Diversification of Simple Arenes into Complex (Amino)cyclitols.

Highly oxygenated cyclohexanes, including (amino)cyclitols, are featured in natural products possessing a notable range of biological activities. As such, these building blocks are valuable tools for medicinal chemistry. While de novo synthetic strategies have provided access to select compounds, challenges including stereochemical density and complexity have hindered the development of a general approach to (amino)cyclitol structures. This work reports the use of arenophile chemistry to access dearomatized intermediates which are amenable to diverse downstream transformations. Practical guidelines were developed for the synthesis of natural and non-natural (amino)cyclitols from simple arenes through a series of strategic functionalization events.

Enantioselective Synthesis of Nabscessin C.

Enantioselective synthesis of nabscessin C (1), an aminocyclitol amide with antimicrobial activity, is reported. Starting from myo-inositol, (+)-nabscessin C was synthesized in 12 isolation steps. Desymmetrization of 2-deoxygenated 4,6-dibenzylinositol was achieved using lipase from porcine pancreas (PPL), and the stereochemistry was established by X-ray crystallography. This method has the potential for synthesizing other cyclitol-derived compounds.

Vinyl Halide-Modified Unsaturated Cyclitols are Mechanism-Based Glycosidase Inhibitors.

Suitably configured allyl ethers of unsaturated cyclitols act as substrates of ß-glycosidases, reacting via allylic cation transition states. Incorporation of halogens at the vinylic position of these carbasugars, along with an activated leaving group, generates potent inactivators of ß-glycosidases. Enzymatic turnover of these halogenated cyclitols (F, Cl, Br) displayed a counter-intuitive trend wherein the most electronegative substituents yielded the most labile pseudo-glycosidic linkages. Structures of complexes with the Sulfolobus ß-glucosidase revealed similar enzyme-ligand interactions to those seen in complexes with a 2-fluorosugar inhibitor, the lone exception being displacement of tyrosine 322 from the active site by the halogen. Mutation of Y322 to Y322F largely abolished glycosidase activity, consistent with lost interactions at O5, but minimally affected (7-fold) rates of carbasugar hydrolysis, yielding a more selective enzyme for unsaturated cyclitol ether hydrolysis.

Biosynthesis of cyclitols.

Review covering up to 2021Cyclitols derived from carbohydrates are naturally stable hydrophilic substances under ordinary physiological conditions, increasing the water solubility of whole molecules in cells. The stability of cyclitols is derived from their carbocyclic structures bearing no acetal groups, in contrast to sugar molecules. Therefore, carbocycle-forming reactions are critical for the biosynthesis of cyclitols. Herein, we review naturally occurring cyclitols that have been identified to date and categorize them according to the type of carbocycle-forming enzymatic reaction. Furthermore, the cyclitol-forming enzymatic reaction mechanisms and modification pathways of the initially generated cyclitols are reviewed.

Analyses of Antioxidative Properties of Selected Cyclitols and Their Mixtures with Flavanones and Glutathione.

The conditions for determining the antioxidant properties of cyclitols (d-pinitol, l-quebrachitol, myo-, l-chiro-, and d-chiro-inositol), selected flavanones (hesperetin, naringenin, eriodictyol, and liquiritigenin) and glutathione by spectrophotometric methods-CUPRAC and with DPPH radical, and by a chromatographic method DPPH-UHPLC-UV, have been identified. Interactions of the tested compounds and their impact on the ox-red properties were investigated. The RSA (%) of the compounds tested was determined. Very low antioxidative properties of cyclitols, compared with flavanones and glutathione alone, were revealed. However, a significant increase in the determined antioxidative properties of glutathione by methyl-ether derivatives of cyclitols (d-pinitol and l-quebrachitol) was demonstrated for the first time. Thus, cyclitols seem to be a good candidate for creating drugs for the treatment of many diseases associated with reactive oxygen species (ROS) generation.

Cancer Prevention by Natural Products Introduced into the Diet-Selected Cyclitols.

Cancer is now the second leading cause of death worldwide. It is estimated that every year, approximately 9.6 million people die of oncologic diseases. The most common origins of malignancy are the lungs, breasts, and colorectum. Even though in recent years, many new drugs and therapeutic options have been introduced, there are still no safe, effective chemopreventive agents. Cyclitols seem poised to improve this situation. There is a body of evidence that suggests that their supplementation can decrease the incidence of colorectal cancer, lower the risk of metastasis occurrence, lower the proliferation index, induce apoptosis in malignant cells, enhance natural killer (NK) cell activity, protect cells from free radical damage, and induce positive molecular changes, as well as reduce the side effects of anticancer treatments such as chemotherapy or surgery. Cyclitol supplementation appears to be both safe and well-tolerated. This review focuses on presenting, in a comprehensive way, the currently available knowledge regarding the use of cyclitols in the treatment of different malignancies, particularly in lung, breast, colorectal, and prostate cancers.

Synthesis and mannosidase inhibitory profile of a small library of aminocyclitols from shikimic acid-derived scaffolds.

A short synthetic route to a small library of aminocyclitols 14·HCl-19·HCl has been elaborated from the common shikimic acid-derived scaffolds 20 and 21. The developed strategy features three oxidative processes ‒ ozonolysis, dihydroxylation and epoxidation ‒ as the key transformations. The stereochemistry of the newly created stereocentres was confirmed either via crystallographic analysis or by means of NOESY experiments conducted on advanced intermediates. Glycosidase inhibition study revealed no glucosidase inhibition and only weak inhibitory activity against recombinant Drosophila melanogaster Golgi mannosidase (GMIIb).

Substituent Position of Iminocyclitols Determines the Potency and Selectivity for Gut Microbial Xenobiotic-Reactivating Enzymes.

Selective inhibitors of gut bacterial ß-glucuronidases (GUSs) are of particular interest in the prevention of xenobiotic-induced toxicities. This study reports the first structure-activity relationships on potency and selectivity of several iminocyclitols (2-7) for the GUSs. Complex structures of Ruminococcus gnavus GUS with 2-7 explained how charge, conformation, and substituent of iminocyclitols affect their potency and selectivity. N1 of uronic isofagomine (2) made strong electrostatic interactions with two catalytic glutamates of GUSs, resulting in the most potent inhibition (Ki ≥ 11 nM). C6-propyl analogue of 2 (6) displayed 700-fold selectivity for opportunistic bacterial GUSs (Ki = 74 nM for E. coli GUS and 51.8 µM for RgGUS). In comparison with 2, there was 200-fold enhancement in the selectivity, which was attributed to differential interactions between the propyl group and loop 5 residues of the GUSs. The results provide useful insights to develop potent and selective inhibitors for undesired GUSs.

The Impact of Phytases on the Release of Bioactive Inositols, the Profile of Inositol Phosphates, and the Release of Selected Minerals in the Technology of Buckwheat Beer Production.

A relatively high concentration of phytate in buckwheat malt, and the low activity of endogenous buckwheat phytases, both of which limit the effective use of substrates (starch, proteins, minerals) for fermentation and yeast metabolism, gives rise to the potential for application of phytases in beer production. This study aims at obtaining a 100% buckwheat wort with high bioactive cyclitols (myo-inositol and D-chiro-inositol) concentrations released by exogenous phytases and acid phosphatases. Two mashing programs were used in the study, i.e., (1) typical for basic raw materials, namely the well-established Congress method, and (2) optimized for phytase activity. The results indicated a nearly 50% increase in the level of bioactive myo-inositol and an 80% degradation of phytate in the wort as a result of simultaneous application of phytase and phosphatase enzymes in the mashing of buckwheat malt. In addition, high D-chiro-inositol concentrations were released from malt to the buckwheat wort. The concerted action of the two phytases significantly increased (19-44%) Zn2+ concentrations in wort. This may be of great importance during mash fermentation by Saccharomyces cerevisiae yeasts. There is a potential to develop technology for buckwheat beer production, which, in addition to being free from gluten, comprises high levels of bioactive myo- and D-chiro-inositols.

An Oviposition Stimulant for a Magnoliaceae-Feeding Swallowtail Butterfly, Graphium doson, from its Primary Host Plant, Michelia compressa.

Chemical examination of plant constituents responsible for oviposition by a Magnoliaceae-feeding butterfly, Graphium doson, was conducted using its major host plant, Michelia compressa. A methanol extract prepared from young leaves of the plant elicited a strong oviposition response from females. The methanolic extract was then separated by solvent partition into three fractions: CHCl3, i-BuOH, and aqueous fractions. Active substance(s) resided in both i-BuOH- and water-soluble fractions. Bioassay-guided further fractionation of the water-soluble substances by means of various chromatographic techniques led to the isolation of an oviposition stimulant. The stimulant was identified as D-(+)-pinitol on the basis of 13C NMR spectra and physicochemical properties. D-(+)-Pinitol singly exhibited a moderate oviposition-stimulatory activity at a dose of 150 µg/cm2. This compound was present also in another host plant, Magnolia grandiflora, in a sufficient amount to induce oviposition behavior of G. doson females. Certain cyclitols including D-(+)-pinitol have been reported to be involved in stimulation of oviposition by some Aristolochiaceae- and Rutaceae-feeding papilionid butterflies. A possible pathway of phytochemical-mediated host shifts in the Papilionidae, in which certain cyclitols could enact important mediators, is discussed in relation to the evolution of cyclitol biosynthesis in plants.

The Application of Dioxygenase-Based Chemoenzymatic Processes to the Total Synthesis of Natural Products.

This Minireview describes the exploitation of certain enzymatically derived, readily accessible, and enantiomerically pure cis-1,2-dihydrocatechols as starting materials in the chemical synthesis of a range of biologically active natural products, most notably sesquiterpenoids and alkaloids.

Design, synthesis and glycosidase inhibition studies of novel triazole fused iminocyclitol-δ-lactams.

Synthesis of novel triazole fused iminocyclitol-δ-lactams is described. The synthetic sequence involves the intermolecular [3 + 2] cycloaddition reaction of five-membered iminocyclitol derived azides with diethylacetylene dicarboxylate followed by intramolecular lactamisation, decarboxylation/reduction and final deprotection. Compound 3 is found to be a selective inhibitor of α-glucosidase from baker's yeast while two other compounds (2 and 4) that possess an additional hydroxymethyl group in the triazole ring are selective against ß-galactosidase from E. coli. Docking studies suggest the significance of the lactam carbonyl group for effective binding of these inhibitors with the active sites through hydrogen bonding.

Pressurized liquid extraction of cyclitols and sugars: optimization of extraction parameters and selective separation.

Cyclitols and sugars were obtained as a mixture from Medicago sativa L., in a comparative study by using maceration, and pressurized liquid extraction, as a modern and green extraction techniques. The influence of extraction parameters including: extraction temperature, time and number of cycles on the content of sugars and cyclitols was investigated based on response surface methodology. The highest total amount of sugars and cyclitols (62.27 ± 2.30 and 50.35 ± 0.77 mg/g of dry material, respectively) was obtained when extraction was performed at 88°C, for 22 min, in two cycles. The methodology used involved extraction, purification, selective separation (using yeast and anion exchange resin) and derivatization, followed by gas chromatography -mass spectrometry analysis. The use of yeast treatment realized an effective fractionation of cyclitols and sugars, which allowed the removal of most sugars. The involvement of anion exchange resin after yeast allowed the removal of sugar alcohols and lactose, together with other sugar traces remained and to obtain a solution containing six cyclitols. The recrystallization of dry residue after solvent evaporation, from ethanol, allowed us to obtain 14.65 mg of white pure crystals identified with NMR spectroscopy, liquid chromatography with mass spectrometry, gas chromatography with mass spectrometry, optical rotation and melting point as analysis D-pinitol.

The Healing-Promoting Properties of Selected Cyclitols-A Review.

INTRODUCTION: Myo-inositol and its derivatives cyclitols play an important role in the processes of cell regulation, signal transduction, osmoregulation, and ion channel physiology, and are a component of the cell membrane. Free cyclitols present in food or released during the degradation of galactosyl cyclitols by bacteria (in digestive tract) show some physiological benefits. AIM: The aim of this paper is to present and analyze the documented data about curative and healing properties of cyclitols. RESULTS AND DISCUSSION: Cyclitols are well known compounds in the treatment of an accompanied diabetes insulin resistance, and also obesity and polycystic ovarian syndrome. d-chiro-Inositol deficiency exacerbates insulin resistance in the liver, muscles, and fat, while depletion of myo-inositol results in the development of diabetic complications. Cyclitols are successfully applied in treatment of polycystic ovarian syndrome, simultaneous are observed effective reducing of BMI, improving the hormonal profile, and increasing fertility. Moreover, cyclitols have anti-atherogenic, anti-oxidative, anti-inflammatory, and anti-cancer properties. CONCLUSION: The properties of cyclitols may be a good therapeutic option in the reduction of metabolically induced inflammation. Due to well drugs tolerance and low toxicity of these compounds, cyclitols are recommend for pregnant women and also for children. Another advantage is their widespread presence and easy availability, which encourages their use in medicine.

Isolation of Nabscessin C from Nocardia abscessus IFM 10029T and a Study on Biosynthetic Pathway for Nabscessins.

A new aminocyclitol derivative, designated nabscessin C (1), was isolated from Nocardia abscessus IFM 10029T. Nabcessin C is an isomer of nabscessins A (2) and B (3) with different positioning of the acyl group. Absolute configuration of nabscessin A was determined by conversion into the 2-deoxy-scyllo-inosamine pentaacetyl derivative (4) by hydrolysis and acetylation of 2. The biosynthetic pathway of nabscessins is proposed based on gene expression analysis.

Forced degradation of l-(+)-bornesitol, a bioactive marker of Hancornia speciosa: Development and validation of stability indicating UHPLC-MS method and effect of degraded products on ACE inhibition.

The antihypertensive activity of the medicinal plant Hancornia speciosa has been previously demonstrated by us, being the activity ascribed to polyphenols and cyclitols like l-(+)-bornesitol. We herein evaluated the stability of the bioactive marker bornesitol submitted to forced degradation conditions. Bornesitol employed in the study was isolated from H. speciosa leaves. An UHPLC-ESI-MS/MS method was developed to investigate bornesitol stability based on MRM (Multiple Reaction Monitoring) acquisition mode and negative ionization mode, employing both specific (m/z 193 → 161 Da) and confirmatory (m/z 193 → 175 Da) transitions. A gradient elution of 0.1% formic acid in water and acetonitrile was performed on a HILIC column. The method was validated and showed adequate linearity (r2 > 0.99), selectivity, specificity, accuracy, and precision (RSD < 2.9%). The method was robust for deliberate variations on dessolvation temperature, but not for changes in the flow rate and dessolvation gas. The results from the stability studies allowed us to classify bornesitol as labile for acidic and alkaline hydrolysis, but as very stable for oxidative and neutral hydrolysis exposure. Bornesitol was categorized as practically stable under photolysis degradation, whereas a considerable reduction on its contents was induced by metal ions and thermolysis exposure. Degraded samples from neutral hydrolysis and thermolysis were assayed in vitro for ACE inhibition and showed a substantial decrease in biological activity as compared to intact bornesitol. myo-Inositol was identified as the major degradation products in both matrices. This is the first report on bornesitol stability under different stress conditions and the obtained data are relevant for the development and quality control of standardized products from H. speciosa leaves.

Evolution and Distribution of C7-Cyclitol Synthases in Prokaryotes and Eukaryotes.

2-Epi-5-epi-valiolone synthase (EEVS), a C7-sugar phosphate cyclase (SPC) homologous to 3-dehydroquinate synthase (DHQS), was discovered during studies of the biosynthesis of the C7N-aminocyclitol family of natural products. EEVS was originally thought to be present only in certain actinomycetes, but analyses of genome sequences showed that it is broadly distributed in both prokaryotes and eukaryotes, including vertebrates. Another SPC, desmethyl-4-deoxygadusol synthase (DDGS), was later discovered as being involved in the biosynthesis of mycosporine-like amino acid sunscreen compounds. Current database annotations are quite unreliable, with many EEVSs reported as DHQS, and most DDGSs reported as EEVS, DHQS, or simply hypothetical proteins. Here, we identify sequence features useful for distinguishing these enzymes, report a crystal structure of a representative DDGS showing the high similarity of the EEVS and DDGS enzymes, identify notable active site differences, and demonstrate the importance of two of these active site residues for catalysis by point mutations. Further, we functionally characterized two representatives of a distinct clade equidistant from known EEVS and known DDGS groups and show them to be authentic EEVSs. Moreover, we document and discuss the distribution of genes that encode EEVS and DDGS in various prokaryotes and eukaryotes, including pathogenic bacteria, plant symbionts, nitrogen-fixing bacteria, myxobacteria, cyanobacteria, fungi, stramenopiles, and animals, suggesting their broad potential biological roles in nature.

Biosynthesis of nitrogen-containing natural products, C7N aminocyclitols and bis-indoles, from actinomycetes.

Actinomycetes are a major source of bioactive natural products with important pharmaceutical properties. Understanding the natural enzymatic assembly of complex small molecules is important for rational metabolic pathway design to produce "artificial" natural products in bacterial cells. This review will highlight current research on the biosynthetic mechanisms of two classes of nitrogen-containing natural products, C7N aminocyclitols and bis-indoles. Validamycin A is a member of C7N aminocyclitol natural products from Streptomyces hygroscopicus. Here, two important biosynthetic steps, pseudoglycosyltranferase-catalyzed C-N bond formation, and C7-sugar phosphate cyclase-catalyzed divergent carbasugar formation, will be reviewed. In addition, the bis-indolic natural products indolocarbazole, staurosporine from Streptomyces sp. TP-A0274, and rearranged bis-indole violacein from Chromobacterium violaceum are reviewed including the oxidative course of the assembly pathway for the bis-indolic scaffold. The identified biosynthesis mechanisms will be useful to generating new biocatalytic tools and bioactive compounds.

Nabscessins A and B, Aminocyclitol Derivatives from Nocardia abscessus IFM 10029T.

Two new aminocyclitol amide derivatives, nabscessins A (1) and B (2), were isolated from the culture broth of a pathogenic actinomycete species, Nocardia abscessus IFM 10029T. The structures of nabscessins A and B were elucidated by spectral studies, and the compounds showed antifungal activity against Cryptococcus neoformans, with IC50 values of 32 and 16 µg/mL, respectively.

Characterization of cyclitol glycosides by gas chromatography coupled to mass spectrometry.

Several cyclitol glycosides have been characterised as trimethylsilyl derivatives by their gas chromatographic (GC) retention data (linear retention indices) and electron impact mass spectrometric (MS) profiles. Both GC-MS results have been related to cyclitol glycosides structural features. Abundance ratios of characteristic m/z ions 133/129 and 260/265 have been proposed to distinguish glycosyl-inositols from glycosyl-methyl-inositols. These ratios in combination with the presence or absence of m/z 375 ion allowed the unequivocal characterization of cyclitol glycosides. These criteria have been applied to the characterization of new cyclitol glycosides in chickpea (Cicer arietinum) and adzuki bean (Vigna angularis) and in leaves of Coriaria myrtifolia and Coriaria ruscifolia.