On-Surface Synthesis of Non-Benzenoid Nanographenes Embedding Azulene and Stone-Wales Topologies.

The incorporation of non-benzenoid motifs in graphene nanostructures significantly impacts their properties, making them attractive for applications in carbon-based electronics. However, understanding how specific non-benzenoid structures influence their properties remains limited, and further investigations are needed to fully comprehend their implications. Here, we report an on-surface synthetic strategy toward fabricating non-benzenoid nanographenes containing different combinations of pentagonal and heptagonal rings. Their structure and electronic properties were investigated via scanning tunneling microscopy and spectroscopy, complemented by computational investigations. After thermal activation of the precursor P on the Au(111) surface, we detected two major nanographene products. Nanographene Aa-a embeds two azulene units formed through oxidative ring-closure of methyl substituents, while Aa-s contains one azulene unit and one Stone-Wales defect, formed by the combination of oxidative ring-closure and skeletal ring-rearrangement reactions. Aa-a exhibits an antiferromagnetic ground state with the highest magnetic exchange coupling reported up to date for a non-benzenoid containing nanographene, coexisting with side-products with closed shell configurations resulted from the combination of ring-closure and ring-rearragement reactions (Ba-a , Ba-s , Bs-a and Bs-s ). Our results provide insights into the single gold atom assisted synthesis of novel NGs containing non-benzenoid motifs and their tailored electronic/magnetic properties.

Novel oxidative routes to N-arylpyridoindazolium salts.

A novel facile approach to N-arylpyridoindazolium salts is proposed, based on direct oxidation of the ortho-pyridine substituted diarylamines, either using bis(trifluoroacetoxy)iodobenzene as an oxidant, or electrochemically, via potentiostatic oxidation. Electrochemical synthesis occurs under mild conditions; no chemical reagents are required except electric current. Both approaches can be considered as a late-stage functionalization; easily available ortho-pyridyl-substituted diarylamines are used as the precursors.

Design and synthesis of novel rigid dibenzo[b,f]azepines through ring closure technique as promising anticancer candidates against leukaemia and acting as selective topoisomerase II inhibitors and DNA intercalators.

In this research, two novel series of dibenzo[b,f]azepines (14 candidates) were designed and synthesised based on the rigidification principle and following the reported doxorubicin's pharmacophoric features. The anti-proliferative activity was evaluated at the NCI against a panel of 60 cancer cell lines. Further, the promising candidates (5a-g) were evaluated for their ability to inhibit topoisomerase II, where 5e was noticed to be the most active congener. Moreover, its cytotoxicity was evaluated against leukaemia SR cells. Also, 5e arrested the cell cycle at the G1 phase and increased the apoptosis ratio by 37.34%. Furthermore, in vivo studies of 5e showed the inhibition of tumour proliferation and the decrease in its volume. Histopathology and liver enzymes were examined as well. Besides, molecular docking, physicochemical, and pharmacokinetic properties were carried out. Finally, a SAR study was discussed to open the gate for further optimisation of the most promising candidate (5e).HighlightsTwo novel series of dibenzo[b,f]azepines were designed and synthesised based on the rigidification principle in drug design.The anti-proliferative activity was evaluated at the NCI against a panel of 60 cancer cell lines.5e was the most active anti-topo II congener (IC50 = 6.36 ± 0.36 µM).5e was evaluated against leukaemia SR cells and its cytotoxic effect was confirmed (IC50 = 13.05 ± 0.62 µM).In vivo studies of 5e significantly inhibited tumour proliferation by 62.7% and decreased tumour volume to 30.1 mm3 compared to doxorubicin treatment.

Heck Macrocyclization in Forging Non-Natural Large Rings including Macrocyclic Drugs.

The intramolecular Heck reaction is a well-established strategy for natural product total synthesis. When constructing large rings, this reaction is also referred to as Heck macrocyclization, which has proved a viable avenue to access diverse naturally occurring macrocycles. Less noticed but likewise valuable, it has created novel macrocycles of non-natural origin that neither serve as nor derive from natural products. This review presents a systematic account of the title reaction in forging this non-natural subset of large rings, thereby addressing a topic rarely covered in the literature. Walking through two complementary sections, namely (1) drug discovery research and (2) synthetic methodology development, it demonstrates that beyond the well-known domain of natural product synthesis, Heck macrocyclization also plays a remarkable role in forming synthetic macrocycles, in particular macrocyclic drugs.

Decomposition of Al13 promoted by salicylic acid under acidic condition: Mechanism study by differential mass spectrometry method and DFT calculation.

Decomposition of the polycation Al13O4(OH)24(H2O)127+ (Al13) promoted by ligand is a vital subject to advance our understanding of natural and artificial occurrence and evolution of aluminum ions, especially in the case of acidic condition that dissolved Al3+ species can be released from the Al-bearing substances. However, the microscopic pathway of synchronous proton-promoted and ligand-promoted decomposition process for Al13 is still in the status of ambiguity. Herein, we applied differential mass spectrometry method and DFT calculation to study the initial detailed process of Al13 decomposition under the presence of proton and salicylic acid (H2Sal). Mass results showed that the mononuclear Al3+-H2Sal complexes dominated the resulting Al species, whereas the monodentate complex Al13HSal6+ was not observed in the spectra. The difference of decomposition levels between the ligand/Al ratio 0.2 and 0.5 cases revealed that proton and ligand performed synergistic effect in initial Al13 decomposition process, and the proton transfer determined the ring closure efficiency. The ring closure reaction is the prerequisite for the collapse of Al13 structure and detachment of the mononuclear complex. DFT calculations reveal that hydrogen bond plays an important role in inducing the formation of chelated complex accompanying proton transfer. Attachment of protons at the bridging OH- can elongate and weaken the critical bond between targeted Al3+ and µ4-O2- resulting from delocalization of electron pairs in the oxygen atom. These results demonstrate the detailed mechanism of Al13 composition promoted by ligand and proton, and provide significant understanding for further application and control of Al13.

Synthesis of Cyclopropenes and Fluorinated Cyclopropanes via Michael Initiated Ring Closure of Alkyl Triflones.

A facile synthesis of cyclopropenes and fluorinated cyclopropanes from readily available alkyl triflones was developed. The reaction, regardless of electronic effect, gave products in good to excellent yields and moderate diastereoselectivity. The mechanism may involve tandem Michael addition of triflones/intramolecular nucleophilic cyclization (elimination of -SO2 CF3 )/elimination of fluoride.

Photochemically Induced 1,3-Butadiene Ring-Closure from the Topological Analysis of the Electron Localization Function Viewpoint.

The electronic rearrangement featuring the photochemically-induced 1,3-cis-butadiene is discussed within a bonding evolution theory (BET) perspective based on the topological analysis of the electron localization function and Thom's catastrophe theory. The process involves the vertical singlet-singlet excitation S0 →S2 , and the subsequent deactivation implying the S2 /S1 and S1 /S0 conical intersection regions. BET results reveal that the new CC bond is finally formed on the S0 surface, as also recently found in the photochemical addition of two ethylenes [Phys. Chem. Chem. Phys. 23, 20598, (2021)].

A universal strategy of glyconanoparticle preparation using a bifunctional linker for lectin sensing and cell imaging.

Glyconanoparticles (G-NPs), biofunctional nanomaterials that can fully combine the unique properties of nanoparticles (NPs) with the bioactivities of carbohydrates, have become an appealing nanoplatform in analytical chemistry and biomedical research. However, there is currently a lack of an efficient and universal method for facile immobilization of reducing carbohydrates on NPs while maintaining their structure integrity, greatly limiting the preparation and application of G-NPs. Herein, a new and universal strategy for preparing carbohydrate-functionalized gold nanoclusters (Au NCs) was developed by using S-(3-(methoxyamino)propyl) thioacetate (MPTA) as a new bifunctional linker. MPTA with an N-methoxyamine group (-NHOMe) and a thioacetyl group (-SAc) was synthesized by a two-step strategy and then grafted onto Au NCs by an efficient click reaction. Subsequently, reducing carbohydrates could be readily immobilized onto MPTA-functionalized Au NCs (MPTA-Au NCs) by a reducing end ring-closure reaction under mild conditions. The obtained G-NPs showed average size of 1.9 ± 0.42 nm and strong fluorescence at 610 nm. Carbohydrates grafted on G-NPs still retained their structure integrity and specific recognition ability toward their receptor proteins. Notably, the affinity between G-NPs and proteins was increased by 1300 times compared with free carbohydrates with an association constant of (1.47 ± 0.356) × 106 M-1. The prepared fluorescent G-NPs were also successfully applied to lectin sensing and targeted breast cancer cell imaging with good performance. These results indicated that the intact immobilization of reducing carbohydrates (whether naturally or chemically accessed) on NPs could be easily achieved using MPTA, providing a simple, efficient, and universal strategy for G-NP preparation.

Reaction of 3-Oxa-2-oxobicyclo[4.2.0]oct-4-ene-1-carboxylate with Dimethylsulfoxonium Methylide.

We have been interested in the reactivities of small-ring compounds and have reported reactions that proceed through cyclopropane intermediates starting from coumarin derivatives bearing an electron-withdrawing group at the 3-position or 2-oxo-2H-pyran-3-carboxylate derivatives and dimethylsulfoxonium methylide. This time, the reaction between 3-oxa-2-oxobicyclo[4.2.0]oct-4-ene-1-carboxylate and dimethylsulfoxonium methylide has been investigated. 3a,4,5,7a-Tetrahydro-7-hydroxybenzofuran-6-carboxylate and/or 2-hydroxybicyclo[4.1.0]hept-2-ene-3-carboxylate were obtained. The compounds were characterized using various spectral and X-ray crystallographic techniques. A plausible reaction mechanism has been discussed. This reaction was applied to some 3-oxa-2-oxobicyclo[4.2.0]oct-4-ene-1-carboxylate derivatives to clarify the generality.

Macrocyclic sulfone derivatives: Synthesis, characterization, in vitro biological evaluation and molecular docking.

An artificial series of macrocycles based on 4,4'-sulfonyldiphenol intermediate was synthesized using a multistep procedure involving oxidation of bisphenol sulfide, etherification of phenolic hydroxyl groups, and final ring closure with different diamines. Different chemical species having aromatic, heteroaromatic, and aliphatic characters were incorporated into macrocyclic frameworks in the final step of ring closure. This simple and easily executable synthetic strategy was applied to synthesize 15 macrocycles (5a-o) in excellent yields. Characterization of the synthesized products was achieved through well-known modern spectroscopic techniques such as IR, NMR, and Mass. Macrocycles 5m and 5n were found to show significant AChE inhibition with IC50 values of 76.9 ± 0.24 and 71.2 ± 0.77 µM, respectively. Macrocycle 5n was also found to be an active inhibitor of butyrylcholinesterase (BChE) with IC50 score of 55.3 ± 0.54 µM. Among others, macrocycle 5l cyclized with o-phenylenediamine demonstrated moderate inhibition with IC50 value of 81.1 ± 0.54 µM. Increasing interest in studying interactions of macrocycles with different enzymatic targets compelled us to design and synthesize sulfone-based macrocycles that might prove as highly potent class of biologically active compounds.

Fused 1,2-Diboraoxazoles Based on closo-Decaborate Anion-Novel Members of Diboroheterocycle Class.

The novel members of the 1,2-diboraoxazoles family have been obtained. In the present work, we have carried out the intramolecular ring-closure reaction of borylated iminols of general type [B10H9N=C(OH)R]- (R = Me, Et, nPr, iPr, tBu, Ph, 4-Cl-Ph). This process is conducted in mild conditions with 83-87% yields. The solid-state structures of two salts of 1,2-diboraoxazoles were additionally investigated by X-ray crystallography. In addition, the phenomena of bonding interactions in the 1,2-diboraoxazole cycles have been theoretically studied by the Quantum Theory of Atoms in Molecules analysis. Several local and integral topological properties of the electron density involved in these interactions have been computed.

An Efficient Ring-Closure Method for Preparing Well-Defined Cyclic Polynorbornenes.

An efficient bimolecular ring-closure method is developed to prepare the well-defined cyclic polynorbornenes by combining the living ring-opening metathesis polymerization (ROMP) with the self-accelerating double strain-promoted azide-alkyne cycloaddition (DSPAAC) reaction. In this method, ROMP is used to synthesize the well-defined linear polynorbornenes with both azide terminals by virtue of a N-hydroxysuccinimide-ester-functionalized Grubbs initiator following the modification of polymer end groups. DSPAAC click reaction is then used to ring-close the linear polymer precursors and prepare the corresponding well-defined cyclic polynorbornenes using the sym-dibenzo-1,5-cyclooctadiene-3,7-diyne (DIBOD) as small linkers. The self-accelerating DSPAAC ring-closing reaction facilitates this method to efficiently prepare pure cyclic polynorbornenes in the presence of a molar excess of DIBOD small linkers to the linear polynorbornene precursors. This is the first report to prepare well-defined polynorbornenes with cyclic topology based on the ring-closure strategy for cyclic polymers.

(+)-(R)- and (-)-(S)-Perhexiline maleate: Enantioselective synthesis and functional studies on Schistosoma mansoni larval and adult stages.

Schistosomiasis is a neglected tropical disease mainly affecting the poorest tropical and subtropical areas of the world with the impressive number of roughly 200 million infections per year. Schistosomes are blood trematode flukes of the genus Schistosoma causing symptoms in humans and animals. Organ morbidity is caused by the accumulation of parasite eggs and subsequent development of fibrosis. If left untreated, schistosomiasis can result in substantial morbidity and even mortality. Praziquantel (PZQ) is the most effective and widely used compound for the treatment of the disease, in prevention and control programs in the last 30 years. Unfortunately, it has no effect on juvenile immature schistosomes and cannot prevent reinfection or interfere with the schistosome life cycle; moreover drug-resistance represents a serious threat. The search for an alternative or complementary treatment is urgent and drug repurposing could accelerate a solution. The anti-anginal drug perhexiline maleate (PHX) has been previously shown to be effective on larval, juvenile, and adult stages of S. mansoni and to impact egg production in vitro. Since PHX is a racemic mixture of R-(+)- and S-(-)-enantiomers, we designed and realized a stereoselective synthesis of both PHX enantiomers and developed an analytical procedure for the direct quantification of the enantiomeric excess also suitable for semipreparative separation of PHX enantiomers. We next investigated the impact of each enantiomer on viability of newly transformed schistosomula (NTS) and worm pairs of S. mansoni as well as on egg production and vitellarium morphology by in vitro studies. Our results indicate that the R-(+)-PHX is mainly driving the anti-schistosomal activity but that also the S-(-)-PHX possesses a significant activity towards S. mansoni in vitro.

Al/P- and Ga/P-Based Frustrated Lewis Pairs and Electronically Unsaturated Substrates: Ring Cleavage and Ring Closure, C-C and C-N Bond Formation.

Al/P- and Ga/P-based frustrated Lewis pairs (FLPs) reacted with an azirine under mild conditions under cleavage of the heterocycle on two different positions. Opening of the C-C bond yielded an unusual nitrile-ylide adduct in which a C-N moiety coordinated to the FLP backbone. Cleavage of a C-N bond afforded the thermodynamically favored enamine adduct with the N atom bound to P and Al or Ga atoms. Ring closure was observed upon treatment of an Al/P FLP with electronically unsaturated substrates (4-(1-cyclohexenyl)-1-aza-but-1-en-3-ynes) and yielded by C-N bond formation hexahydroquinoline derivatives, which coordinated to the FLP through P-C and Al-C bonds. Diphenylcyclopropenone showed a diverse reactivity, which depending on steric shielding and the polarizing effect of Al or Ga atoms afforded different products. An AltBu2 /P FLP yielded an adduct with the C=O group coordinated to P and Al. The dineopentyl derivative gave an equilibrium mixture consisting of a similar product and a simple adduct with O bound to Al and a three-coordinate P atom. Both compounds co-crystallize. The Ga/P FLP only formed the simple adduct with the same substrate. Rearrangement resulted in all cases in C3 -ring cleavage and migration of a mesityl group from P to a former ring C atom by C-C bond formation. Diphenylthiocyclopropenone (evidence for the presence of P=C bonds) and an imine derivative afforded similar products.

Efficient Heterodifunctional Unimolecular Ring-Closure Method for Cyclic Polymers by Combining RAFT and SuFEx Click Reactions.

A novel ring-closure strategy for cyclic polymers by combining reversible addition-fragmentation chain transfer polymerization (RAFT) and the sulfur(VI)-fluoride exchange (SuFEx) click reaction is presented. Herein, a new heterodifunctional trithiocarbonate RAFT agent, 2-((tert-butyldimethylsilyl)oxy)ethyl (4-(fluorosulfonyl)benzyl) carbonotrithioate (TBDMS-FSBCT), containing both tert-butyldimethylsilyl ether and sulfonyl fluoride moieties, is developed. The polymerization behavior of TBDMS-FSBCT is first demonstrated by a standard RAFT polymerization procedure for two types of vinyl monomers, N-isopropylacrylamide (NIPAAm) (conjugated vinyl monomer) and N-vinylpyrrolidone (NVP) (unconjugated vinyl monomer). The tert-butyldimethylsilyl ether and sulfonyl fluoride groups at the α and ω positions of the obtained linear polymer precursors (L-PNIPAAm and L-PVP) are verified by 1 H, 13 C, and 19 F NMR spectra. Subsequent intramolecular SuFEx click cyclization of the α,ω-heterofunctionalized linear precursors in air at room temperature conveniently yields the corresponding cyclic polymers (C-PNIPAAm and C-PVP). Overall, this is the first report on the preparation of cyclic polymers based on the SuFEx reaction under ambient conditions. It is envisioned that the approach may open an avenue for the formation of cyclic polymers.

Synthesis of Novel N-Heterocyclic Compounds Containing 1,2,3-Triazole Ring System via Domino, "Click" and RDA Reactions.

An uncomplicated, high-yielding synthetic route has been developed to constitute complicated heterocycles, applying domino, click and retro-Diels⁻Alder (RDA) reaction sequences. Starting from 2-aminocarboxamides, a new set of isoindolo[2,1-a]quinazolinones was synthesized with domino ring closure. A click reaction was performed to create the 1,2,3-triazole heterocyclic ring, followed by an RDA reaction resulting in dihydropyrimido[2,1-a]isoindole-2,6-diones. The absolute configuration, concluded by the norbornene structure that served as a chiral source, remained constant throughout the transformations. The structure of the synthesized compounds was examined by ¹H and 13C Nuclear Magnetic Resonance (NMR) methods.

Synthesis, characterization and antibacterial activity of novel heterocycle, coumacine, and two of its derivatives.

Heterocyclic nucleus plays a fundamental role in the medicinal chemistry and serves as a key template for the development of various therapeutic agents including broad spectrum antibacterial drugs. In an effort to develop new antibacterial agents, a bicyclic twelve-membered heterocyclic nucleus derived from coumarin was prepared by an uncomplicated method. The rate of ring closure for this nucleus, which was given the name coumacine, in addition to two of its derivatives was monitored spectroscopically and this rate followed zero order kinetics. The chemical structures of the synthesized products were established by detecting their physicochemical properties and analyzing their IR, 1H NMR and 13C NMR spectra. The in vitro antibacterial activity of coumacines was evaluated via agar dilution method against different standard aerobic and anaerobic bacterial strains using ciprofloxacin and metronidazole as positive controls, respectively; the results indicated that coumacine I has an excellent broad spectrum antibacterial activity against the tested bacterial strains with percentage of growth inhibition approximating to those of positive controls.

IschioPubic Osteotomy, A Simple and Effective Technique for Pelvic Ring Closure in Repair of Classic Exstrophy Bladder.

AIM: The aim of this study is to report the technique and outcome of ischiopubic (IP) osteotomy for pelvic ring closure in classic exstrophy bladder. METHODS: A total of 85 male classic exstrophies were selected based on trapezoid-shaped space between IP ramus on three-dimensional computed tomography pelvis. Using midline scroto-perineal approach, after bladder plate mobilization and radical corporal detachment; the pelvic surface of superior pubic ramus (SPR) was exposed. Above the obturator canal, H-shaped incision was made on periosteum of the SPR. The horizontal line of H was placed above the obturator canal. Rectangular periosteal flaps above and below the horizontal line was raised. In the subperiosteal plane, curved hemostats encircled the SPR that were divided using a bone drill. On the medial aspect of ischial tuberosity, a notch was created as hinge using a bone drill. Forks of bone holding forceps hooked the pubic bone and tightened for its midline approximation, lengthening of the SPR and inward rotation of IP ramus. Linea alba and pubic bones were approximated with interrupted Polygalactin sutures. RESULTS: Midline approximation of pubic bone and linea alba was possible in all. There was no injury to obturator nerve, vessels, or other structures . CONCLUSIONS: IP osteotomy is the safe and effective technique of pelvic ring closure in patients with specific pelvic configuration.

Cyclic Multiblock Copolymers via Combination of Iterative Cu(0)-Mediated Radical Polymerization and Cu(I)-Catalyzed Azide-Alkyne Cycloaddition Reaction.

Cyclic multiblock polymers with high-order blocks are synthesized via the combination of single-electron transfer living radical polymerization (SET-LRP) and copper-catalyzed azide-alkyne cycloaddition (CuAAC). The linear α,ω-telechelic multiblock copolymer is prepared via SET-LRP by sequential addition of different monomers. The SET-LRP approach allows well control of the block length and sequence as A-B-C-D-E, etc. The CuAAC is then performed to intramolecularly couple the azide and alkyne end groups of the linear copolymer and produce the corresponding cyclic copolymer. The block sequence and the cyclic topology of the resultant cyclic copolymer are confirmed by the characterization of 1 H nuclear magnetic resonance spectroscopy, gel permeation chromatography, Fourier transform infrared spectroscopy, and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.

Efficient Homodifunctional Bimolecular Ring-Closure Method for Cyclic Polymers by Combining RAFT and Self-Accelerating Click Reaction.

An efficient metal-free homodifunctional bimolecular ring-closure method is developed for the formation of cyclic polymers by combining reversible addition-fragmentation chain transfer (RAFT) polymerization and self-accelerating click reaction. In this approach, α,ω-homodifunctional linear polymers with azide terminals are prepared by RAFT polymerization and postmodification of polymer chain end groups. By virtue of sym-dibenzo-1,5-cyclooctadiene-3,7-diyne (DBA) as small linkers, well-defined cyclic polymers are then prepared using the self-accelerating double strain-promoted azide-alkyne click (DSPAAC) reaction to ring-close the azide end-functionalized homodifunctional linear polymer precursors. Due to the self-accelerating property of DSPAAC ring-closing reaction, this novel method eliminates the requirement of equimolar amounts of telechelic polymers and small linkers in traditional bimolecular ring-closure methods. It facilitates this method to efficiently and conveniently produce varied pure cyclic polymers by employing an excess molar amount of DBA small linkers.