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A novel class of spiroimidazolidine-2',4'-diones substituted with aryl sulfonyl group at different positions was designed and synthesized. The target compounds were evaluated for their potential to release insulin from MIN6 cell line derived from in-vivo immortalized insulin-secreting pancreatic cells. The MIN6 cells represent an important model of beta cells, which as passage numbers increases, lose the first phase but retain partial second phase glucose stimulated insulin secretion (GSIS), similar to patients in early type 2 diabetes onset. Some of the compounds exhibited high potency. Compound 2d and 3f exhibited excellent insulin release activity from MIN6 cells when compared with standard drug, tolbutamide. Some of these compounds had a potent inhibitory activity for human recombinant aldose reductase (ALR2), an enzyme which converts glucose into sorbitol and plays a key role in development of complications arising from diabetes, such as retinopathy, nephropathy, neuropathy and cataract formation. Against human recombinant ALR2, compounds 2a, 3a-d, and 3f-h displayed effective inhibition activities. The results were augmented by the ability of the compounds to prevent sorbitol accumulation in the isolated rat lenses, sciatic nerves and erythrocytes. Some of the compounds were found to possess excellent dual activity, hence they may be promising candidates to modify and evaluate their dual action, i.e., insulin release to combat diabetes and ALR2 inhibition to prevent/treat diabetic complications. The compounds were also found to possess good antioxidant efficacy. Furthermore, most of the compounds lack toxicity as determined on human embryonic kidney cell lines 293 (HEK293)., (Copyright © 2019. Published by Elsevier Masson SAS.)

Addition of 1-alkyl-3-methylimidazolium (C(n)-mim) cations 3-5 to a mixture of bis-phosphonium cation 2 and sodium p-sulfonatocalix[4]arene (1) in the presence of lanthanide ions results in the selective binding of an imidazolium cation into the cavity of the calixarene. The result is a multi-layered solid material with an inherently flexible interplay of the components. Incorporating ethyl-, n-butyl- or n-hexyl-mim cations into the multi-layers results in significant perturbation of the structure, the most striking effect is the tilting of the plane of the bowl-shaped calixarene relative to the plane of the multi-layer, with tilt angles of 7.2, 28.9 and 65.5 degrees , respectively. The lanthanide ions facilitate complexation, but are not incorporated into the structures and, in all cases, the calixarene takes on a 5- charge, with one of the lower-rim phenolic groups deprotonated. ROESY NMR experiments and other (1)H NMR spectroscopy studies establish the formation of 1:1 supermolecules of C(n)-mim and calixarene, regardless of the ratio of the two components, and indicate that the supermolecules undergo rapid exchange on the NMR spectroscopy timescale.

Four ternary multi-component crystal structures comprising water-soluble p-sulfonatocalix[4]arene anion as the cavitand in the presence of different types of positively charged guest molecules comprising 1-butylimidazolium, 3,3′-(1,4-phenylenebis(methylene))bis(1-methylimidazolium), 3,3′,3′′-(benzene-1,3,5-triyltris(methylene))tris(1-methylimidazolium), or 3,3′,3′′,3′′′-(benzene-1,2,4,5-tetrayltetrakis(methylene))tetrakis(1-methylimidazolium) and aquated lanthanide(III) ions (Gd(III) or Ce(III)) are reported. Careful crystallographic analysis shows that all positively charged imidazole rings are encapsulated by p-sulfonatocalix[4]arene for 1-butylimidazolium and 3,3′-(1,4-phenylenebis(methylene))bis(1-methylimidazolium), however, partial encapsulation was observed for 3,3′,3′′-(benzene-1,3,5-triyltris(methylene))tris(1-methylimidazolium) and 3,3′,3′′,3′′′-(benzene-1,2,4,5-tetrayltetrakis(methylene))tetrakis(1-methylimidazolium). The formation of a molecular capsule prevails in all structures regardless of the type of guest species. Supermolecules in three of the complexes self-assemble into a bilayer arrangement in the extended structure, whilst those involving p-sulfonatocalix[4]arene and 1-butylimidazolium form hydrated channels through alternative packing. [ABSTRACT FROM AUTHOR]

A molecular capsule based on two p-sulfonated calix[4]arenes along with Gd(iii) coordination spheres arranged around the equator of the capsule effectively confined a 1-butyl-3-methylimidazolium cation, affording a relatively small capsule size. For a bis-imidazolium cation, only one of the imidazole rings is included in the calixarene cavity with the other ring extending towards a sulfonate group of an adjacent calixarene. Thus, the included molecule breaches the equatorial seam of the larger capsule, but here there is no incorporation of Gd(iii). In both complexes the capsules themselves are arranged such that the calixarenes are in bilayer arrangements, with (3-methoxyphenyl)triphenylphosphonium cations at the interface of the hydroxyl groups of the calixarene. The interplay of the components was also investigated using Hirshfeld surface analysis. [ABSTRACT FROM AUTHOR]

Long flexible bis-imidazolium dications form discrete multi-component complexes with anionic p-sulfonatocalix[4]arene, cationic tetraphenylphosphonium, and hydrated lanthanide ions (La3+ and Gd3+). The terminally charged head groups of the dications reside in either one or two calixarene cavities of different bilayers depending on the length of the terminal alkyl group with the central spacer penetrating across the multi-layers and adjusted to fit in the tight bilayer. [ABSTRACT FROM AUTHOR]

Multi-component self-assembly involving bis-phosphonium and bis-imidazolium cations, and p-sulfonatocalix[4]arene feature supermolecules based on two geometrically opposed calixarenes end-capping each bis-imidazolium cation, either with coordinated lanthanide cations or with the phosphonium cations residing around the upper rim of the calixarenes. The nature of the calixarene-bis-imidazolium interaction is mapped out using Hirshfeld surface analysis. 1H NMR and ROESY experiments establish the formation of the supermolecules of the bis-imidazolium cation and calixarenes in solution. [ABSTRACT FROM AUTHOR]

p-Sulfonatocalix[5]arene forms host–guest complexes in the solid state with hydroxyl-functionalized imidazolium and bis-imidazolium cations, also involving gadolinium(III) ions which form a coordination polymer through the sulfonate groups of the calixarene. The interplay of the components have been investigated using Hirshfeld surface analysis, with the nature of the species in aqueous solution in the absence of the paramagnetic lanthanide ions studied using 1H NMR and modeled using molecular simulations. p-Sulfonatocalix[5]arene forms host−guest complexes in the solid state with 3-(2-hydroxyethyl)-1-methylimidazolium and 1,1′-[1,4-phenylenebis(methylene)]bis(3-butyl-1H-imidazolium-1-yl) cations, along with gadolinium(III) ions which form a coordination polymer through the sulfonate groups. [ABSTRACT FROM AUTHOR]