Under the Influence of Water: Molecular Recognition of Organic Hydrophilic Molecules in Water with a Prismarene Host Driven by Hydration Effects.

A water-soluble prism[5]arene host can form endo-cavity complexes with hydrophilic organic substances in water by displacing frustrated water molecules from its deep cavity. Water molecules structured at both rims of the prismarene host can mediate hydrogen bonding interactions with the guest. Water-mediated hydrogen bonding interactions were invoked here to elucidate the elevated binding affinities and selectivity of the prismarene host toward hydrophilic organic guests. We show that water at the interface of a host-guest complex can act as an extension of the host structure, facilitating the accommodation of neutral guests within the binding site. This study highlights the crucial role of water in facilitating supramolecular interactions between a deep-cavity prismarene host and organic hydrophilic guests in aqueous medium.

Chirality Sensing of Cryptochiral Guests with Prism[n]arenes.

Optical chirality sensing has gained significant attention in recent years. Within this field, the quest for stereodynamic chiroptical probes capable of detecting cryptochiral guests presents a formidable challenge. Macrocycles exhibiting planar chirality have emerged as promising candidates for amplifying the chirality of cryptochiral guests. In this study, we demonstrate that the formation of host-guest complexes between cryptochiral molecules and planar chiral prismarenes triggers electronic circular dichroism (ECD) signals via host-guest complexation-induced chirality amplification. The absolute configuration of the most stable chiral macrocyclic host-guest complex has been established by resorting to both exciton model and DFT computations. Furthermore, we demonstrated that this supramolecular chirality sensing system can be employed to determine the enantiomeric composition of scalemic mixtures by measuring the ECD bands intensity. The information described here opens the way for the use of prismarenes as stereodynamic probes for sensing of cryptochiral guests.

The Resorcinarene Hexameric Capsule as a Supramolecular Photoacid to Trigger Olefin Hydroarylation in Confined Space.

The self-assembled resorcinarene capsule C6 shows remarkable photoacidity upon light irradiation, which is here exploited to catalyze olefin hydroarylation reactions in confined space. An experimental pKa* value range of -3.3--2.8 was estimated for the photo-excited hexameric capsule C6*, and consequently an increase in acidity of 8.8 log units was observed with respect to its ground state (pKa=5.5-6.0). This makes the hexameric capsule the first example of a self-assembled supramolecular photoacid. The photoacid C6* can catalyze hydroarylation reaction of olefins with aromatic substrates inside its cavity, while no reaction occurred between them in the absence of irradiation and/or capsule. DFT calculations corroborated a mechanism in which the photoacidity of C6* plays a crucial role in the protonation step of the aromatic substrate. A further proton transfer to olefin with a concomitant C-C bond formation and a final deprotonation step lead to product releasing.

Hexahexyloxycalix[6]arene, a Conformationally Adaptive Host for the Complexation of Linear and Branched Alkylammonium Guests.

Hexahexyloxycalix[6]arene 2b leads to the endo-cavity complexation of linear and branched alkylammonium guests showing a conformational adaptive behavior in CDCl3 solution. Linear n-pentylammonium guest 6a+ induces the cone conformation of 2b at the expense of the 1,2,3-alternate, which is the most abundant conformer of 2b in the absence of a guest. In a different way, branched alkylammonium guests, such as tert-butylammonium 6b+ and isopropylammonium 6c+, select the 1,2,3-alternate as the favored 2b conformation (6b+/6c+⊂2b1,2,3-alt), but other complexes in which 2b adopts different conformations, namely, 6b+/6c+⊂2bcone, 6b+/6c+⊂2bpaco, and 6b+/6c+⊂2b1,2-alt, have also been revealed. Binding constant values determined via NMR experiments indicated that the 1,2,3-alternate was the best-fitting 2b conformation for the complexation of branched alkylammonium guests, followed by cone > paco > 1,2-alt. Our NCI and NBO calculations suggest that the H-bonding interactions (+N-H···O) between the ammonium group of the guest and the oxygen atoms of calixarene 2b are the main determinants of the stability order of the four complexes. These interactions are weakened by increasing the guest steric encumbrance, thus leading to a lower binding affinity. Two stabilizing H-bonds are possible with the 1,2,3-alt- and cone-2b conformations, whereas only one H-bond is possible with the other paco- and 1,2-alt-2b stereoisomers.

Size-age population structure of an endangered and anthropogenically introgressed northern Adriatic population of marble trout (Salmo marmoratus Cuv.): insights for its conservation and sustainable exploitation.

Salmonid species are main actors in the Italian socio-ecological landscape of inland fisheries. We present novel data on the size-age structure of one of the remnant Italian populations of the critically endangered marble trout Salmo marmoratus, which co-occurs with other stocked non-native salmonids in a large glacial river of the Lake Maggiore basin (Northern Italy-Southern Switzerland). Like other Italian native trout populations, the Toce River marble trout population is affected by anthropogenic introgression with the non-native brown trout S. trutta. Our sample includes 579 individuals, mainly collected in the Toce River main channel. We estimated the length-weight relationship, described the population size-age structure, estimated the age-specific growth trajectories, and fit an exponential mortality model. A subset of the sample was also used to measure numerical and biomass density. The estimated asymptotic maximum length is ~105 cm total length (TL). Mean length at first maturity is ~55 cm TL, and mean length at maximum yield per recruit is ~68 cm TL. Approximately 45-70% of the population are estimated to die annually, along with a fishing annual mortality of ~37%, with an exploitation ratio of ~0.5. The frequency distribution of length classes in a sample collected by angling shows that ~80% of the individuals that could be retained according to the current recreational fishing regulations likely never reproduced, and large fish disproportionally contributing to recruitment are fished and retained. We identify possible overfishing risks posed by present regulations, and propose updated harvest-slot length limits to mitigate such risks. More detailed and long-term datasets on this system are needed to more specifically inform the fishery management and monitor the effects of any change in the management strategy on the size-age structure of the marble trout population of the Toce River.

Confused-Prism[5]arene: a Conformationally Adaptive Host by Stereoselective Opening of the 1,4-Bridged Naphthalene Flap.

The confused-prism[5]arene macrocycle (c-PrS[5]Me ) shows conformational adaptive behavior in the presence of ammonium guests. Upon guest inclusion, the 1,4-bridged naphthalene flap reverses its planar chirality from pS to pR (with reference to the pS(pR)4 enantiomer). Stereoselective directional threading is also observed in the presence of directional axles, in which up/down stereoisomers of homochiral (pR)5 -c-PrS[5]Me pseudorotaxanes are formed.

Carbocation catalysis in confined space: activation of trityl chloride inside the hexameric resorcinarene capsule.

Carbocation catalysis can be performed inside the confined space of the hexameric resorcinarene capsule. The inner cavity of the capsule can host the trityl carbocation, which catalyses the Diels-Alder reaction between dienes and unsaturated aldehydes. Experimental results and in silico calculations show that the hexameric resorcinarene capsule C6 can promote the formation of the trityl carbocation from trityl chloride through the cleavage of the carbon-halogen bond promoted by OH⋯X- hydrogen bonding. Here it is shown that the combination of the nanoconfined space and the latent carbocation catalysis provides a convenient complementary strategy for the typical carbocation catalysis. The latent strategy bypasses the typical pitfalls associated with active carbocations and provides control of the reaction efficiency in terms of reaction rate, conversion, and selectivity.

Molecular Recognition in an Aqueous Medium Using Water-Soluble Prismarene Hosts.

The synthesis of water-soluble prism[n]arenes (n = 5 and 6) bearing anionic carboxylato groups on the rims is described. The binding properties of this novel class of water-soluble hosts are studied by nuclear magnetic resonance and calorimetry. The complexation of singly and doubly charged ammonium guests with the more rigid pentamer is enthalpically driven by secondary interactions, while the thermodynamic fingerprint for the larger hexamer reveals driving forces that strongly depend on the guest charge and/or size.

Neoadjuvant Chemotherapy Followed by Radical Surgery versus Concurrent Chemo-Radiotherapy in the Treatment of Locally Advanced Cervical Cancer: A Multicenter Retrospective Analysis.

OBJECTIVES: This study aims to evaluate oncological outcomes in women affected by locally advanced cervical cancer (LACC) treated by neoadjuvant chemotherapy before radical surgery (NACT + RS) or concurrent chemo-radiotherapy (CCRT). METHODS: This was a multicenter retrospective analysis of data related to women with LACC (FIGO stage IB2-IVA), who were treated by NACT + RS or CCRT between November 2006 and January 2018. The first endpoints were the evaluation of disease-free survival (DFS) and overall survival (OS); univariate and multivariate analyses were performed for identifying the prognostic factors independently associated with these oncological outcomes. RESULTS: Overall, 106 women were included in the analysis; 55 of them (51.9%) underwent NACT + RS and 51 (48.1%) CCRT, respectively. Patients in the NACT + RS group had a significant better five-year DFS and five-year OS than those in the CCRT group (77.4% vs. 33.4%, p < .001 and 93.8% vs. 56.5%, p = .003). In the multivariate analyses, treatment choice (NACT + RS or CCRT) was the only independent prognostic factor for predicting both DFS (HR = 3.954; 95 CI = 1.898-8.236; p < 0.001) and OS (HR = 5.330; 95 CI = 1.563-18.178; p = 0.008). CONCLUSIONS: This retrospective study demonstrated an improved survival outcome for patients undergoing NACT + RS compared with those undergoing CCRT. Our findings seem to support the use of NACT before RS as an effective alternative option to CCRT standard therapy.

Unusual Calixarenes Incorporating Chromene and Benzofuran Moieties Obtained via Propargyl Claisen Rearrangement.

Monopropargyloxy-tripropoxy-calix[4]arene 1 was subjected to a propargyl Claisen rearrangement to give unusual calix[3]arene[1]chromene and homocalix[3]arene[1]benzofuran macrocycles. Quantum mechanical density functional theory calculations indicated that an initial [3,3] sigmatropic reaction affords a highly reactive allene intermediate, stabilized by two main diradical pathways leading to six- and five-membered oxygenated rings. In the presence of a n-butylammonium guest, calix[3]arene[1]chromane 6 forms two stereoisomeric complexes stabilized by +N-H···O and cation···π interactions.

per-Hydroxylated Prism[n]arenes: Supramolecularly Assisted Demethylation of Methoxy-Prism[5]arene.

Methoxy-prism[5]arene PrS[5]Me is demethylated by a supramolecularly assisted reaction. In the presence of a tetramethylammonium cation, PrS[5]Me is demethylated by BBr3 in high yield, while in its absence a 55/40 mixture of PrS[5]OH/PrS[6]OH is formed. The dealkylation of prismarenes, such as PrS[6]R (R = Et, nPr) and c-PrS[5]Me, can be easily obtained in high yields in the presence of BBr3.

Chromogenic Properties of p-Pyridinium- and p-Viologen-Calixarenes and Their Cation-Sensing Abilities.

The synthesis of calix[4]- and -[6]arene derivatives P6(H)22+·(Cl-)2, V4(H)24+·(Cl-)2·(I-)2, and V6(H)24+·(Cl-)2·(I-)2 bearing N-linked pyridinium (P) and viologen (V) units at the upper rim is described here. A rare example of an anionic conformational template is reported for p-pyridiniumcalix[6]arene P6(H)22+, which adopts a 1,3,5-alternate conformation in the presence of chloride anions. Derivatives P6(H)22+·(Cl-)2, V6(H)24+·(Cl-)2·(I-)2, and V4(H)24+·(Cl-)2·(I-)2 show a negative solvatochromism, while their UV-vis acid-base titration evidenced that upon addition of a base, new bands appear at 487, 583, and 686 nm, respectively, due to the formation of betainic monodeprotonated species P6(H)1+, V6(H)13+, and V4(H)13+. These new bands were attributable to the intramolecular charge-transfer (CT) transition from the phenoxide to the pyridinium or viologen moiety and were responsive to the presence of cations. In fact, the band at 487 nm of P6(H)1+ was quenched in the presence of a hard Li+ cation, and the color of its acetonitrile solution was changed from pink to colorless upon addition of LiI. Consequently, this derivative can be considered as a useful host for the recognition and sensing of lithium cations.

Efficacy and safety of prolonged-release hyaluronic acid derivative vaginal application in the postpartum period: a prospective randomised clinical trial.

INTRODUCTION: In puerperium, the hypoestrogenic state induced by delivery and subsequently sustained by lactation may lead to vaginal dryness, burning, and itching sensation, contributing to the onset of sexual dysfunction. MATERIAL AND METHODS: This was a prospective, randomized, controlled, open-label study (NCT04560283) for evaluating the effects of application of a prolonged-release hyaluronic acid derivative vaginal gel in restoring sexual function during the postpartum period. Eighty-five patients were randomized to apply prolonged-release Hydeal-D 0.2% vaginal gel (Fidia Farmaceutici, Abano Terme, Italy; n = 43) every three days for 12 consecutive weeks or expectant management (n = 42). RESULTS: Women undergoing treatment had a more elevate increase in Female Sexual Function Index (FSFI) total score (+15.1 ± 11.9 vs +6.5 ± 8.9, p < 0.001) and a higher decrease in vaginal pH (-1.2 ± 0.7 vs -0.2 ± 1.1; p < 0.001). Moreover, the proportion of vaginal smears with maturation index (VMI) >65 was significantly higher in patients treated (80.6% vs 35.3%; p = 0.004). Edinburgh Postnatal Depression Scale (EPDS) decreased significantly in both groups with no inter-group difference (p = 0.459). Only two cases (4.8%) of moderate vaginal burning sensation were reported in patients undergoing local vaginal therapy. CONCLUSIONS: The results of our study demonstrated that hyaluronic acid derivative vaginal gel (Hydeal-D) was able to improve sexual function of puerperal women in the short-term treatment.KEY MESSAGEIn the puerperium, the hypoestrogenic state induced by delivery and subsequently sustained by lactation may lead to vaginal dryness, burning, and itching sensation, contributing to the onset of sexual dysfunction.Hydeal-D is a prolonged-release hyaluronic acid derivative characterised by elevated resistance to enzymatic breakdown. During puerperium, its local application may improve the vaginal microenvironment by ensuring a better migration and proliferation of cells involved in local tissue repair.Among puerperal women, Hydeal-D vaginal gel causes a significant improvement of sexual function, including desire, arousal, and lubrification, compared to expectant management. Furthermore, it leads to a decrease in vaginal pH and an increase of the trophic status of vaginal epithelium.

An intramolecularly self-templated synthesis of macrocycles: self-filling effects on the formation of prismarenes.

Ethyl- and propyl-prism[6]arenes are obtained in high yields and in short reaction times, independent of the nature and size of the solvent, in the cyclization of 2,6-dialkoxynaphthalene with paraformaldehyde. PrS[6]Et or PrS[6]nPr adopt, both in solution and in the solid state, a folded cuboid-shaped conformation, in which four inward oriented alkyl chains fill the cavity of the macrocycle. On these bases, we proposed that the cyclization of PrS[6]Et or PrS[6]nPr occurs through an intramolecular thermodynamic self-templating effect. In other words, the self-filling of the internal cavity of PrS[6]Et or PrS[6]nPr stabilizes their cuboid structure, driving the equilibrium toward their formation. Molecular recognition studies, both in solution and in the solid state, show that the introduction of guests into the macrocycle cavity forces the cuboid scaffold to open, through an induced-fit mechanism. An analogous conformational change from a closed to an open state occurs during the endo-cavity complexation process of the pentamer, PrS[5]. These results represent a rare example of a thermodynamically controlled cyclization process driven through an intramolecular self-template effect, which could be exploited in the synthesis of novel macrocycles.

Poly(Ethylene Glycol)/ß-Cyclodextrin Pseudorotaxane Complexes as Sustainable Dispersing and Retarding Materials in a Cement-Based Mortar.

Pseudorotaxane complexes between ß-CD and mPEG derivatives bearing a carboxylic acid function (mPEG-COOH) were synthesized and investigated for their dispersing properties in a cement-based mortar. The formation of mPEG-COOH derivatives and their pseudorotaxanes was investigated by 1D nuclear magnetic resonance, diffusion ordered spectroscopy, and thermogravimetric analysis experiments. Mortar tests clearly indicate that mPEG-COOH@ß-CD-interpenetrated supramolecules show excellent dispersing abilities. In addition, the supramolecular complexes show a retarding effect, analogously to other known ß-CD-based superplasticizers in which the ß-CD is covalently grafted on a polymeric backbone.

Study on the Influence of Chirality in the Threading of Calix[6]arene Hosts with Dialkylammonium Axles.

: The influence of chirality in calixarene threading has been studied by exploiting the "superweak anion approach". In particular, the formation of chiral pseudo[2]rotaxanes bearing a classical stereogenic center in their axle and/or wheel components has been considered. Two kind of pseudo[2]rotaxane stereoadducts, the "endo-chiral" and "exo-chiral" ones, having the stereogenic center of a cationic axle inside or outside, respectively, the calix-cavity of a chiral calixarene were preferentially formed with specifically designed chiral axles by a fine exploitation of the so-called "endo-alkyl rule" and a newly defined "endo-α-methyl-benzyl rule" (threading of a hexaalkoxycalix[6]arene with a directional (α-methyl-benzyl)benzylammonium axle occurs with an endo-α-methyl-benzyl preference). The obtained pseudorotaxanes were studied in solution by 1D and 2D NMR, and in the gas-phase by means of the enantiomer-labeled (EL) mass spectrometry method, by combining enantiopure hosts with pseudoracemates of one deuterated and one unlabeled chiral axle enantiomer. In both instances, there was not a clear enantiodiscrimination in the threading process with the studied host/guest systems. Possible rationales are given to explain the scarce reciprocal influence between the guest and host chiral centers.

Synthesis and Glycosidase Inhibition Properties of Calix[8]arene-Based Iminosugar Click Clusters.

A set of 6- to 24-valent clusters was constructed with terminal deoxynojirimycin (DNJ) inhibitory heads through C6 or C9 linkers by way of Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reactions between mono- or trivalent azido-armed iminosugars and calix[8]arene scaffolds differing in their valency and their rigidity but not in their size. The power of multivalency to upgrade the inhibition potency of the weak DNJ inhibitor (monovalent DNJ Ki being at 322 and 188 µM for C6 or C9 linkers, respectively) was evaluated on the model glycosidase Jack Bean α-mannosidase (JBα-man). Although for the clusters with the shorter C6 linker the rigidity of the scaffold was essential, these parameters had no influence for clusters with C9 chains: all of them showed rather good relative affinity enhancements per inhibitory epitopes between 70 and 160 highlighting the sound combination of the calix[8]arene core and the long alkyl arms. Preliminary docking studies were performed to get insights into the preferred binding modes.

Kinetic and Thermodynamic Modulation of Dynamic Imine Libraries Driven by the Hexameric Resorcinarene Capsule.

The composition of dynamic covalent imine libraries (DCL) adapts to the presence of the hexameric resorcinarene capsule. In the presence of the self-assembled capsule, a kinetic and thermodynamic modulation of the imine constituents of the DCLs was observed, which was induced by an unusual predatory action of the capsule on specific imine constituents. More complex 2 × 2 DCLs also adapt to the presence of the hexameric capsule, showing a thermodynamic and kinetic modulation of the constituents induced by the predatory action of the capsule. By cross-referencing experimental data, a good selectivity (up to 66%) for one constituent can be induced in a 2 × 2 DCL.

Dispersing and Retarding Properties of Water-Soluble Tetrasulfonate Resorcin[4]arene and Pyrogallol[4]arene Macrocycles in Cement-Based Mortar.

Water-soluble tetrasulfonate resorcin[4]arene (1a and 1c) and pyrogallol[4]arene (1b) macrocycles were synthesized and investigated for their dispersing properties in cement-based mortars. Mortar tests clearly show that these polyhydroxylated macrocycles (nonpolymeric) work as cement dispersants. Setting time determinations indicate that the macrocycles 1a and 1b show a retarding effect that is reminiscent of the behavior of superplasticizers (SPs) functionalized with polyhydroxylated ß-CDs. Finally, the addition of sulfate anions to the cement paste does not affect the dispersing abilities of 1b, probably due to the sulfate anion capture by H-bonding interactions with its OH groups at the upper rim.

Calix[2]naphth[2]arene: A Class of Naphthalene-Phenol Hybrid Macrocyclic Hosts.

Calix[2]naphth[2]arenes make up a new class of phenol-naphthalene hybrid macrocycles. X-ray studies show that calix[2]naphth[2]arene 1 adopts a 1,2-alternate conformation. Alkali metal cations are complexed by the calixnaphtharenes in a 1,2-alternate conformation, by cation···π interactions with the naphthalene walls, and by RO···M+ ion-dipole interactions. In the presence of Cs+, chiral complexes of calixnaphtharenes 5 and 6 were observed in which the cation is nested on one of the two faces of the macrocycle.