.

Synthesis and antifungal activity of novel streptochlorin analogues.

Streptochlorin, first isolated as a new antibiotic in 1988 from the lipophilic extracts of the mycelium of a Streptomyces sp, is an indole natural products with a variety of biological activities. Based on the methods developed for the synthesis of pimprinine in our laboratory, we have synthesized a series of indole-modified streptochlorin analogues and measured their activities against seven phytopathogenic fungi. Some of the analogues displayed good activity in the primary assays, and the seven compounds 10b, 10c, 11e, 13e, 21, 22c and 22e (shown in Figure 1) were identified as the most promising candidates for further study. Structural optimization is still ongoing with the aim of discovering synthetic analogues with improved antifungal activity.

Synthesis and antifungal activity of 3-(1,3,4-oxadiazol-5-yl)-indoles and 3-(1,3,4-oxadiazol-5-yl)methyl-indoles.

On the basis of the principle of combination of active structural moieties, a modified and efficient synthetic method for three series of novel indole-based 1,3,4-oxadiazoles is described. Bioassays conducted at Syngenta showed that several of the synthesized compounds exhibit higher antifungal activity than pimprinine, the natural product which inspired this synthesis. Two main structural alterations were found to broaden the spectrum of biological activity in most cases. Compounds 3g, 6c, 6e, 6h, 9d, 9e, 9h and 9m (Fig. 1) were identified as the most active on the biological assays, and will be studied further.

PPARγ agonist from Chromolaena odorata.

A phytochemical investigation of Chromolaena odorata resulted in the isolation of five new compounds, 5aα,6,9,9aß,10-pentahydro-10ß-hydroxy-7-methylanthra[1,2-d][1,3]dioxol-5-one (1), 1,2-methylenedioxy-6-methylanthraquinone (2), 3-hydroxy-1,2,4-trimethoxy-6-methylanthraquinone (3), 3-hydroxy-1,2-dimethoxy-6-methylanthraquinone (4), and 7-methoxy-7-epi-medioresinol (5), together with 12 known compounds, odoratin (6), 3ß-acetyloleanolic acid (7), ursolic acid (8), ombuin (9), 4,2'-dihydroxy-4',5',6'-trimethoxychalcone (10), (-)-pinoresinol (11), austrocortinin (12), tianshic acid (13), cleomiscosin D (14), (-)-medioresinol (15), (-)-syringaresinol (16), and cleomiscosin A (17). All the compounds were evaluated for their PPARγ transactivation activity, and compound 6 showed moderate activity with an EC(50) value of 3.10 µM.

Design, synthesis and fungicidal activity of novel sclerotiorin derivatives.

Sclerotiorin, a chlorine-containing azaphilone-type natural product, was first isolated from Penicillium sclerotiorum and has been reported to exhibit weak fungicidal activity. Optimization of the substituents at the 3- and 5-positions of the sclerotiorin framework was investigated with the aim of discovering novel fungicides with improved activity. The design of sclerotiorin analogues involved replacing the diene side chain with a phenyl group or an aromatic- or heteroaromatic-containing aliphatic side chain. The designed compounds were synthesized by cycloisomerization and subsequent oxidation of suitable 2-alkynylbenzaldehydes, in which a variety of substituents were introduced using a Sonogashira coupling reaction. The structures of these newly prepared compounds were confirmed by 1H and 13C NMR spectroscopy, HRMS and single-crystal X-ray analysis. The antifungal activity of the synthesized compounds was evaluated against seven phytopathogenic species. Compounds 3, 9g and 9h were found to have a broad spectrum of fungicidal activity, and these structurally simpler products can be recognized as lead compounds for further optimization.

Synthesis and fungicidal activity of novel pimprinine analogues.

A simple and efficient synthetic protocol for 5-(3-indolyl)-oxazoles has been developed and further used to synthesize a series of novel analogues of natural product pimprinine. All new compounds were identified by (1)H NMR, high resolution mass spectrometry, and the structures of 10 and 18o were further confirmed by X-ray crystallographic diffraction analysis. Bioassay conducted at Syngenta showed that several of the synthesized compounds exhibited fungicidal activity. Compounds 10, 17, 18 h, 18o, 19 h, 19i and 19 l all showed effective control of three out of the seven tested phytopathogenic fungi at the highest rate screened. Compounds 17 and 19 h in particular showed activity against the four pathogens screened in artificial media; Pythium dissimile, Alternaria solani, Botryotinia fuckeliana and Gibberella zeae.

Synthesis and antifungal activity of novel sclerotiorin analogues.

Sclerotiorin 1, first isolated from Penicillium sclerotiorum, has weak antifungal activity and belongs to the azaphilone-type family of natural products. Several series of sclerotiorin analogues were designed and synthesized with the aim of discovering novel fungicides with improved activity. The syntheses involved two key steps, cycloisomerization and then oxidation, and used a simple and efficient Sonogashira cross-coupling reaction to construct the required functionalized precursor. With sclerotiorin as a control, the activities of the newly synthesized analogues were evaluated against seven fungal pathogens, and several promising candidates (compounds 3a1, 3d2, 3e2, 3f2 and 3k2) with greater activity and simpler structures than sclerotiorin were discovered. In addition, preliminary structure-activity relationships were studied, which revealed that not only the chlorine or bromine substituent at the 5-position of the nucleus but also the phenyl group at the 3-position and the substituent pattern on it contributed crucially to the observed antifungal activity. Analogues with a methyl substituent at the 1-position have reduced levels of activity, while those with a free hydroxyl group in place of acetoxy at the quaternary center of the bicyclic ring system retain activity.

Further Daphniphyllum alkaloids with insecticidal activity from the bark of Daphniphyllum macropodum M(IQ).

Two new Daphniphyllum alkaloids, macropodumines J and K (1 and 2, resp.), together with six known structurally related alkaloids, 3-8, were isolated from the bark of Daphniphyllum macropodum M(IQ). The structures of the new compounds 1 and 2 were elucidated on the basis of a comprehensive analysis of their spectroscopic and chemical data. Macropodumine J (1) contains a CN group which is relatively rare in naturally occurring alkaloids. All isolated compounds were tested for their insecticidal activities against a number of insect species. Daphtenidine C (5) is the most active compound against Plutella xylostella. This is the first report of insecticidal properties of Daphniphyllum alkaloids.

Serialynic acid, a new phenol with an isopentenyne side chain from Antrodia serialis.

A new phenolic compound serialynic acid was isolated from an agar culture of the basidiomycete Antrodia serialis, through bioactivity-guided fractionations. It showed weak growth inhibitory activity towards phytopathogenic fungi and a dose-independent anti-Pythium graminicola activity.

Insect antifeedant furanocoumarins from Tetradium daniellii.

The dried fruits of Tetradium daniellii yielded a new linear furanocoumarin, 5-(6-hydroxy-3,7-dimethylocta-2,7-dienyloxy)psoralen, together with six other structurally related furanocoumarins. A similar chemical profile was recorded by HPLC analysis of a fragment of T. daniellii fruit obtained from an historic herbarium voucher specimen collected in September 1917 during an expedition to Yunnan province, China. Four of the compounds identified caused a potent feeding deterrent effect towards larvae of Spodoptera littoralis and Heliothis virescens.