Total synthesis, stereochemical assignment, and biological evaluation of opantimycin A and analogues thereof.

Opantimycin A, a rare antimycin-class antibiotic without the macrolide core, was isolated from sp. RK88-1355 in 2017. In this study, we explored the total synthesis and stereochemical assignment of opantimycin A.

Total synthesis of isoneoantimycin.

Antimycins are one of the well-known antifungal metabolites produced by bacteria. Neoantimycin and its analogues, the ring-expanded antimycins featuring a 15-membered tetraester ring, have been shown to be effective regulators of the oncogenic proteins GRP78/BiP and K-Ras. Isoneoantimycin was isolated from IFO12773 (ISP 5063) as a minor metabolite during the fermentation of neoantimycin and is the first reported antibiotic of the antimycin family without the macrolide core.

Ligand-Dependant Selective Synthesis of Mono- and Dialkenylcarbazoles through Rhodium(III)-Catalyzed C-H Alkenylation.

The C-H alkenylation of N-acetylcarbazoles proceeds smoothly at the C1-position in the presence of a cationic Cp*Rh(III) catalyst to produce 1-alkenylcarbazoles. The use of a cationic Cp Rh(III) catalyst enables further alkenylation to give 1,8-dialkenylcarbazoles. The direct alkenylation procedure in combination with the ready removal of the acetyl directing group provides a straightforward synthetic pathway to 1- and/or 8-alkenyl-N-H-carbazole derivatives.

Suppression of Linear Ubiquitination Ameliorates Cytoplasmic Aggregation of Truncated TDP-43.

TAR DNA-binding protein 43 (TDP-43) is a predominant component of inclusions in the brains and spines of patients with amyotrophic lateral sclerosis (ALS). The progressive accumulation of inclusions leads to proteinopathy in neurons. We have previously shown that Met1(M1)-linked linear ubiquitin, which is specifically generated by the linear ubiquitin chain assembly complex (LUBAC), is colocalized with TDP-43 inclusions in neurons from -associated familial and sporadic ALS patients, and affects NF-κB activation and apoptosis.

Rhodium(III)-Catalyzed Redox-Neutral Coupling of α-Trifluoromethylacrylic Acid with Benzamides through Directed C-H Bond Cleavage.

A rhodium(III)-catalyzed redox-neutral coupling of α-trifluoromethylacrylic acid with bezamides proceeds smoothly accompanied by amide-directed C-H bond cleavage to produce β-[2-(aminocarbonyl)phenyl]-α-trifluoromethylpropanoic acid derivatives. One of the products can be transformed to a trifluoromethyl substituted heterocyclic compound. In addition, the redox-neutral coupling of α-trifluoromethylacrylic acid with related aromatic substrates possessing a nitrogen-containing directing group can also be conducted under similar conditions.

Total Syntheses and Configuration Assignments of JBIR-06 and Related Depsipeptides.

The first total syntheses of JBIR-06 and two analogous depsipeptides, 12-membered antimycin-class antibiotics, have been accomplished via Shiina macrolactonization. Comparison of the spectroscopic data of the synthesized compounds with those reported for natural products verified that the absolute configutation of the natural products was (2 S,4 S,6 S,7 R,14 S).

Evaluation of Inhibitory Activities of UK-2A, an Antimycin-Type Antibiotic, and Its Synthetic Analogues against the Production of Anti-inflammatory Cytokine IL-4.

The inhibitory activities of the antimycin-class antibiotics UK-2A, antimycin A, and splenocin B against the production of anti-inflammatory cytokine IL-4, which is related to IgE-mediated allergic responses in rat basophilic leukemia (RBL-2H3) cells, were evaluated. Although antimycin A and splenocin B showed cytotoxicity at concentrations at which IL-4 release from the cells was restricted, UK-2A was found to restrict IL-4 release without cytotoxicity. Three UK-2A analogues (4-6) were then synthesized and assessed.

Iridium-Catalyzed Aerobic Coupling of Salicylaldehydes with Alkynes: A Remarkable Switch of Oxacyclic Product.

The iridium(III)/copper(II)-catalyzed dehydrogenative coupling of salicylaldehydes with internal alkynes proceeds efficiently under atmospheric oxygen through aldehyde C-H bond cleavage and decarbonylation. A variety of benzofuran derivatives can be synthesized by the environmentally benign procedure. DFT calculations suggest that this unique transformation involves the facile deinsertion of CO in the key metallacycle intermediate, which is in marked contrast to the corresponding rhodium(III) catalysis that leads to CO-retentive chromone derivatives.

Total syntheses and configuration assignments of JBIR-04 and unantimycin A.

First total syntheses of JBIR-04 and unantimycin A have been achieved. Comparison of our spectroscopic data with those reported for natural samples verified the structure of the natural products; (2S,4S,6S,7R,9S,28S) configuration was thus assigned via total synthesis.

Synthesis of Difluorinated Enynes through Sonogashira-Type Coupling.

The Sonogashira-type coupling of 2,2-difluoroethenyl tosylate with a variety of aliphatic and aromatic terminal alkynes proceeds smoothly even at room temperature to produce the corresponding difluorinated enyne derivatives. 2,2-Difluoroethenyl tosylate is a useful difluoroethenyl source because of its ready availability from 2,2,2-trifluoroethanol. Some of the obtained enynes exhibit strong fluorescence in the solid state.

Visualization analysis of the vacuole-targeting fungicidal activity of amphotericin B against the parent strain and an ergosterol-less mutant of Saccharomyces cerevisiae.

Here, we sought to investigate the vacuole-targeting fungicidal activity of amphotericin B (AmB) in the parent strain and AmB-resistant mutant of Saccharomyces cerevisiae and elucidate the mechanisms involved in this process. Our data demonstrated that the vacuole-targeting fungicidal activity of AmB was markedly enhanced by N-methyl-N″-dodecylguanidine (MC12), a synthetic analogue of the alkyl side chain in niphimycin, as represented by the synergy in their antifungal activities against parent cells of S. cerevisiae.

Antifungal thiopeptide cyclothiazomycin B1 exhibits growth inhibition accompanying morphological changes via binding to fungal cell wall chitin.

Cyclothiazomycin B1 (CTB1) is an antifungal cyclic thiopeptide isolated from the culture broth of Streptomyces sp. HA 125-40. CTB1 inhibited the growth of several filamentous fungi including plant pathogens along with swelling of hyphae and spores.

Enhancement effect of N-methyl-N″-dodecylguanidine on the vacuole-targeting fungicidal activity of amphotericin B against the pathogenic fungus Candida albicans.

The alkylguanidium chain attached to the polyol lactone ring of niphimycin (NM) is considered a requisite for the fungicidal activity of NM characterized by vacuole membrane fragmentation and oxidative stress induction. The addition of N-methyl-N″-dodecylguanidine to the medium can enhance the vacuole-targeting fungicidal activity of amphotericin B (AmB), in which the lactone ring has no such alkylguanidium chain, on Saccharomyces cerevisiae cells. In this study, the enhancement effect of N-methyl-N″-dodecylguanidine on the vacuole-targeting fungicidal activity of AmB was examined against Candida albicans in RPMI 1640 medium at 37  °C.

Evaluation of uridine 5'-eicosylphosphate as a stimulant of cyclic AMP-dependent cellular function.

Sporulation of the yeast Saccharomyces cerevisiae is negatively regulated by cyclic AMP (cAMP). This microbial cell differentiation process was applied for the screening of a substance that can elevate the intracellular cAMP level. Among nucleoside 5'-alkylphosphates, uridine 5'-eicosylphosphate (UMPC20) selectively and predominantly inhibited ascospore formation of the yeast cells.

Targeted yeast vacuole disruption by polyene antibiotics with a macrocyclic lactone ring.

In this study, the polyene macrolide antibiotics amphotericin B (AmB), nystatin and filipin III were evaluated for their fungicidal activity and their ability to produce vacuole disruption as well as enhancement of these activities by allicin using Saccharomyces cerevisiae. Nystatin has a macrocyclic lactone ring analogous to AmB and their fungicidal activities were both increased by allicin, an allyl-sulfur compound, whereas filipin III, a pentaene macrolide, did not show an increase in fungicidal activity in the presence of allicin. Vacuole staining with the fluorescent probe FM4-64 showed that both AmB and nystatin induced vacuole membrane disintegration at their lethal concentrations; in addition, the vacuole disruptive effect was also enhanced by allicin.

Selective inhibition of embryonic development in starfish by long-chain alkyl derivatives of UMP, TMP and AMP.

Nucleoside analogs have been evaluated as useful tools for the investigation of the mechanism of cell differentiation. We thus examined the effects of nucleoside 5'-alkylphosphates (1-10) on the morphogenetic development of starfish embryos. These nucleotide derivatives were all permissive for their development up to the blastula stage, but the derivatives with lauryl side chain selectively inhibited one of the following stages into bipinnaria larvae.

Antimycin A-induced cell death depends on AIF translocation through NO production and PARP activation and is not involved in ROS generation, cytochrome c release and caspase-3 activation in HL-60 cells.

A respiratory inhibitor, antimycin A (AA), induced an apoptotic-like cell death characterized by nuclear and DNA fragmentation in human leukemia HL-60 cells. This cell death was significantly restricted by a nitric oxide synthase (NOS) inhibitor, N(G)-monomethyl-L-arginine (L-NMMA), and a poly(ADP-ribose) polymerase (PARP) inhibitor, 5-aminoisoquinoline (AIQ). Indeed, NO production and PARP overactivation were detected in the cells treated with AA.

Isolation of an Acremonium sp. capable of liquefying cross-linked poly(gamma-glutamic acid) hydrogels and the fungal enzyme involved in the disruption of gamma-ray irradiation-mediated cross-linking.

A microorganism capable of liquefying cross-linked poly(gamma-glutamic acid) (C-L PGA) was isolated and identified to be an Acremonium sp. The fungus produced an enzyme that can disrupt the cross-linkages of C-L PGA generated by gamma-ray irradiation. The enzyme can also liquefy C-L PGA prepared by chemical cross-linkage, suggesting the involvement of ester bonds in the gamma-ray irradiation-mediated cross-linking of PGA.

Identification of phoslactomycin E as a metabolite inducing hyphal morphological abnormalities in Aspergillus fumigatus IFO 5840.

In our survey for antifungal compounds, a fermentation broth of Streptomyces sp. HA81-2 was found to inhibit the in vitro growth of Aspergillus fumigatus IFO 5840 accompanied by hyphal morphological abnormalities. One of the isolated antibiotics was identified as phoslactomycin E based on LC-MS and NMR spectral data.

Synergistic fungicidal activities of amphotericin B and N-methyl-N"-dodecylguanidine: a constituent of polyol macrolide antibiotic niphimycin.

The synergy between the alkylguanidinium chain of niphimycin (NM), a polyol macrolide antibiotic, and polyene macrolide amphotericin B (AmB) without such an alkyl side chain was examined using N-methyl-N"-alkylguanidines as its synthetic analogs. Among the analogs, N-methyl-N"-dodecylguanidine (MC12) most strongly inhibited the growth of Saccharomyces cerevisiae cells and those of other fungal strains in synergy with AmB. MC12 itself was not lethal but the analog could be a cause of a rapid cell death progression of yeast cells in the presence of AmB at a nonlethal concentration.

Synthesis of fluorescent molecular probes specific for the receptor of blepharismone, a mating-inducing pheromone of the ciliate Blepharisma japonicum.

Blepharismone (gamone 2) is a mating-inducing pheromone of the ciliate Blepharisma japonicum. N-Pyrenylbutyryl-blepharismone and N-biphenylacetyl-blepharismone, which are fluorescent derivatives of blepharismone, were synthesized as molecular probes for the gamone 2 receptor. Further, we proved that they have inhibitory activities against the blepharismone-induced monotypic pairing of B.

Inhibitory activity of 1-farnesylpyridinium on the spatial control over the assembly of cell wall polysaccharides in Schizosaccharomyces pombe.

The modes of actions of 1-farnesylpyridinium (FPy) on yeast cell growth were investigated on the basis of its effects on cell cycle progression, morphogenesis and the related events for construction of cell wall architecture in Schizosacchromyces pombe. FPy predominantly inhibited the growth of the yeast cells after various cycles of cell division so that cells were arrested at the phase of separation into daughter cells accompanying morphological changes to swollen spherical cells at 24 h of incubation. FPy-treated cells were osmotically stable but were susceptible to the lytic action of (1, 3) beta-D-glucanases, and characterized by serious damages to the cell wall architecture as represented by a rough and irregular surface outlook.

Synthesis of the sugar moiety of TIME-EA4, a glycopeptide isolated from silkworm diapause eggs.

We describe the efficient synthesis of the tetrasaccharide, 2-O-acetyl-3,4,6-tri-O-benzyl-alpha-D-mannopyranosyl-(1-->6)-2,4-di-O-acetyl-3-O-allyl-beta-D-mannopyranosyl-(1-->4)-3,6-di-O-benzyl-2-deoxy-2-phthalimido-beta-D-glucopyranosyl-(1-->4)-3,6-di-O-benzyl-2-deoxy-2-phthalimido-beta-D-glucopyranosyl azide, which is the protected form of the sugar unit of TIME-EA4 that is isolated from the diapausing eggs of the silkworm, Bombyx mori. The beta-linked D-mannoside of the tetrasaccharide was obtained using the conventional oxidation-reduction method for inversion of the configuration at the C-2 hydroxyl group of beta-D-glucoside. The reduction was effected with NaBH(4) in a methanolic solution in a ratio of 98:2 in favor of the beta-D-mannoside that was obtained in 87% yield.

Structure-activity relationship studies on UK-2A, a novel antifungal antibiotic from Streptomyces sp. 517-02. Part 5: Roles of the 9-membered dilactone-ring moiety in respiratory inhibition.

Several open-chained analogues of UK-2A, a novel antifungal antibiotic isolated from Streptomyces sp. 517-02, were prepared for structure-activity studies. The in vitro antifungal activities of these compounds against Rhodotorula mucilaginosa IFO 0001 and the inhibition of uncoupler-stimulated respiration in bovine heart submitochondrial particles (SMP) were evaluated.

Involvement of oxidative stress induction in Na+ toxicity and its relation to the inhibition of a Ca2+ -dependent but calcineurin-independent mechanism in Saccharomyces cerevisiae.

Uridine 5'-hexadecylphosphate (UMPC16) inhibited the growth of Saccharomyces cerevisiae under a hypersaline stress condition with Na+ more strongly than the calcineurin inhibitor cyclosporine A (CsA). Additional Ca2+ supplementation similarly suppressed the inhibitory activities of UMPC16 and CsA on yeast cell growth in a medium with Na+. UMPC16, but not CsA, accelerated mitochondrial reactive oxygen species (ROS) generation in combination with Na+, suggesting its inhibition of a Ca2+ -dependent but calcineurin-independent mechanism for protection against Na+ toxicity.