Search

An efficient synthesis of both enantiomers of lycoperdic acid, a 4-hydroxyglutamic acid derivative from edible mushroom Lycoperdon perlatum, was achieved from a chiral aminoalcohol. The key steps were a stereoselective introduction of a C3 unit into a bicyclic ketone and oxidative cleavage of a cyclic vicinal diol into a dicarboxylic acid. This report provides the first synthesis of (−)-lycoperdic acid.

The heterothallic group of the plant pathogen Phytophthora can sexually reproduce between the cross-compatible mating types A1 and A2. The mating hormone α2, produced by A2 mating type and utilized to promote the sexual reproduction of the partner A1 type, is known to be biosynthesized from phytol. In this study, we identified 2 biosynthetic intermediates, 11- and 16-hydroxyphytols (1 and 2), for α2 by administering the synthetic intermediates to an A2-type strain to produce α2 and by administering phytol to A2 strains to detect the intermediates in the mycelia. The results suggest that α2 is biosynthesized by possibly 2 cytochrome P450 oxygenases via 2 hydroxyphytol intermediates (1 and 2) in A2 hyphae and secreted outside.

The crop destroyer Phytophthora uses mating hormones α1 and α2 to commence its sexual reproduction. The α1-induced sexual reproduction of the A2 mating type was unexpectedly found to be interfered with by the counterhormone α2 that the A2 type itself produces to induce the sexual reproduction of the A1 type. A plausible mechanism is proposed based on structure–activity relationships.

Formosusin A, a specific inhibitor of an X-family DNA polymerase (rat DNA polymerase β), was synthesized using a Sharpless asymmetric dihydroxylation as the key step for the preparation of a chiral building block. This Letter describes the first example of the total synthesis of formosusin A. The absolute configuration of the natural formosusin A was determined to be ( R ) from the specific rotation value. Racemization of formosusin A was observed under acidic conditions, suggesting that the reported natural product might have low optical purity.

In response to environmental stressors such as blast fungal infections, rice produces phytoalexins, an antimicrobial diterpenoid compound. Together with momilactones, phytocassanes are among the major diterpenoid phytoalexins. The biosynthetic genes of diterpenoid phytoalexin are organized on the chromosome in functional gene clusters, comprising diterpene cyclase, dehydrogenase, and cytochrome P450 monooxygenase genes. Their functions have been studied extensively using in vitro enzyme assay systems. Specifically, P450 genes (CYP71Z6, Z7; CYP76M5, M6, M7, M8) on rice chromosome 2 have multifunctional activities associated with ent-copalyl diphosphate-related diterpene hydrocarbons, but the in planta contribution of these genes to diterpenoid phytoalexin production remains unknown. Here, we characterized cyp71z7 T-DNA mutant and CYP76M7/M8 RNAi lines to find that potential phytoalexin intermediates accumulated in these P450-suppressed rice plants. The results suggested that in planta, CYP71Z7 is responsible for C2-hydroxylation of phytocassanes and that CYP76M7/M8 is involved in C11α-hydroxylation of 3-hydroxy-cassadiene. Based on these results, we proposed potential routes of phytocassane biosynthesis in planta.

Formosusin A, a specific inhibitor of an X-family DNA polymerase (rat DNA polymerase β), was synthesized using a Sharpless asymmetric dihydroxylation as the key step for the preparation of a chiral building block. This Letter describes the first example of the total synthesis of formosusin A. The absolute configuration of the natural formosusin A was determined to be ( R ) from the specific rotation value. Racemization of formosusin A was observed under acidic conditions, suggesting that the reported natural product might have low optical purity.

Microbial signaling molecules such as quorum-sensing pheromones and microbial hormones play a central role in the interspecies or even interkingdom communication of microorganisms. The signaling molecules typically regulate important genes that are necessary for their survival. Recent advances in the field of signaling molecules have initiated progress in translating microbial molecular messages into our language to gain insight into their intercellular communication system. Described herein are the recent advances in the chemistry and chemical biology of eight main classes of important microbial signaling molecules: autoinducer-2 (AI-2), N-acylhomoserine lactones (AHLs), CAI-1-related α-hydroxy ketones (AHKs), ComX pheromones, IQS, diffusible signal factors (DSFs), diffusible extracellular factor (DF), and Phytophthora mating hormones.

The mating hormones α1 and α2 induce sexual reproduction of the phytopathogenic genus Phytophthora. To demonstrate the structural elements responsible to hormonal activity, 17 derivatives of α1 and α2 were synthesized and their hormonal activity (oospore-inducing activity) was evaluated. The terminal ester derivatives of α1 (diacetate and dibenzoate) retained the hormonal activity, whereas a dicarbamate derivative completely suppressed the activity. Even monocarbamates showed weak activities; among them the 1-O-carbamate was less active than 16-O-carbamate, suggesting that the 1-OH group is a little more important than 16-OH. Dihydro, dehydro, and demethyl derivatives exhibited the minimum level of activity. Surviving activity of 15-epi-α1 suggested a less importance of this stereochemistry. Contrary to α1, not only the terminal diacetate derivative but also monoacetates of α2 exhibited no or little activity. Among the monoacetates, 1-O-acetyl-α2 exhibited little yet relatively better activity than the others. No activity was observed for mono- and dicarbamoyl derivatives of α2. Dihydro α2 with the saturated double bond lost most of the activity. These findings suggest that both the mating hormones α1 and α2 require most of the functional (hydroxyl, keto, and olefinic) groups they possess in their natural form for inducing the sexual reproduction of Phytophthora.

Four stereoisomers of Phytophthora mating hormone α2 were synthesized using both enantiomers of citronellol as starting materials. The absolute configuration of the natural product was determined to be 7 S ,11 R ,15 R by oospore-inducing assays of the synthetic isomers. A concise synthetic procedure of α1 was also established using a common synthetic intermediate of α2.

The first synthesis of (±)-cyclic dehypoxanthine futalosine (cyclic DHFL), a biosynthetic intermediate in the futalosine pathway for menaquinones operating in microorganisms, has been achieved. Efficient growth of the Streptomyces coelicolor mutant, which lacks the cyclic DHFL synthetase gene (mqnC gene) was observed in the presence of synthetic (±)-cyclic DHFL.

Microbial signaling molecules such as autoinducers and microbial hormones play important roles in intercellular communication in microorganisms. Information transfer between the individual cells of a microorganism is one of the most important biological events among them. Researchers often suffer from extremely low levels of microbial signaling molecule contents, which prevent them from understanding chemistry and biology of intercellular communication in microorganisms. Chemical synthesis is a powerful tool to obtain sufficient amounts of sample and to clarify the structure of a molecule. This review focuses on the synthesis and stereochemistry-bioactivity relationships of five microbial signaling molecules, Vibrio cholerae autoinducer-1 (CAI-1), AI-2 precursor (DPD), an acylhomoserine lactone from Rhizobium leguminosarum (small bacteriocin), a diffusible extracellular factor of Xanthomondas campestris pv. campestris, and Phytophthora mating hormone α1.

Short-step syntheses of (2RS,8R,10R)-YM-193221 (1) and tyroscherin (2), which are biologically active compounds isolated from Pseudallescheria sp., were accomplished in six and eight steps from L-tyrosine. The relative stereochemistry of natural YM-193221 was determined to be 8R *,10R *.

Callosobruchus analis (Coleoptera: Chrysomelidae: Bruchinae), found throughout tropical Asia and Africa, is a pest of stored legumes. Previous work has shown that females of this species produce a contact sex pheromone that elicits copulatory behavior in males. Comparisons of copulatory activity between any two of four congeneric species suggest that the contact sex pheromones are species specific. In laboratory bioassays, male C. analis exhibited copulatory behavior to a female dummy to which a crude extract of virgin females was applied. The extract had been collected by a filter paper method and was purified by acid–base partition and chromatographic techniques. Gas chromatography-mass spectrometry (GC-MS) analyses of active fractions revealed that the active compounds were 2,6-dimethyloctane-1,8-dioic acid (1) and callosobruchusic acid, (E)-3,7-dimethyl-2-octene-1,8-dioic acid (2), previously identified as contact sex pheromones of Callosobruchus maculatus (F.) and C. chinensis (L.), respectively. The stereoisomeric and chemical compositions were determined by the 2D-HPLC-Ohrui-Akasaka method as (2S,6R)-1:(S)-2 = 1.8:1, which meant that both compounds in C. analis were stereochemically pure, unlike the case of C. maculatus and C. chinensis. An examination of the influence of synthetic pheromone compounds on male copulatory activity revealed that (2S,6R)-1 is the main component, and that (S)-2 has an additive effect. In the examination of the stereochemistry-activity relationship, no copulatory behavior was elicited by (2R,6S)-1, and, furthermore, the enantiomer significantly masked the pheromonal activity of (2S,6R)-1. Glass rod dummy assays also suggested the presence of synergists. These results could elucidate the specificity of mate recognition in C. analis.

Callosobruchus rhodesianus (Pic) (Coleoptera: Chrysomelidae: Bruchinae) is a pest of stored legumes through the Afro-tropical region. In laboratory bioassays, males of C. rhodesianus were attracted to volatiles collected from virgin females. Collections were purified by various chromatographic techniques, and the biologically active component isolated using gas chromatographic-electroantennographic detection analysis. Gas chromatography-mass spectrometry and NMR analyses suggested that the active compound was 2,3-dihydrohomofarnesal, i.e., 7-ethyl-3,11-dimethyl-6,10-dodecadienal. The structure was confirmed by non-stereoselective and enantioselective total synthesis. Using chiral gas chromatography, the absolute configuration of the natural compound was confirmed as (3S,6E)-7-ethyl-3,11-dimethyl-6,10-dodecadienal. Y-tube olfactomter assays showed that only the (S)-enantiomer attracted males of C. rhodesianus. The (R)-enantiomer and racemate did not attract males, suggesting that the (R)-enantiomer inhibits the activity of the natural compound. In combination with previous reports about sex attractant pheromones of congeners, we suggest that a saltational shift of the pheromone structure arose within the genus Callosobruchus.

A proposed structure for the diffusible extracellular factor (DF) of Xanthomonas campestris pv. campestris (Xcc) has been synthesized. Its MS spectrum and biological activity, however, contradict those of the natural product previously reported, suggesting that the structure for DF of Xcc must be reexamined.

An asymmetric total synthesis of ent-sandaracopimaradiene, a biosynthetic intermediate of oryzalexins, via B-alkyl Suzuki-Miyaura coupling and Lewis acid-mediated B-ring formation as key steps was achieved.

The copulation release pheromone of the cowpea weevil, Callosobruchus maculatus, was re-isolated from about 30,000 virgin female. The natural pheromone was confirmed to be stereochemically impure by Ohrui–Akasaka-2D-HPLC methodology. The structure–activity relationship of the pheromone was also clarified.

Two stereoisomers of penazetidine A (1a), the azetidine alkaloid isolated from the Indo-Pacific marine sponge Penares sollasi, were synthesized by starting from (S)-serine and (R)-or (S)-citronellol. The natural penazetidine A must be either (2S,3R,4S,12′R)- or (2S,3R,4S,12′S)-1a.

The structure of the antibacterial sesquiterpene from Premna oligotricha was shown to be not 1 but 2 (relative stereochemistry) by the unambiguous synthesis of both (±)-1 and (±)-2.

A diastereomeric mixture and the four stereoisomers of 2,6-dimethyloctane-1,8-dioic acid (2), a copulation release pheromone of the cowpea weevil, Callosobruchus maculatus, were synthesized. The stereoisomeric purities of the four synthetic isomers of 2 were determined by the HPLC analyses of their bis-2-(2,3-anthracenedicarboximide)-1-cyclohexyl esters.

The heterothallic species of the agricultural pest Phytophthora use mating hormones α1 and α2 to regulate their sexual reproduction. Here we describe the absolute stereostructure of the second mating hormone α2 as defined by spectroscopic analysis and total synthesis. We have uncovered not only the interspecies universality of α hormones but also the pathway by which α2 is biosynthesized from phytol by A2-mating type strains and metabolized to α1 by A1 strains.

The first synthesis of a stereoisomeric mixture of hormone α1, the mating hormone of Phytophthora , was achieved, and the synthetic mixture was confirmed to be hormonally active.

Vialinin A, a small compound isolated from the Chinese mushroom Thelephora vialis, exhibits more effective anti-inflammatory activity than the widely used immunosuppressive drug tacrolimus (FK506). Here, we show that ubiquitin-specific peptidase 5/isopeptidase T (USP5/IsoT) is a target molecule of vialinin A, identified by using a beads-probe method. Vialinin A inhibited the peptidase activity of USP5/IsoT and also inhibited the enzymatic activities of USP4 among deubiquitinating enzymes tested. Although USPs are a member of thiol protease family, vialinin A exhibited no inhibitions for other thiol proteases, such as calpain and cathepsin.

The four stereoisomers of small bacteriocin, an autoinducer of the symbiotic nitrogen-fixing bacterium Rhizobium leguminosarum, were synthesized via a versatile methodology for 3′-hydroxyacyl homoserine lactones based on the Nagao asymmetric aldol reaction. The synthetic isomers were much less effective at inhibiting the growth of R. leguminosarum RBL5523 than the natural isomer, showing the importance of stereochemistry for activity.

An efficient and stereoselective synthesis of three stereoisomers of the sex pheromone of the cowpea weevil, Callosobruchus maculatus, is reported.

An important biological event in phytopathogens of the genus Phytophthora is sexual reproduction, which is conducted by two mating types, A1 and A2. A factor known as hormone alpha1 is secreted by the A1 mating type and induces the formation of sexual spores (oospores) in the A2 mating type. Here we describe the asymmetric synthesis and assignment of the absolute configuration of hormone alpha1 by oospore-inducing assays of the synthesized isomers.

The stereoisomeric composition of the copulation release pheromone of the azuki bean weevil, Callosobruchus chinensis L., was determined to be R:S = 3.3–3.4:1 by the 2D-Ohrui–Akasaka method.

Summary We have isolated and characterized a cDNA encoding a novel diterpene cyclase, OsDTC1, from suspension-cultured rice cells treated with a chitin elicitor. OsDTC1 functions as ent-cassa-12,15-diene synthase, which is considered to play a key role in the biosynthesis of (−)-phytocassanes recently isolated as rice diterpenoid phytoalexins. The expression of OsDTC1 mRNA was also confirmed in ultraviolet (UV)-irradiated rice leaves. In addition, we identified ent-cassa-12,15-diene, a putative diterpene hydrocarbon precursor of (−)-phytocassanes, as an endogenous compound in the chitin-elicited suspension-cultured rice cells and the UV-irradiated rice leaves. The OsDTC1 cDNA isolated here will be a useful tool to investigate the regulatory mechanisms of the biosyntheis of (−)-phytocassanes in rice.

Total synthesis of cordiaquinone K, a new antifungal and larvicidal meroterpenoid, is reported. The absolute configuration of cordiaquinone K was confirmed by the synthesis.

Tumor necrosis factor alpha (TNF-α), a central mediator of the inflammatory response, is released from basophilic cells and other cells in response to a variety of proinflammatory stimuli. Vialinin A is a potent inhibitor of TNF-α production and is released from RBL-2H3 cells. Ubiquitin-specific peptidase 5 (USP5), a deubiquitinating enzyme, was identified as a target molecule of vialinin A and its enzymatic activity was inhibited by vialinin A. Here we report production of TNF-α is decreased in USP5 siRNA-knockdown RBL-2H3 cells, compared with control cells. The finding of the present study strongly suggests that USP5 is one of the essential molecules for the production of TNF-α in RBL-2H3.