This paper describes the first detailed NMR analysis of the borylated intermediates and target compounds for a small library of pyrrolidine iminosugars of l-gulose absolute stereochemical configuration. The iminosugars were functionalised via N-alkylation to bear a boronate ester or boronic acid groups. The addition of the organic boron pharmacophore allows to further explore the chemical space around and in the active sites, where the boron atom has the capability to make reversible covalent bonds with enzyme nucleophiles and other nucleophiles. We discuss the concurrent complex equilibrium processes of mutarotation and borarotation as studied by NMR.

Drug leads with a high Fsp3 index are more likely to possess desirable properties for progression in the drug development pipeline. This paper describes the first detailed NMR analysis of the borylated intermediate 3-deoxy-3-boronodiethanolamine-1,2:5,6-di-O-isopropylidene-α-d-galactofuranose and of the corresponding free monosaccharide analogue 3-boronic-3-deoxy-d-galactose in the early stage of the concurrent equilibrium processes of mutarotation and borarotation. A discussion of all potential equilibria is also presented alongside a comparison with relevant 11B-NMR data available from the scientific literature and our own library.

Drug leads with a high Fsp3 index are more likely to possess desirable properties for progression in the drug development pipeline. This paper describes the development of an efficient two-step protocol to completely diastereoselectively access a diethanolamine (DEA) boronate ester derivative of monosaccharide d-galactose from the starting material 1,2:5,6-di-O-isopropylidene-α-d-glucofuranose. This intermediate, in turn, is used to access 3-boronic-3deoxy-d-galactose for boron neutron capture therapy (BNCT) applications. The hydroboration/borane trapping protocol was robustly optimized with BH3.THF in 1,4-dioxane, followed by in-situ conversion of the inorganic borane intermediate to the organic boron product by the addition of DEA. This second step occurs instantaneously, with the immediate formation of a white precipitate. This protocol allows expedited and greener access to a new class of BNCT agents with an Fsp3 index = 1 and a desirable toxicity profile. Furthermore, presented is the first detailed NMR analysis of the borylated free monosaccharide target compound during the processes of mutarotation and borarotation.

This review covers the literature in the past 15 years on glycosidase inhibitors lacking a basic nitrogen (for example iminosugars/azasugars) with a focus on natural terpenoids, and mono- and polycyclic aromatic hydrocarbons. From quite diverse structures, insight into inhibitor structural features that may be applicable to optimisation of all glycosidase inhibitors including iminosugars are identified.

Tetrachlorinated phthalimide analogues bearing a boron-pinacolate ester group were synthesised via two synthetic routes and evaluated in their glycosidase modulating and anticancer properties, with a view to use them in boron neutron capture therapy (BNCT), a promising radiation type for cancer, as this therapy does little damage to biological tissue. An unexpected decarbonylation/decarboxylation to five 2,3,4,5-tetrachlorobenzamides was observed and confirmed by X-ray crystallography studies, thus, giving access to a family of borylated 2,3,4,5-tetrachlorobenzamides. Biological evaluation showed the benzamide drugs to possess good to weak potencies (74.7–870 μM) in the inhibition of glycosidases, and to have good to moderate selectivity in the inhibition of a panel of 18 glycosidases. Furthermore, in the inhibition of selected glycosidases, there is a core subset of three animal glycosidases, which is always inhibited (rat intestinal maltase α-glucosidase, bovine liver β-glucosidase and β-galactosidase). This could indicate the involvement of the boron atom in the binding. These glycosidases are targeted for the management of diabetes, viral infections (via a broad-spectrum approach) and lysosomal storage disorders. Assays against cancer cell lines revealed potency in growth inhibition for three molecules, and selectivity for one of these molecules, with the growth of the normal cell line MCF10A not being affected by this compound. One of these molecules showed both potency and selectivity; thus, it is a candidate for further study in this area. This paper provides numerous novel aspects, including expedited access to borylated 2,3,4,5-tetrachlorophthalimides and to 2,3,4,5-tetrachlorobenzamides. The latter constitutes a novel family of glycosidase modulating drugs. Furthermore, a greener synthetic access to such structures is described.

Bicyclic compounds with boron atoms at the bridgehead are a rare but growing class of heterocycles. We have identified several new compounds in this class including B-N isosteres of aromatic compounds that are of interest for their electronic properties. Also, we have covered compounds where a tetrahedral boron atom is the central atom of a spirocyclic system. In some cases, these structures can form transiently when boron acids undergo exchange with diols and related ligands.

A glucose-based vector for targeting cancer cells conjugated to a tris(methylpyridyl)amine (tpa) ligand to generate targeted chaperone and caging complexes for active anticancer agents is described. The ligand, tpa(CONHPEGglucose)1, inhibits hexokinase, suggesting that it will be phosphorylated in the cell. A Co(III) complex incorporating this ligand and coumarin-343 hydroximate (C343ha), [Co(C343ha){tpa(CONHPEGglucose)(1)}]Cl, is shown to exhibit glucose-dependent cellular accumulation in DLD-1 colon cancer cells. Cellular accumulation of [ Co( C343ha){tpa(CONHPEGglucose)(1)}](+) is slower than for the glucose null and glucosamine analogues, and the glucose complex also exhibits a lower ability to inhibit antiproliferative activity. Distributions of cobalt (X-ray fluorescence) and C343ha (visible light fluorescence) in DLD-1 cancer cell spheroids are consistent with uptake of [Co(C343ha){tpa(CONHPEGglucose)(1)}](+) by rapidly dividing cells, followed by release and efflux of C343ha and trapping of the Co{tpa(CONHPEGglucose)(1)} moiety. The Co{tpa(CONHPEGglucose)(1)} moiety is shown to have potential for the caged and targeted delivery of highly toxic anticancer agents.

Three cinnamate derivatives bearing a boronate pinacol ester group para , meta and ortho to the a,b-unsaturated ester group have been synthesized via a solventless, expedited Wittig protocol in the best stereoisomeric ratios yet reported, purified by recrystallization, characterized and analyzed by X-ray crystallography. These are valuable building blocks to biologically active derivatives and are themselves biologically active drug leads, displaying excellent selectivities as glycosidase modulators and for future testing as boron neutron capture therapy (BNCT) agents. In a panel of 15 glycosidases, IC 50 values of 351 mM and 374 mM were shown for para 2 against almond b-glucosidase and bovine liver b-galactosidase, respectively. For meta 2 the selectivity profile is improved with only inhibition of bovine liver b-galactosidase with an IC 50 of 780 mM. These borylated derivatives also possess the capability to be used as BNCT agents. This occurs via irradiation with slow neutrons, thus granting them a switch-on/switch-off toxicity. This is an important new capability imbued into anticancer drugs, too many of which are too toxic in their therapeutic window. BNCT drugs bearing the organic boron pharmacophore have the potential to fine-tune the timing of toxicity delivery.

Ionic liquids (ILs) have many advantageous properties exploited in an increasing number of applications. Crucial to their continued and expanded use is the fine-tuning of IL structures to refine their capability profiles. Organic chemistry can play an important role in providing ILs with more sophisticated properties. In this communication, we provide relevant examples of the use of organic chemistry in the planning and delivery of novel structures and improved capabilities. Here we present three novel ILs characterized by X-ray crystallography resulting from partnering known anions, tetrafluoroborate (BF4−), bis (trifluoromethane) sulfonimide (TFSI−), and bromide (Br−) with novel cations based on three main structural types. The crystallographic analyses reported here highlight intermolecular and supramolecular features particularly the role of van der Waals interactions.

Short syntheses to high Fsp 3 index natural-product analogues such as imino-sugars are of paramount importance in the investigation of their biological activities and reducing the use of protecting groups is an advantageous synthetic strategy. An iso-propyl-idene group was employed towards the synthesis of seven-membered ring imino-sugars and the title compound, C9H15N3O5, was crystallized as an inter-mediate, in which the THF ring is twisted and the dioxolane ring adopts an envelope conformation: the dihedral angle between the rings is 67.50 (13)°. In the crystal, the hydroxyl groups participate in O-H⋯(O,O) and O-H⋯N hydrogen-bonding inter-actions, which generate chains of mol-ecules propagating parallel to the a-axis direction. There is a notable non-classical C-H⋯O hydrogen bond, which cross-links the [100] chains into (001) sheets.

Twelve tin(IV) compounds (5-16) derived from four tridentate thiosemicarbazone Schiff bases of 4-methyl-3-thiosemicarbazide with 2-hydroxy-3-methoxybenzaldehyde (1, 2) and 4-phenyl-3-thiosemicarbazide with 2,3 dihydroxybenzaldehyde (3, 4) of the general formulae [R2Sn(L-n)] and [Sn(L-n)(2)] (where R = Ph or Me; L-n = 1, 2, 3 and 4) were synthesized and characterized by elemental analysis, IR, UV-vis, mass spectrometry and multinuclear NMR (H-1, C-13 and Sn-119) spectroscopy. X-ray crystallographic data was obtained for 11', a 2:1 co-crystal between Ph2Sn(L-2) (11) and 3-methoxysalicylaldehyde azine, and Me2Sn(L-2) (12) where (LH2)-H-2 is 2-(2-hydroxy-3-methoxybenzylidene)-N-phenylhydrazinecarbothioamide. The analysis revealed distinct coordination geometries for 11 and 12 approaching trigonal-bipyramidal. In the crystal of 11', supramolecular dimers arising from amine-N-H center dot center dot center dot S(thiolate) hydrogen bonding and {center dot center dot center dot HNCS}(2) synthons are evident; pi(chelate ring)center dot center dot center dot pi(oxidobenzylidene) stacking is also apparent. In the crystal of 12, supramolecular, helical chains are generated by a combination of amine-N-H center dot center dot center dot O(phenoxide) hydrogen bonding and Sn S secondary bonding. The cytotoxic activity of the compounds against a panel of ten cancer cell lines, [HT29 (colon), U87 and SJ-G2 (glioblastoma), MCF-7 (breast), A2780 (ovarian), H460 (lung), A431 (skin), DU145 (prostate), BE2-C (neuroblastoma) and MIA (pancreas), and one normal cell line, MCF-10A (normal breast)] were investigated. The thiosemicarbazone Schiff bases 1 and 4 as well as the diphenyltin(IV) compounds showed a strong ability to inhibit the growth of cancer cells, with particular selectivity against HT29, MCF-7, A2780, A431, BE2-C, SJ-G2 and MIA cell lines. The structure-activity relationship of all these compounds were studied by evaluating the effect of alkyl and aryl groups attached on the thiosemicarbazone backbone, the methoxy/hydroxyl groups present at the meta-position of the phenyl ring and alkyl or aryl groups bound to the tin center. (C) 2020 Elsevier Ltd. All rights reserved.

Ionic liquids (ILs) have advantageous physical properties, which resulted in a rapid growth of research in this area in the past 15 years. One of the biggest challenges preventing the widespread use of ILs is the cost of production due to complex synthetic routes and/or expensive starting materials. Keeping in mind these industrial needs for scale-up and the desirable properties for applications in the lubrification area, here, we report the design and synthesis of four novel series of hydrophobic room-temperature ILs (RTILs) achieved from cheap and commercially available starting materials, namely, silicon-based, imidazolium-based, phosphonium-based, and monomer imidazolium-based. These syntheses were developed as expedited chemistry protocols and possess a greener synthetic profile compared to previously reported ILs of similar structures. All the RTILs were characterized by 1D NMR (1H NMR, 13C NMR, 31P NMR, 19F NMR, and 11B NMR) and 2D NMR (COSY, HSQC, and HMBC) analyses, high-resolution mass spectrometry, and chemical tests (primarily the silver nitrate test). Preliminary thermal analysis tests by thermogravimetric analysis show all novel RTILs display remarkably high thermal stabilities (386–474 °C). Differential scanning calorimetry data show low glass transitions ranging from −36 to −72 °C, which suggests good free volume and ion mobility.

Short syntheses to high Fsp3 index natural-product analogues such as imino­sugars are of paramount importance in the investigation of their biological activities and reducing the use of protecting groups is an advantageous synthetic strategy. An iso­propyl­idene group was employed towards the synthesis of seven-membered ring imino­sugars and the title compound, C9H15N3O5, was crystallized as an inter­mediate, in which the THF ring is twisted and the dioxolane ring adopts an envelope conformation: the dihedral angle between the rings is 67.50 (13)°. In the crystal, the hydroxyl groups participate in O—H⋯(O,O) and O—H⋯N hydrogen-bonding inter­actions, which generate chains of mol­ecules propagating parallel to the a-axis direction. There is a notable non-classical C—H⋯O hydrogen bond, which cross-links the [100] chains into (001) sheets.

Short syntheses to high Fsp3 index natural-product analogues such as iminosugars are of paramount importance in the investigation of their biological activities and reducing the use of protecting groups is an advantageous synthetic strategy. An isopropylidene group was employed towards the synthesis of seven-membered ring iminosugars and the title compound, C9H15N3O5, was crystallized as an intermediate, in which the THF ring is twisted and the dioxolane ring adopts an envelope conformation: the dihedral angle between the rings is 67.50 (13)°. In the crystal, the hydroxyl groups participate in O—H...(O,O) and O—H...N hydrogen-bonding interactions, which generate chains of molecules propagating parallel to the a-axis direction. There is a notable non-classical C—H...O hydrogen bond, which cross-links the [100] chains into (001) sheets.

Glycoconjugation to target the Warburg effect provides the potential to enhance selective uptake of anticancer or imaging agents by cancer cells. A Warburg effect targeting group, rationally designed to facilitate uptake by glucose transporters and promote cellular accumulation due to phosphorylation by hexokinase (HK), has been synthesised. This targeting group, the C2 modified glucose analogue 2-(2-[2-(2-aminoethoxy)ethoxy]ethoxy)-D-glucose, has been conjugated to the fluorophore nitrobenzoxadiazole to evaluate its effect on uptake and accumulation in cancer cells. The targeting vector has demonstrated inhibition of glucose phosphorylation by HK, indicating its interaction with the enzyme and thereby confirming the potential to facilitate an intracellular trapping mechanism for compounds it is conjugated with. The cellular uptake of the fluorescent analogue is dependent on the glucose concentration and is so to a greater extent than is that of the widely used fluorescent glucose analogue, 2-NBDG. It also demonstrates selective uptake in the hypoxic regions of 3D spheroid tumour models whereas 2-NBDG is distributed primarily through the normoxic regions of the spheroid. The increased selectivity is consistent with the blocking of alternative uptake pathways.

Six new organotin(IV) compounds of Schiff bases derived from S-R-dithiocarbazate [R = benzyl (B), 2- or 4-methylbenzyl (2M and 4M, respectively)] condensed with 2-hydroxy-3-methoxybenzaldehyde (oVa) were synthesised and characterised by elemental analysis, various spectroscopic techniques including infrared, UV-vis, multinuclear (1H, 13C, 119Sn) NMR and mass spectrometry, and single crystal X-ray diffraction. The organotin(IV) compounds were synthesised from the reaction of Ph2SnCl2 or Me2SnCl2 with the Schiff bases (S2MoVaH/S4MoVaH/SBoVaH) to form a total of six new organotin(IV) compounds that had a general formula of [R2Sn(L)] (where L = Schiff base; R = Ph or Me). The molecular geometries of Me2Sn(S2MoVa), Me2Sn(S4MoVa) and Me2Sn(SBoVa) were established by X-ray crystallography and verified using density functional theory calculations. Interestingly, each experimental structure contained two independent but chemically similar molecules in the crystallographic asymmetric unit. The coordination geometry for each molecule was defined by thiolate-sulphur, phenoxide-oxygen and imine-nitrogen atoms derived from a dinegative, tridentate dithiocarbazate ligand with the remaining positions occupied by the methyl-carbon atoms of the organo groups. In each case, the resulting five-coordinate C2NOS geometry was almost exactly intermediate between ideal trigonal-bipyramidal and square-pyramidal geometries. The cytotoxic activities of the Schiff bases and organotin(IV) compounds were investigated against EJ-28 and RT-112 (bladder), HT29 (colon), U87 and SJ-G2 (glioblastoma), MCF-7 (breast) A2780 (ovarian), H460 (lung), A431 (skin), DU145 (prostate), BE2-C (neuroblastoma) and MIA (pancreatic) cancer cell lines and one normal breast cell line (MCF-10A). Diphenyltin(IV) compounds exhibited greater potency than either the Schiff bases or the respective dimethyltin(IV) compounds. Mechanistic studies on the action of these compounds against bladder cancer cells revealed that they induced the production of reactive oxygen species (ROS). The bladder cancer cells were apoptotic after 24 h post-treatment with the diphenyltin(IV) compounds. The interactions of the organotin(IV) compounds with calf thymus DNA (CT-DNA) were experimentally explored using UV-vis absorption spectroscopy. This study revealed that the organotin(IV) compounds have strong DNA binding affinity, verified via molecular docking simulations, which suggests that these organotin(IV) compounds interact with DNA via groove-binding interactions.

Amidine synthesis by amine addition to nitriles normally requires high temperatures or harsh catalysts. Here, we report that boronate esters can facilitate amidination of proximal amines with moderate heating. With amidines present in a number of drugs and the synthetic handle provided by the boron, this chemistry should find useful applications.

The effect of different leaving groups on the substitution versus elimination outcomes with C-5 d-glucose derivatives was investigated. The stereochemical configurations of 3-O-benzyl-1,2-O-iso-propyl-idene-5-O-methane-sulfonyl-6-O-tri-phenyl-methyl-α-d-gluco-furan-ose, C36H38O8S (3) [systematic name: 1-[(3aR,5R,6S,6aR)-6-benz-yloxy-2,2-di-methyl-tetra-hydro-furo[2,3-d][1,3]dioxol-5-yl)-2-(trit-yloxy)ethyl methane-sulfonate], a stable inter-mediate, and 5-azido-3-O-benzyl-5-de-oxy-1,2-O-iso-propyl-idene-6-O-tri-phenyl-methyl-β-l-ido-furan-ose, C35H35N3O5 (4) [systematic name: (3aR,5S,6S,6aR)-5-[1-azido-2-(trit-yloxy)eth-yl]-6-benz-yloxy-2,2-di-methyl-tetra-hydro-furo[2,3-d][1,3]dioxole], a substitution product, were examined and the inversion of configuration for the azido group on C-5 in 4 was confirmed. The absolute structures of the mol-ecules in the crystals of both compounds were confirmed by resonant scattering. In the crystal of 3, neighbouring mol-ecules are linked by C-H⋯O hydrogen bonds, forming chains along the b-axis direction. The chains are linked by C-H⋯π inter-actions, forming layers parallel to the ab plane. In the crystal of 4, mol-ecules are also linked by C-H⋯O hydrogen bonds, forming this time helices along the a-axis direction. The helices are linked by a number of C-H⋯π inter-actions, forming a supra-molecular framework.

A light-yellow crystalline product (1), which was isolated after one week from the filtrate of the reaction between S-2-methylbenzyldithiocarbazate and 2,3-dihydroxybenzaldehyde, was characterised by single crystal X-ray diffraction, FIR and NMR spectroscopic analyses. The experimental molecular structure of 1 has been established by X-ray crystallography and showed, to a first approximation, a planar C2N2S2 + dihydroxyphenyl region that has an almost orthogonal relationship to the rings of the pendant S-bound benzyl groups. This structure has been verified via density functional theory calculations using the B3LYP/6311G(d,p) level of theory. The molecular packing featured linear supramolecular chains along the b-axis sustained by tolyl-C-H (center dot center dot center dot) N(imine) and tolyl-C-H (center dot center dot center dot) pi(tolyl) interactions; the importance of these contacts is indicated by a Hirshfeld surface analysis. (C) 2018 Elsevier B.V. All rights reserved.