Designed Mannosylerythritol Lipid Analogues Exhibiting both Selective Cytotoxicity against Human Skin Cancer Cells and Recovery Effects on Damaged Skin Cells.

Mannosylerythritol lipids (MELs) are a class of amphipathic molecules bearing a hydrophilic 4-O-ß-D-mannopyranosyl-D-erythritol skeleton. Here, we designed and synthesized four kinds of MEL analogues R-MEL-A ([2R,3S]-erythritol type), S-mannosylthreitol lipid (MTL)-A ([2S,3S]-threitol type), R-MTL-A ([2R,3R]-threitol type), and α-S-MEL-A ([2S,3R]-erythritol type) using our previously reported boron-mediated aglycon delivery (BMAD) method and a neighboring group assisted glycosylation method. The selective cytotoxicity of the target compounds against cancer cells was evaluated, with R-MTL-A showing the highest selective cytotoxicity against human skin squamous carcinoma HSC-5 cells. Our findings suggest that R-MTL-A induces necrosis-like cell death against HSC-5 cells by decreasing cell membrane fluidity. R-MTL-A also exhibits an efficient recovery effect on damaged skin cells, indicating that R-MTL-A has potential as a lead compound for new cosmeceuticals with both cancer cell-selective toxicity and recovery effects on damaged skin cells.

Photo-induced glycosylation using the edible polyphenol curcumin.

Photo-induced glycosylations of trichloroacetimidate donors and alcohols using an edible polyphenol, curcumin, were examined under visible photo-irradiation (470 nm). It was found, for the first time, that these glycosylations proceed smoothly under mild reaction conditions to give the corresponding glycosides in high yields. In addition, the present glycosylation method was applicable to a wide range of trichloroacetimidate donors and alcohol acceptors and showed high chemoselectivity over glycosyl phosphite, phosphate, (N-phenyl)trifluoroacetimidate, fluoride, glycal and thioglycoside.

Regioselective and Stereospecific ß-Arabinofuranosylation by Boron-Mediated Aglycon Delivery.

Regio- and stereoselective formation of the 1,2-cis-furanosidic linkage has been in great demand for efficient synthesis of biologically active natural glycosides. In this study, we developed a regioselective and ß-stereospecific d-/l-arabinofuranosylation promoted by a boronic acid catalyst under mild conditions. The glycosylations proceeded smoothly for a variety of diols, triols, and unprotected sugar acceptors to give the corresponding ß-arabinofuranosides (ß-Arbf) in high yields with complete ß-stereoselectivity and high regioselectivity. The regioselectivity was completely reversed depending on the optical isomerism of the donor used and was predictable a priori using predictive models. Mechanistic studies based on DFT calculations revealed that the present glycosylation occurs through a highly dissociative concerted SN i mechanism. The usefulness of the glycosylation method was demonstrated by the chemical synthesis of trisaccharide structures of arabinogalactan fragments.

Self-Assembling Properties and Recovery Effects on Damaged Skin Cells of Chemically Synthesized Mannosylerythritol Lipids.

Mannosylerythritol lipids (MELs), which are one of the representative sugar-based biosurfactants (BSs) produced by microorganisms, have attracted much attention in various fields in the sustainable development goals (SDGs) era. However, they are inseparable mixtures with respect to the chain length of the fatty acids. In this study, self-assembling properties and structure-activity relationship (SAR) studies of recovery effects on damaged skin cells using chemically synthesized MELs were investigated. It was revealed, for the first time, that synthetic and homogeneous MELs exhibited significant self-assembling properties to form droplets or giant vesicles. In addition, a small difference in the length of the fatty acid chains of the MELs significantly affected their recovery effects on the damaged skin cells. MELs with medium or longer length alkyl chains exhibited much higher recovery effects than that of C18-ceramide NP.

Synthesis of Mannosylerythritol Lipid Analogues and their Self-Assembling Properties, Recovery Effects on Damaged Skin Cells, and Antibacterial Activity.

Synthesis of three types of purpose-designed mannosylerythritol lipid (MEL)-D analogues with decanoyl groups, ß-GlcEL-D, α-GlcEL-D, and α-MEL-D, was accomplished utilizing our boron-mediated aglycon delivery (BMAD) methods. Their self-assembling properties, recovery effects on damaged skin cells, and antibacterial activity were evaluated. It was revealed, for the first time, that α-GlcEL-D and α-MEL-D only generated giant vesicles, indicating that slight differences in the steric configuration of an erythritol moiety and fatty acyl chains affect the ability to form vesicles. Analogue α-MEL-D exhibited significant recovery effects on damaged skin cells. Furthermore, α-MEL-D exhibited antibacterial activity as high as that for MEL-D, indicating that α-MEL-D is a promising artificial sugar-based material candidate for enhancing the barrier function of the stratum corneum, superior to a known cosmetic ingredient, and possesses antibacterial activity.

Synthesis of a Pentasaccharide Repeating Unit of Lipopolysaccharide Derived from Virulent E. coli O1 and Identification of a Glycotope Candidate of Avian Pathogenic E. coli O1.

Avian pathogenic Escherichia coli (APEC) is a common bacterial pathogen infecting chickens, resulting in economic losses to the poultry industry worldwide. In particular, APEC O1, one of the most common serotypes of APEC, is considered problematic due to its zoonotic potential. Therefore, many attempts have been made to develop an effective vaccine against APEC O1. In fact, the lipopolysaccharide (LPS) O-antigen of APEC O1 has been shown to be a potent antigen for inducing specific protective immune responses. However, the detailed structure of the O-antigen of APEC O1 is not clear. The present study demonstrates the first synthesis of a pentasaccharide repeating unit of LPS derived from virulent E. coli O1 and its conjugate with BSA. ELISA tests using the semi-synthetic glycoconjugate and the APEC O1 immune chicken serum revealed that the pentasaccharide is a glycotope candidate of APEC O1, with great potential as an antigen for vaccine development.

Total Synthesis of Terpioside B.

The first total synthesis of terpioside B (1) has been accomplished. Key steps include the stereoselective installments of a set of challenging 1,2-cis-glycosidic linkages. Thus, α(1,4)-linked d-galactoside was effectively constructed from a 1,2-anhydrogalactose donor and an unprotected 1,6-anhydrogalactose acceptor by using a boron-mediated aglycon delivery (BMAD) method. In addition, α-l-fucofuranosides were stereoselectively and simultaneously constructed by remote group-assisted 1,2-cis-α-stereoselective glycosylations.

2-Naphthol Moiety of Neocarzinostatin Chromophore as a Novel Protein-Photodegrading Agent and Its Application as a H2 O2 -Activatable Photosensitizer.

A 2-naphthol derivative 2 corresponding to the aromatic ring moiety of neocarzinostatin chromophore was found to degrade proteins under photo-irradiation with long-wavelength UV light without any additives under neutral conditions. Structure-activity relationship studies of the derivative revealed that methylation of the hydroxyl group at the C2 position of 2 significantly suppressed its photodegradation ability. Furthermore, a purpose-designed synthetic tumor-related biomarker, a H2 O2 -activatable photosensitizer 8 possessing a H2 O2 -responsive arylboronic ester moiety conjugated to the hydroxyl group at the C2 position of 2, showed significantly lower photodegradation ability compared to 2. However, release of the 2 from 8 by reaction with H2 O2 regenerated the photodegradation ability. Compound 8 exhibited selective photo-cytotoxicity against high H2 O2 -expressing cancer cells upon irradiation with long-wavelength UV light.

Diboron-Catalyzed Regio- and 1,2-cis-α-Stereoselective Glycosylation of trans-1,2-Diols.

Regio- and 1,2-cis-α-stereoselective glycosylations were investigated using 1,2-anhydroglucose donors and trans-1,2-diol sugar acceptors in the presence of a diboron catalyst. The reactions proceeded smoothly to provide the corresponding 1,2-cis-α-glycosides with consistently very high stereoselectivity and were regioselectivity controlled by the protecting groups of the acceptor. The present glycosylation method was applied successfully to the efficient synthesis of α-1,3-glucan pentasaccharide.

Photo-induced glycosylation using a diaryldisulfide as an organo-Lewis photoacid catalyst.

Photo-induced glycosylations of several acceptors with trichloroacetimidate donors using bis(2-naphthyl)disulfide as an organo-Lewis photoacid (LPA) catalyst proceeded effectively to give the corresponding glycosides in good to high yields. In addition, the ground and excited state absorption spectra of bis(2-naphthyl)disulfide with or without NEt3 suggested the Lewis acidity of bis(2-naphthyl)disulfide upon photo-irradiation.

Total Synthesis and Structure-Activity Relationship Study of Vineomycin A1.

The first total synthesis of vineomycin A1 (1) has been accomplished. Structure-activity relationship studies for cytotoxicity against human breast cancer MCF-7 cells using several synthetic vineomycin A1 analogues differing in the number and position of glycon moieties revealed that the cytotoxicity increased as the number of glycon moieties increased. The position of the glycon moiety was one of the key factors for the cytotoxicity of 1. Moreover, in vitro analysis of the cytotoxicity of 1 against MCF-7 cells indicated for the first time that 1 effectively induced cancer cell death by apoptosis, not by acting as a DNA intercalating agent.

Boronic-Acid-Catalyzed Regioselective and 1,2- cis-Stereoselective Glycosylation of Unprotected Sugar Acceptors via SNi-Type Mechanism.

Regio- and 1,2- cis-stereoselective chemical glycosylation of unprotected glycosyl acceptors has been in great demand for the efficient synthesis of natural glycosides. However, simultaneously regulating these selectivities has been a longstanding problem in synthetic organic chemistry. In nature, glycosyl transferases catalyze regioselective 1,2- cis-glycosylations via the SNi mechanism, yet no useful chemical glycosylations based on this mechanism have been developed. In this paper, we report a highly regio- and 1,2- cis-stereoselective SNi-type glycosylation of 1,2-anhydro donors and unprotected sugar acceptors using p-nitrophenylboronic acid (10e) as a catalyst in the presence of water under mild conditions. Highly controlled regio- and 1,2- cis-stereoselectivities were achieved via the combination of boron-mediated carbohydrate recognition and the SNi-type mechanism. Mechanistic studies using the KIEs and DFT calculations were consistent with a highly dissociative concerted SNi mechanism. This glycosylation method was applied successfully to the direct glycosylation of unprotected natural glycosides and the efficient synthesis of a complex oligosaccharide with minimal protecting groups.

Systematic and Stereoselective Total Synthesis of Mannosylerythritol Lipids and Evaluation of Their Antibacterial Activity.

The total synthesis of the 20 homogeneous members of mannosylerythritol lipids (MELs) with different alkyl chain lengths was effectively and systematically accomplished from a strategically designed common key intermediate that was stereoselectively constructed by the borinic acid catalyzed ß-mannosylation reaction. In addition, their antibacterial activities against Gram-positive bacteria were evaluated. Our results demonstrated that not only the length of the alkyl chains but also the pattern of Ac groups on the mannose moiety were important factors for antibacterial activity.

Stereospecific ß-l-Rhamnopyranosylation through an SN i-Type Mechanism by Using Organoboron Reagents.

Stereospecific ß-l-rhamnopyranosylations were conducted using a 1,2-anhydro-l-rhamnopyranose donor and mono-ol or diol acceptors in the presence of a glycosyl-acceptor-derived borinic or boronic ester. Reactions proceeded smoothly to provide the corresponding ß-l-rhamnopyranosides (ß-l-Rhap) with complete stereoselectivity in moderate to high yields without any further additives under mild conditions. Mechanistic studies of the borinic ester mediated glycosylation using 13 C kinetic isotope effect (KIE) measurements and DFT calculations were consistent with a concerted SN i mechanism with an exploded transition state. In addition, the present glycosylation method was applied successfully to the synthesis of a trisaccharide, α-l-Rhap-(1,2)-ß-l-Rhap-(1,4)-Glcp, derived from Streptococcus pneumoniae serotypes 7B, 7C, and 7D.

Total Synthesis of Aquayamycin.

An efficient and practical total synthesis of aquayamycin has been accomplished. The highly oxidized and stereochemically complex tetracyclic ring system was constructed using three key reactions: 1) highly diastereoselective 1,2-addition of C-glycosyl naphthyllithium to a cyclic ketone, 2) indium-mediated site-selective allylation-rearrangement sequence of naphthoquinone, and 3) diastereoselective intramolecular pinacol coupling. This synthetic strategy offers a novel and efficient pathway to prepare aquayamycin-type angucycline antibiotics.

Hierarchical CaCO3 chromatography: a stationary phase based on biominerals.

In biomineralization, acidic macromolecules play important roles for the growth control of crystals through a specific interaction. Inspired by this interaction, we report on an application of the hierarchical structures in CaCO3 biominerals to a stationary phase of chromatography. The separation and purification of acidic small organic molecules are achieved by thin-layer chromatography and flash chromatography using the powder of biominerals as the stationary phase. The unit nanocrystals and their oriented assembly, the hierarchical structure, are suitable for the adsorption site of the target organic molecules and the flow path of the elution solvents, respectively. The separation mode is ascribed to the specific adsorption of the acidic molecules on the crystal face and the coordination of the functional groups to the calcium ions. The results imply that a new family of stationary phase of chromatography can be developed by the fine tuning of hierarchical structures in CaCO3 materials.

Chemical approach for target-selective degradation of oligosaccharides using photoactivatable organic molecules.

Molecular design, chemical synthesis, and biological evaluation of several organic molecules, which can target-selectively photodegrade oligosaccharides by irradiation with a specific wavelength of light under mild conditions without any additives, are introduced. These novel class of photochemical agents promise bright prospects for finding not only molecular-targeted bioprobes for understanding of the structure-activity relationships of oligosaccharides but also novel therapeutic drugs targeting biologically important oligosaccharides.

Glycosylations of Glycals using N-Iodosuccinimide (NIS) and Phosphorus Compounds for Syntheses of 2-Iodo- and 2-Deoxyglycosides.

The glycosylations of glycals and alcohols using N-iodosuccinimide (NIS) and a catalytic amount of PPh3 effectively proceeded under mild conditions to provide the corresponding 2-deoxy-2-iodoglycosides in high yields. The reactivity of the iodoglycosylations with PPh3 significantly increased in comparison to that using NIS alone as an activator. In addition, the glycosylations of glycals and alcohols using catalytic amounts of NIS and P(OPh)3 were effectively realized to give the corresponding 2-deoxyglycosides in high yields.

Systematic synthesis of low-molecular weight fucoidan derivatives and their effect on cancer cells.

Low-molecular weight type I and II fucoidan derivatives with different sulfation patterns were designed and systematically synthesized from the corresponding common key intermediate and their anti-proliferative activities and apoptosis-inducing activities against human breast cancer (MCF-7) and human cervical epithelioid carcinoma (HeLa) cells were evaluated. Our results demonstrated that one of the type II fucoidan derivatives, 9, effectively reduced the number of viable MCF-7 and HeLa cells in a dose-dependent manner without causing cytotoxicity toward normal WI-38 cells, and that the anti-proliferative activity of 9 was comparable to that of fucoidan 2 isolated from Fucus vesiculosus. Moreover, it was found that both 2 and 9 exhibited similar apoptosis-inducing activities through activation of caspase-8 and -9 on MCF-7 and HeLa cells, respectively.

Regioselective and 1,2-cis-α-Stereoselective Glycosylation Utilizing Glycosyl-Acceptor-Derived Boronic Ester Catalyst.

Regioselective and 1,2-cis-α-stereoselective glycosylations using 1α,2α-anhydro glycosyl donors and diol glycosyl acceptors in the presence of a glycosyl-acceptor-derived boronic ester catalyst. The reactions proceed smoothly to give the corresponding 1,2-cis-α-glycosides with high stereo- and regioselectivities in high yields without any further additives under mild reaction conditions. In addition, the present glycosylation method was successfully applied to the synthesis of an isoflavone glycoside.