Thioether Groups Research Articles

Preparation of chitosan-based macromolecular antioxidant with high-efficiency free radical scavenging ability to improve the antioxidative properties of styrene-butadiene rubber/silica composites

To address the disadvantages of traditional rubber antioxidants with low molecular weight such as easy migration, poor extraction resistance, low thermal stability and antioxidant efficiency, in this work, we first prepared an antioxidant containing primary and secondary antioxidant groups (MC-MPA) through thiol-ene click reaction between N-(4-aminophenyl)maleimide (MC) and 3-mercaptopropionic acid (MPA). Then, we synthesized a chitosan-based macromolecular antioxidant with long-chain alkene, aromatic secondary amine, and thioether groups (COS-UC-MC-MPA) by sequentially grafting functional compounds 10-undecanonyl chloride (UC) and antioxidant MC-MPA onto natural macromolecular polymer chitosan (COS). The free radical scavenging ability of COS-UC-MC-MPA was assessed by using 2,2-Diphenyl-1-picrylhydrazyl (DPPH), and the results demonstrated that COS-OC-MC-MPA has high scavenging rate of 76.5 % for DPPH free radicals after 1 min of contact with DPPH dimethyl sulfoxide solution, showing excellent free radical scavenging ability. In addition, the results of accelerated thermo-oxidative aging test, thermogravimetric (TG) test, kinetic analysis of thermal-oxidative degradation, extraction resistance test, and volatilization resistance test indicated that COS-UC-MC-MPA with superior migration resistance and volatilization resistance could effectively enhance the antioxidative properties, thermal stability and thermal-oxidative stability of rubber composites. Moreover, the results of rubber processibility analysis (RPA) test and scanning electron microscopy (SEM) implied that the addition of COS-UC-MC-MPA is also conductive to improving the dispersibility of silica in rubber matrix. This study supplies a new perspective for the preparation of environmentally friendly and highly efficient macromolecular antioxidants for rubber composites.

BioMOF@PAN Mixed Matrix Membranes as Fast and Efficient Adsorbing Materials for Multiple Heavy Metals' Removal.

Heavy metal ions are a common source of water pollution. In this study, two novel membranes with biobased metal-organic frameworks (BioMOFs) embedded in a polyacrylonitrile matrix with tailored porosity were prepared via nonsolvent induced phase separation methods and designed to efficiently adsorb heavy metal ions from oligomineral water. Under optimized preparation conditions, stable membranes with high MOF loading up to 50 wt % and a cocontinuous sponge-like morphology and a high water permeability of 50-60 L m-2 h-1 bar-1 were obtained. The tortuous flow path in combination with a low water flow rate guarantees maximum contact time between the fluid and the MOFs, and thus a high heavy metal capture efficiency in a single pass. The performances of these BioMOF@PAN membranes were investigated in the dynamic regime for the simultaneous removal of Pb2+, Cd2+, and Hg2+ heavy metals from aqueous environments in the presence of common interfering ions. The new composite adsorbing membranes are capable of reducing the concentration of heavy metal pollutants in a single pass and at much higher efficiency than previously reported membranes. The enhanced performance of the mixed matrix membranes is attributed to the presence of multiple recognition sites which densely decorate the BioMOF channels: (i) the thioether groups, deriving from the S-methyl-l-cysteine and (S)-methionine amino acid residues, able to recognize and capture Pb2+ and Hg2+ ions and (ii) the oxygen atoms of the oxamate moieties, which preferentially interact with Cd2+ ions, as revealed by single crystal X-ray diffraction. The flexibility of the pore environments allows these sites to work synergically for the simultaneous capture of different metal ions. The stability of the membranes for a potential regeneration process, a key-factor for the effective feasibility of the process in real life applications, was also evaluated and confirmed less than 1% capacity loss in each cycle.

Enhancing the uranium (VI) adsorption performance of phosphoric acid functionalized porous silica by controlled introduction of phosphoric acid group

The post-grafting of porous silica with organic group is a common method for the synthesis of organo-functionalized silica adsorbent. However, this method usually produces adsorbents with limited adsorption performances due to the pore blocking caused by the irregular introduction of organic group. In this work, we report the controllable synthesis of phosphoric acid functionalized porous silica adsorbent based on the co-condensation method for uranium (VI) adsorptive removal with enhanced adsorption performance. Characterizations of the obtained silica verify its porous structure and confirm the homogeneous distribution of phosphoric acid groups inside the silica. This silica is able to efficiently remove 98 % of uranium from a 100 mg/L uranium (VI) solution within 10 min at a dosage of 0.6 g/L and the maximum uranium (VI) adsorption amount reaches 509 mg/g. Both adsorption capacity and adsorption rate of this silica are superior than that of the silica synthesized based on conventional post-grafting method. Moreover, this silica can be reused for five times with uranium (VI) removal efficiency above 95 % and it is well applied in adsorption column for dynamically adsorptive removal of uranium (VI) from real nuclear wastewater. Mechanism-related investigations reveal that uranium (VI) adsorption on this silica proceeds by effective ion exchange of uranium (VI) ion with either phosphoric acid or silanol group and the formation of uranyl phosphonate or uranyl silicate complex. This work provides a feasible strategy to synthesize functionalized porous silica without significant pore blocking, and demonstrates the enhancement effect of regulating surface adsorption groups on the adsorption performances of porous silica. Besides, this work offers a promising adsorbent for efficient treatment of uranium-containing nuclear wastewater and reveals the mechanism of uranium adsorption on those silica adsorbent containing phosphoric acid, thiol or thioether group.

Chromatographic evaluation and application of nitrogenous heterocyclic ring-bonded stationary phase in hydrophilic interaction liquid chromatography

Hydrophilic interaction liquid chromatography (HILIC) based on polar stationary phases has vital research significance in the separation of polar compounds. Numerous HILIC stationary phases with different structures have been developed, which do not have universal properties and broad selectivity, making it a challenge to select the suitable column based on the properties of the samples. Consequently, it is particularly important to develop a bonded phase capable of separating a wide variety of samples, while having enhanced retention, improved selectivity, symmetric peak shape and good stability. Herein, a novel nitrogen-containing heterocyclic bonded phase with multiple functionalities, such as thioether, amino and hydroxyl groups (named AMTA) was employed as HILIC stationary phase. Detailed chromatographic evaluations were carried out, and the results showed that it was superior to other hydrophilic chromatographic columns in terms of selectivity, peak shapes and practical sample separation. Lastly, it has been verified that AMTA exhibited high orthogonality with the XBridge C18 column of reversed-phase liquid chromatography (RPLC) mode. In summary, we anticipate our assay to be instructive to other researchers in developing the HILIC stationary phase.

Electroauxiliary-Assisted C-C Bond Formations in Lithium Perchlorate / Nitromethane Solution

C-nucleosides have C-C bonds between ribosyl moiety and nucleobase at anomeric carbon. This substitution of covalent bond gives hydrolysis resistance to C-nucleosides. Therefore, C-nucleosides are good candidates for antiviral or antitumor drugs as mimic building blocks of oligonucleotide.To synthesize nucleosides, cation intermediate is used for installing nucleobase on ribosyl moiety. When it comes to generation of cation intermediate, electrochemical methodology is one of the useful tools. In electrochemical method, 1’-arylthioriboses are used as glycosyl donors. They have thioether group as electroauxiliary at anomeric carbon forging O,S-acetal that are activated with anodic oxidation to generate corresponding cation intermediate. Since electrochemically generated cation intermediates have high reactivity enough to react with carbon nucleophiles, this method can be adopted to C-nucleoside synthesis.Previously, electrochemical nucleoside synthesis was reported using cation pool method in combination with electroauxiliary. To avoid undesired oxidation of nucleophile, it is important to pool the cation and/or to lower the oxidation potential of ribose. The low temperature condition such as -78 ~ -50 oC is necessary to pool cation intermediates.In this research, we aimed to achieve electrochemical C-C bond formation at anomeric carbon with ambient temperature condition. In this strategy, we use glycosyl donors with lowered oxidation potential to avoid competitive oxidation with carbon nucleophiles. We also adapt lithium perchlorate/nitromethane system for electrolysis. Figure 1

PH-responsive polyaryl sulfide sulfone amide membrane containing tertiary amine unit: Oxidation and reversible acid-base treatment

Developing functional membranes with switchable pores for the separation of contaminants with different sizes has been challenging due to the lack of novel materials with adaptable and adjustable structures. Polymers containing the tertiary amine (TA) unit can be transformed via oxidation into amine oxide (AO) structure that can modulate the membrane pore size. In this study, new monomers containing pH-responsive TA units and diacyl chloride containing reducible thioether (-S-) groups were used to yield pore-size-adjustable membrane resin polyarylene sulfide sulfone amide/amide tertiary amine (PASSA/ATA) at room temperature. By varying the polymerization ratio of the reaction solution, membranes could be prepared directly through non-solvent induce phase separation (NIPS) method without extra treatment. By oxidizing the TA units to AO through acid condition (H2O2/H2SO4/CH3COOH), the PASSA/ATA membrane can be switched from ultrafiltration to loose-nanofiltration with the rejection of RO16 and rhodamine B increased from 18.4% to 34.3 % (pristine membrane) to 91.7 % and 98.5 %. The permeance and rejection rate of the oxidized membrane were found to recover to the initial state after alkali-treatment. The mechanism of the switchable pore size was elucidated by dissipative particle dynamics (DPD) simulations. Interestingly, the oxidized PASSA/ATA membrane showed good organic solvent resistance and in nanofiltration performance, as it was capable of retaining about 95 % of Congo red in N,N-dimethylformamide (DMF) with permeance of about 10 L m−2 h−1 bar−1. This work presents a facile and low-carbon approach to develop novel membranes with multiple filtration capabilities, potentially applicable in various separation processes.

Anchoring Atomically Precise Chiral Bismuth Oxido Nanoclusters on Gold: The Role of Amino Acid Linkers.

The adsorption of chiral molecules onto metallic surfaces triggers electron spin polarization at the interface, paving the way for applications in chiral opto-spintronics. However, the spin effects sensitively depend on the binding and ordering of the chiral species on surfaces. This study explores the adsorption of chiral thioether-functionalized atomically precise bismuth oxido nanoclusters (BiO-NCs) on gold (Au) surfaces, extending the conventional approach of using thiol-containing molecules and complexes to nanoclusters. Starting from the precursor [Bi38O45(NO3)20(dmso)28](NO3)4·4dmso (A), chiral BiO-NCs were synthesized by substituting the nitrates with N-(tert-butoxycarbonyl)-l-methionine (Boc-l-Met-O-) ligands to obtain [Bi38O45(Boc-l-Met-O)24] (2). The full exchange of nitrate by the Boc-l-methionine ligand was demonstrated by powder X-ray diffractograms, dynamic light scattering, electrospray ionization mass spectrometry, nuclear magnetic resonance, infrared, circular dichroism, and X-ray photoelectron spectroscopy. Compared to previously reported [Bi38O45(Boc-l-Phe-O)24(dmso)9] (1), BiO-NC 2 shows differences in the growth mode on a Au surface as revealed by scanning electron microscopy, wherefore a stronger binding of BiO-NC 2 is assumed. Anchoring of BiO-NC 2 to the Au surface through thioether groups induced a discernible change in the optical response of the Au surface analyzed by spectroscopic ellipsometry (SE). From the numerical modeling of the SE parameters, a layer thickness of ∼2 nm, corresponding to a monolayer of BiO-NC 2, was estimated for the samples prepared by dip coating. Thus, strong adsorption of BiO-NC 2 to the Au surface is concluded, which is an essential prerequisite for chiral-induced interface spin polarization.

Hg2+-enhanced oxidase-like activity of platinum nanoparticles immobilized on porphyrin-based porous organic polymer for the colorimetric detection and removal of Hg2.

Porphyrin-based porous organic polymer (POP) with uniformly immobilized platinum nanoparticles (Pt NPs) were designed and synthesized, and it was demonstrated that such nanocomposites (Pt/POP) have oxidase-like activity. Surprisingly, Hg2+ significantly enhanced the oxidase-like activity of Pt/POP. The enhancement was attributed to the capture of Hg2+ by the thioether group in Pt/POP and the subsequent redox reaction of Hg2+ with Pt NPs, accelerating the electron transfer. In the presence of Hg2+, Pt/POP catalyzed the colorless 3,3',5,5'-tetramethylbenzidine (TMB) to turn blue rapidly and changed its absorbance at 652nm. Based on this, a fast-response colorimetric sensor was constructed for the sensitive detection of Hg2+ with a linear range of 0.2-50μM and a detection limit of 36.5nM. Importantly, Pt/POP can be used as an adsorbent for the efficient removal of Hg2+ with a removal efficiency as high as 99.4%. This work provides a valuable strategy for colorimetric detection and efficient removal of Hg2+.

Efficient capture of palladium from nuclear wastewater by the sulfide and thiol modified covalent organic framework

The effective separation of palladium isotopes from high-level radioactive waste offers significant advantages, not only in ensuring the safe management and disposal of radioactive materials but also in addressing the scarcity of noble metals. In this study, a covalent organic framework (COF-SSH) modified with thiol and thioether groups is synthesized for the purpose of palladium separation. The experimental results demonstrate that the adsorption of Pd(II) occurs rapidly, reaching equilibrium within just 10 min. The adsorption isotherm for Pd(II) aligns well with the Langmuir model, revealing a maximum adsorption capacity of 420.2 mg/g at 3 M HNO3. Through Fourier Transform Infrared Spectroscopy (FT-IR), X-ray Photoelectron Spectroscopy (XPS), and Density Functional Theory (DFT) analyses, the interaction between Pd and S atoms as being crucial for the adsorption process is identified. Moreover, COF-SSH exhibits exceptional selectivity for Pd(II) in simulated nuclear wastewater and maintains its performance throughout six consecutive adsorption and regeneration cycles. These results suggest that COF-SSH is a promising adsorbent for palladium separation, offering both acid resistance and high selectivity, making it a valuable candidate to the field of radioactive waste management and noble metal recovery.

Electrochemical hydrodefluorination of an aromatic trifluoromethyl group with ammonia as the hydrogen source

The aromatic difluoromethyl group (Ar-CF2H) is an emerging functional group found in pharmaceutical compounds. For synthesis, the hydrodefluorination of Ar-CF3 molecules is a straightforward approach in terms of atom economy and substrate scope. The reported hydrodefluorination reaction focused on the Ar-CF3 substrate bearing electron-withdrawing groups. In this report, we utilized electricity as the driving force for the hydrodefluorination of ArCF3, which involves electron-donating groups. By using ammonia as a traceless hydrogen and electron donor, the reaction could tolerate a variety of labile groups, including unprotected amine, pyrrole, furan, thioether, and silyl group, without sacrificial anodes in undivided cells. In this work, tBuOLi was found to be an essential additive for achieving good reactivity and chemoselectivity. Several Ar-CF2H pharmaceutical and intermediate products were synthesized via this approach.

Design, synthesis and characterization of high refractive index aromatic polyesters containing fluorene and thioether groups

9,9-bis(4-hydroxyphenyl)fluorene (BPF) is a highly structurally symmetric bisphenol with excellent optical properties of low birefringence and high refractive index, however, the glass transition temperature ( Tg) of its polyester is high ( Tg>300°C), which makes it difficult to be thermally processed and limits its application. On the other hand, 4,4′-Thiobis (2-methylphenol) (T2MP) has a flexible thioether group, its introduction not only brings high refractive index, but also can appropriately reduce the Tg of the polymer. Therefore, by combining the advantages of both of them, we prepared aromatic polyesters with high refractive index and stabilization. This study provides a route that can appropriately reduce Tg without loss of refractive index.

Polyester networks based on Tulipalin A and ε‐caprolactone and activation of the Thioether groups by incorporation of trialkylsulfonium salts

AbstractLinear and star‐shaped poly(ε‐caprolactone‐co‐α‐methylene‐γ‐butyrolactone) P(CL‐co‐MBL) copolyesters with a pendant functional double bond of α‐methylene‐γ‐butyrolactone (MBL) comonomer were used as polymeric precursor for organo‐gels formation. Crosslinking was carried out by light‐initiated thia‐Michael reaction using 1,5‐pentanedithiol (PDT) and pentaerythritol tetrakis(3‐mercaptopropionate) (PETK). Double bond conversion and the content of free thiol groups in the obtained networks was followed and rationally estimated using confocal Raman spectroscopy. The gel content and the crosslinking density varied based on MBL comonomer and crosslinker content and were highest for slight thiol to double bond excess (SH/vinyl; 2/1 molar ratio) while decreasing with further thiol excess. These parameters were more pronounced by the replacement of linear PDT with the star‐shaped PETK crosslinker. The thermal and rheological properties investigation of the obtained materials was performed employing DSC, TGA and using frequency and temperature sweeps rheological measurements. Shear moduli in the range 0.14 up to 0.93 MPa were obtained due to different content of MBL in pre‐polymer and crosslinker in network formation. The strength was caused by the crystalline phase of the PCL segments up to a temperature of 50°C. Formed thioether bond within the network were not reversible up to 150°C as it was found based on temperature sweep rheology. Following, the activation and conversion of thioether bonds within the obtained materials into trialkylsulfonium salts was attained through the alkylation using butyl brosylate. The dynamic nature of the transalkylation at elevated temperature 150°C allowed network rearrangement, which was proved by stress relaxation experiment and investigation of the self‐healing capabilities.

Abstract 4481: Enhancing AOH1996 through structure activity relationship exploration for caPCNA inhibition

Abstract Recently, we have developed AOH1996, a small molecule PCNA ligand currently in phase I clinical trial, designed to selectively inhibit the functions of cancer-associated PCNA (caPCNA). Seeking to enhance the potency and selectivity of AOH1996, we conducted an exhaustive Structure-Activity-Relationship (SAR) investigation. Over 100 analogues of AOH1996 were synthesized, systematically modifying its three main components: the naphthyl group, glycine linker, and diphenyl ether. The glycine linker underwent substitution with various natural and unnatural amino acids, while the 1-naphthyl group saw replacements with diverse monocyclic and bicyclic aromatic groups, including quinoline and isoquinoline derivatives. The diphenyl ether moiety was extensively explored by substituting the bridging oxygen with different functional groups (sulfonyl, imido, sulfur, amide), substituting both phenyl rings with various functional groups (fluorine, chlorine, hydroxy, methoxy, methyl, trifluoromethyl), and adopting a nitrogen-walk approach on the terminal phenyl ring to evaluate critical ligand/caPCNA-binding positions. This meticulous effort resulted in the identification of several analogues, such as AOH1160S (featuring a diphenyl thioether group), AOH1996S-4CH3 (with a methyl group at the para-position of the terminal thiophenyl ring), and AOH1996-3CH3 (incorporating an m-methoxy function in the terminal phenyl ring and bridging oxygen), exhibiting similar or superior potency compared to AOH1996. The target binding of these analogues was verified by capturing the binary complex of the more polar version of these analogues in the crystal structure. The synthesis, characterization, and detailed biological activities of these promising AOH analogues will be thoroughly described. Citation Format: Pouya Haratipour, Maryam Zangi, Mahshid Yaghoubi, Long Gu, Jennifer Jossart, John J. Perry, Linda H. Malkas, Robert J. Hickey. Enhancing AOH1996 through structure activity relationship exploration for caPCNA inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4481.

Screening drug-induced liver injury through two independent parameters of lipid droplets and peroxynitrite with a π-extended coumarin-based NIR fluorescent probe

Drug-induced liver injury (DILI) or hepatotoxicity is a significant concern for public health. However, relying on a single biomarker for early DILI diagnosis poses a high risk of false positives. In this study, we reported a near-infrared fluorescent probe (BCOU-S), which enables independent visualization of LDs status and ONOO fluctuations. BCOU-S was constructed by combining a π-extended coumarin core as the NIR fluorophore and a methyl thioether group as the ONOO recognition site. BCOU-S could emit 655 nm NIR fluorescence excited at 518 nm, with a low detection limit of 27 nM and a large Stokes shift of 137 nm. The response mechanism to ONOO was confirmed by molecular orbital density function theory (DFT) and time-dependent DFT (TD-DFT) calculations. BCOU-S monitors LDs status through co-localization, oleic acid (OA) incubation, and starvation induction experiments. It sensitively distinguishes subtle changes in ONOO induced by different drugs in DILI cell models. In the acetaminophen (APAP)-induced DILI model, BCOU-S reveals significant LDs accumulation and increase in ONOO levels, establishing a clear time-effect and dose-effect relationship. Simultaneously monitoring ONOO levels and LDs accumulation, BCOU-S proves to be a more sensitive and effective tool for early DILI prevention, effectively avoiding false positives caused by changes in a single parameter. BCOU-S is a useful tool for further monitoring early DILI development.

Switchable Coacervate Formation via Amino Acid Functionalization of Poly(dehydroalanine).

Our group recently developed a family of side-chain amino acid-functionalized poly(S-alkyl-l-homocysteines), Xaa-CH (Xaa = generic amino acid), which possess the ability to form environmentally responsive coacervates in water. In an effort to further study how the molecular structure affects polypeptide coacervate formation, we prepared side-chain amino acid-functionalized poly(S-alkyl-rac-cysteines), Xaa-rac-C, via post-polymerization modification of poly(dehydroalanine), ADH. The use of the ADH platform allowed straightforward synthesis of a diverse range of side-chain amino acid-functionalized polypeptides via direct reaction of unprotected l-amino acid 2-mercaptoethylamides with ADH. Despite their differences in the main-chain structure, we found that Xaa-rac-C can form coacervates with properties similar to those seen with Xaa-CH. These results suggest that the incorporation of side-chain amino acids onto polypeptides may be a way to generally favor coacervation. The incorporation of l-methionine in Met-rac-C allowed the preparation of coacervates with improved stability against high ionic strength media. Further, the presence of additional thioether groups in Met-rac-C resulted in an increased solubility change upon oxidation allowing facile reversible redox switching of coacervate formation in aqueous media.

A Smart Skin for Hydrogels That Enables Switchable Solute Release.

Many applications of hydrogels rely on their ability to deliver encapsulated solutes, such as drugs; however, small hydrophilic solutes rapidly leak out of gels by diffusion. A need exists for a way to regulate solute release out of gels─to ensure zero release until a desired time (the OFF state) and thereafter for the release to be switched ON at a high rate. This should ideally be a repeatable switch; i.e., the gel should be cyclable repeatedly between the ON and OFF states. Such perfect, cyclical ON-OFF release of solutes from gels is demonstrated for the first time through a "smart skin" that is synthesized rapidly (in ∼10 min) around an entire gel. The thin (∼100 μm) and transparent polymer skin is endowed with redox-responsive properties through the use of urethane and acrylate monomers, one of which contains a thioether group. Initially, the skin is hydrophobic (water contact angle 102°), and it completely prevents hydrophilic solutes from leaking out of the gel. When contacted with oxidants such as hydrogen peroxide (H2O2), the thioethers are converted to sulfoxides, making the skin hydrophilic (water contact angle 42°) and thereby turning ON the release of solutes. Conversely, solute release can be turned OFF subsequently by adding a reducing agent such as vitamin C that reverts the sulfoxides to thioethers and thus returns the skin to its hydrophobic state. The release rate in the ON state can be tuned via the skin thickness as well as the oxidant concentration. The ability to regulate solute delivery from gels using smart skins is likely to prove significant in areas ranging from separations to agriculture and drug delivery.

Super-assembled periodic mesoporous organosilica membranes with hierarchical channels for efficient glutathione sensing.

Bioinspired nanochannel-based sensors have elicited significant interest because of their excellent sensing performance, and robust mechanical and tunable chemical properties. However, the existing designs face limitations due to material constraints, which hamper broader application possibilities. Herein, a heteromembrane system composed of a periodic mesoporous organosilica (PMO) layer with three-dimensional (3D) network nanochannels is constructed for glutathione (GSH) detection. The unique hierarchical pore architecture provides a large surface area, abundant reaction sites and plentiful interconnected pathways for rapid ionic transport, contributing to efficient and sensitive detection. Moreover, the thioether groups in nanochannels can be selectively cleaved by GSH to generate hydrophilic thiol groups. Benefiting from the increased hydrophilic surface, the proposed sensor achieves efficient GSH detection with a detection limit of 1.2 μM by monitoring the transmembrane ionic current and shows good recovery ranges in fetal bovine serum sample detection. This work paves an avenue for designing and fabricating nanofluidic sensing systems for practical and biosensing applications.

Thermodynamics of spin crossover in a bis(terpyridine) cobalt(II) complex featuring a thioether functionality.

In this contribution, a terpyridine-based ligand bearing a thioether functionality is used to prepare a new cobalt(II) spin crossover complex: [Co(TerpyPhSMe)2](PF6)2 (1), where TerpyPhSMe is 4'-(4-methylthiophenyl)-2,2':6',2''-terpyridine. Its structure, determined by single crystal X-ray diffraction, reveals a mer coordination of the tridentate terpyridine ligands, leading to a tetragonally compressed octahedron. Intermolecular interactions in the crystal lattice freeze the complex in the high spin state in the solid state at all temperatures, as indicated by magnetometry and Electron Paramagnetic Resonance (EPR) spectra. When dissolved in acetonitrile, however, temperature dependent electronic, 1H-NMR and EPR spectra highlight an entropy-driven spin crossover transition, whose thermodynamics parameters have been determined. This is the first report of a cobalt(II) SCO complex featuring a thioether group, allowing its implementation in chemically grown bistable monolayers and may open important perspectives for the use of such systems in molecular spintronics.

ROS-Responsive 4D Printable Acrylic Thioether-Based Hydrogels for Smart Drug Release.

Reactive oxygen species (ROS) play a key role in several biological functions like regulating cell survival and signaling; however, their effect can range from beneficial to nondesirable oxidative stress when they are overproduced causing inflammation or cancer diseases. Thus, the design of tailor-made ROS-responsive polymers offers the possibility of engineering hydrogels for target therapies. In this work, we developed thioether-based ROS-responsive difunctional monomers from ethylene glycol/thioether acrylate (EGnSA) with different lengths of the EGn chain (n = 1, 2, 3) by the thiol-Michael addition click reaction. The presence of acrylate groups allowed their photopolymerization by UV light, while the thioether groups conferred ROS-responsive properties. As a result, smart PEGnSA hydrogels were obtained, which could be processed by four-dimensional (4D) printing. The mechanical properties of the hydrogels were determined by rheology, pointing out a decrease of the elastic modulus (G') with the length of the EG segment. To enhance the stability of the hydrogels after swelling, the EGnSA monomers were copolymerized with a polar monomer, 2-hydroxyethyl acrylate (HEA), leading to P[(EGnSA)x-co-HEAy] with improved compatibility in aqueous media, making it a less brittle material. Swelling properties of the hydrogels increased in the presence of hydrogen peroxide, a kind of ROS, reaching values of ≈130% for P[(EG3SA)7-co-HEA93] which confirms the stimuli-responsive properties. Then, the P[(EG3SA)x-co-HEAy] hydrogels were employed as matrixes for the encapsulation of a chemotherapeutic drug, 5-fluorouracil (5FU), which showed sustained release over time modulated by the presence of H2O2. Finally, the effect of the 5-FU release from P[(EG3SA)x-co-HEAy] hydrogels was tested in vitro with melanoma cancer cells B16F10, pointing out B16F10 growth inhibition values in the range of 40-60% modulated by the EG3SA percentage and the presence or absence of ROS agents, thus confirming their excellent ROS-responsive properties for the treatment of localized pathologies.

Abstract A027: A photoactivatable microtubule-targeting rigidin prodrug

Abstract Analogues of marine alkaloid rigidins have been found to kill cancer cells at nanomolar concentrations by targeting the microtubule network. Here, a rigidin analogue containing a thioether group was “caged” by coordination of its thioether group to a photosensitive ruthenium polypyridyl complex. In the dark, the coordinated ruthenium fragment prevented the rigidin analogue from inhibiting tubulin polymerization and reduced its toxicity in 2D cancer cell lines monolayers, 3D lung cancer tumor spheroids (A549), and in a lung cancer tumor xenograft (A549) in nude mice. Photochemical activation of the prodrug upon green light irradiation led to the photosubstitution of the thioether ligand by water, thereby releasing the free rigidin analogue capable of inhibiting the polymerization of tubulin. In cancer cells, such photorelease was accompanied by a drastic reduction of cell growth, not only when the cells were grown in normoxia (21% O2) but also, remarkably, in hypoxic conditions (1% O2). In vivo, light activation of the compound in the tumor led to 30% tumor volume reduction, which represents the first demonstration of the efficacy of a ruthenium-based photocaged compounds in a tumor xenograft. In subsequent unpublished work, we fine-tuned the excited states in this complex by adding an amide functional group on the ruthenium cage. By doing so, a new caged complex was obtained that was activated by red light (instead of green light). We demonstrated the red light activation of this compound in solution and in vitro. This result demonstrates that functionalization of ruthenium cage with electron-withdrawing groups can radically enhance their photochemical properties, which is essential for this method development (red light penetrates better into tissues than green light). We will present our results of in vivo testing of this caged compound activated by tumor penetrable red light, where significant tumor reduction is seen in mice xenografted with subcutaneous human uveal melanoma liver metastatic cells. Citation Format: Alexander Kornienko, Sylvestre Bonnet. A photoactivatable microtubule-targeting rigidin prodrug [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A027.