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.

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.

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.

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.

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.

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.

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.

Five-Membered Cyclitol Phosphate Formation by a myo-Inositol Phosphate Synthase Orthologue in the Biosynthesis of the Carbocyclic Nucleoside Antibiotic Aristeromycin.

Aristeromycin is a unique carbocyclic nucleoside antibiotic produced by Streptomyces citricolor. In order to elucidate its intriguing carbocyclic formation, we used a genome-mining approach to identify the responsible enzyme. In silico screening with known cyclitol synthases involved in primary metabolism, such as myo-inositol-1-phosphate synthase (MIPS) and dehydroqunate synthase (DHQS), identified a unique MIPS orthologue (Ari2) encoded in the genome of S. citricolor. Heterologous expression of the gene cluster containing ari2 with a cosmid vector in Streptomyces albus resulted in the production of aristeromycin, thus indicating that the cloned DNA region (37.5 kb) with 33 open reading frames contains its biosynthetic gene cluster. We verified that Ari2 catalyzes the formation of a novel five-membered cyclitol phosphate from d-fructose 6-phosphate (F6P) with NAD+ as a cofactor. This provides insight into cyclitol phosphate synthase as a member of the MIPS family of enzymes. A biosynthetic pathway to aristeromycin is proposed based on bioinformatics analysis of the gene cluster.

Construction of Optically Active Isotwistanes and Aminocyclitols Using Chiral Cyclohexadiene as a Common Intermediate.

We have developed a new method for synthesizing chiral isotwistane and homoisotwistane skeletons as well as aminocyclitols in a highly stereoselective manner. These results were achieved through the use of a common intermediate, which was derived from the ytterbium-catalyzed asymmetric Diels-Alder reaction of Danishefsky diene.

Synthesis and evaluation of hydroxymethylaminocyclitols as glycosidase inhibitors.

Four series of C7N aminocyclitol analogues of glucose were synthesized by stereocontrolled epoxide opening of hydroxyl protected forms of the cyclohexane epoxides cyclophellitol and 1,6-epi-cyclophellitol. The resulting hydroxymethyl substituted aminocyclitols were tested as glycosidase inhibitors. Cyclitols having an amino group in an α configuration at a position equivalent to the anomeric in the sugar were found to be low micromolar inhibitors of the α-glucosidase from baker's yeast with Ki's near to 2 µM. On the other hand, N-octyl aminocyclitols having the nitrogen substituents in an α or ß configuration were found to be good inhibitors of recombinant ß-glucocerebrosidase with Ki values between 8.3 and 17 µM, and also inhibited lysosomal ß-glucosidase activity in live cells at low-micromolar concentrations. A computational docking study suggests a differential binding among the different series of ß-glucocerebrosidase inhibitors. In agreement with the experimental results, the binding poses obtained indicate that the presence of an alkyl lipid substituent in the inhibitor mimicking one of the lipid chains in the substrate is critical for potency. In contrast, the matching of hydroxymethyl substituents in the aminocyclitols and the parent glucosylceramide does not seem to be strictly necessary for potent inhibition, indicating the risk of simplifying structural analogies in sugar mimetic design.

Total syntheses of five uvacalols: structural validation of uvacalol A, uvacalol B and uvacalol C and disproval of the structures of uvacalol E and uvacalol G.

Uvacalols are novel carbasugars belonging to the family of C7-cyclitols, and are isolated from the roots of the medicinal plant, Uvaria calamistrata. In this study, we report the first syntheses of five uvacalols starting from a cheap and easily available chiral pool starting material, D-mannitol, in their optically pure form. D-Mannitol was converted to the alkene 2 through a series of regioselective and chemoselective transformations by following our previously reported strategies. Alkene 2 was converted to the enal 5 through a series of protective group manipulations. Enal 5 was converted to the diene 6 by the addition of vinyl magnesium bromide. Ring closing metathesis of the diene 6 using Grubbs' second generation catalyst installed the core cyclohexenyl unit. Through several iterative and selective manipulations of various hydroxyl groups, uvacalol A, uvacalol B, uvacalol C, uvacalol E and uvacalol G were synthesized. A comparison of the (1)H NMR and (13)C NMR data of these synthesized molecules with the reported data, revealed that the reported structures of uvacalols A­C are correct and those of uvacalols E and G are wrong.

Regiodivergent addition of phenols to allylic oxides: control of 1,2- and 1,4-additions for cyclitol synthesis.

Control of 1,2- and 1,4-addition of substituted phenols to allylic oxides is achieved by intercepting palladium π-allyl complexes. The interconversion of palladium complexes results in the total synthesis of MK 7607, cyathiformine B type, streptol, and a new cyclitol.

A Convenient Approach to Stereoisomeric Iminocyclitols: Generation of Potent Brain-Permeable OGA Inhibitors.

Pyrrolidine-based iminocyclitols are a promising class of glycosidase inhibitors. Reported herein is a convenient epimerization strategy that provides direct access to a range of stereoisomeric iminocyclitol inhibitors of O-GlcNAcase (OGA), the enzyme responsible for catalyzing removal of O-GlcNAc from nucleocytoplasmic proteins. Structural details regarding the binding of these inhibitors to a bacterial homologue of OGA reveal the basis for potency. These compounds are orally available and permeate into rodent brain to increase O-GlcNAc, and should prove useful tools for studying the role of OGA in health and disease.

Isolation and Total Synthesis of Kirkamide, an Aminocyclitol from an Obligate Leaf Nodule Symbiont.

The new C7N aminocyclitol kirkamide (1) was isolated from leaf nodules of the plant Psychotria kirkii by using a genome-driven (1)H NMR-guided fractionation approach. The structure and absolute configuration were elucidated by HRMS, NMR, and single-crystal X-ray crystallography. An enantioselective total synthesis was developed, which delivered kirkamide (1) on a gram scale in 11 steps and features a Ferrier carbocyclization and a Pd-mediated hydroxymethylation. We propose that kirkamide is synthesized by Candidatus Burkholderia kirkii, the obligate leaf symbiont of Psychotria kirkii. Kirkamide (1) was shown to be toxic to aquatic arthropods and insects, thus suggesting that bacterial secondary metabolites play a protective role in the Psychotria/Burkholderia leaf nodule symbiosis.

Structural and functional characterization of a novel nonglycosidic type I NKT agonist with immunomodulatory properties.

Activation of type I NKT (iNKT) cells by CD1d-presented agonists is a potent immunotherapeutic tool. α-Galactosylceramide (α-GalCer) is the prototypic agonist, but its excessive potency with simultaneous production of both pro- and anti-inflammatory cytokines hampers its potential therapeutic use. In search for novel agonists, we have analyzed the structure and function of HS44, a synthetic aminocyclitolic ceramide analog designed to avoid unrestrained iNKT cell activation. HS44 is a weaker agonist compared with α-GalCer in vitro, although in vivo it induces robust IFN-γ production, and highly reduced but still functional Th2 response. The characteristic cytokine storm produced upon α-GalCer activation was not induced. Consequently, HS44 induced a very efficient iNKT cell-dependent antitumoral response in B16 animal model. In addition, intranasal administration showed the capacity to induce lung inflammation and airway hyperreactivity, a cardinal asthma feature. Thus, HS44 is able to elicit functional Th1 or Th2 responses. Structural studies show that HS44 binds to CD1d with the same conformation as α-GalCer. The TCR binds to HS44 similarly as α-GalCer, but forms less contacts, thus explaining its weaker TCR affinity and, consequently, its weaker recognition by iNKT cells. The ability of this compound to activate an efficient, but not massive, tailored functional immune response makes it an attractive reagent for immune manipulation.