Synergistic Activity Research Articles

Drug-Drug Cocrystal Alloy and Nanoformulation of Cytarabine: Optimized Biopharmaceutical Property and Synergistic Antitumor Efficacy.

An integrated strategy by combining cocrystallization with nanotechnology is developed to optimize in vitro/vivo performances of marine antitumor drug cytarabine (ARA) and further obtain innovative insights into the exploitation of cocrystal alloy nanoformulation. Therein, the optimization of properties and synergistic effects of ARA mainly depends on assembling with uracil (U) and antitumor drug 5-fluorouracil (FU) into the same crystal by cocrystallization technology, while the long-term efficacy is primarily maintained by playing the superiority of nanotechnology. Along this line, the first cocrystal alloy of ARA, viz., ARA-FU-U (0.6:0.4), is successfully obtained and then transformed into a nanocrystal. Single-crystal X-ray diffraction analysis demonstrates that this cocrystal alloy consists of two isomorphic cocrystals of ARA, namely, ARA-FU and ARA-U, in 0.6:0.4 ratio. An R22(8) hydrogen-bonding cyclic system formed by a cytosine fragment of ARA with U or FU can protect and stabilize the amine group on ARA, laying the foundation for regulating its properties. The in vitro/in vivo properties of the cocrystal alloy and its nanocrystals are investigated by theoretical and experimental means. It reveals that both the alloy and nanocrystal can improve physicochemical properties and promote drug absorption, thus bringing to optimized pharmacokinetic behaviors. The nanocrystal produces superior effects than the alloy that helps to extend therapeutic time and action. Particularly, relative to the corresponding binary cocrystal, the synergistic antitumor activity of ARA and FU in the cocrystal alloy is heightened obviously. It may be that U contributes to reducing the degradation of FU, specifically increasing its concentration in tumors to enhance the synergistic effects of FU and ARA. These findings provide new thoughts for the application of cocrystal alloys in the marine drug field and break fresh ground for cocrystal alloy formulations to optimize drug properties.

Novel cobalt-based aerogels for uric acid detection in fluids at physiological pH

A sensor for uric acid (UA) based on the urate oxidase enzyme (UOx) immobilized in novel Co-based aerogels with transition metals synthesized by the sol-gel method was developed and evaluated. The Co-based aerogels: Co, Ni-Co and Pd-Co were physicochemically characterized by XRD and HR-TEM. The surface area values of 53, 57 and 66 m2 g-1 were determined for Co, Ni-Co and Pd-Co, respectively by N2 adsorption-desorption technique. Co-based aerogels were mixed by cross-linking with UOx enzymes and electrochemically characterized in buffers at pH 7.4 and 5.6 (pH values reported for biological fluids such as blood and sweat) in the presence of different uric acid concentrations. Co-based aerogels with UOx showed improved performance as a uric acid biosensor compared to using the enzyme alone. At a pH of 7.4, a higher sensitivity of 11 μA μM−1 was obtained with Pd-Co/UOx, 1.6 times higher than with UOx. At a pH value of 5.6, the highest sensitivity is achieved with Ni-Co/UOx. Stability and selectivity tests were performed in the presence of biological interferents without significant changes in the sensor. These results indicate a pleasing synergistic activity between Co-based aerogels and the enzyme.

Integrated network pharmacology and transcriptomics to reveal the mechanism of Passiflora against depressive disorder: An observational study.

Relevant studies have pointed out that Passiflora could relieve depressive disorder (DD) related symptoms, such as anxiety and insomnia, but its mechanism in DD has not been reported. In this study, DD-related transcriptome data was extracted from the Gene Expression Omnibus (GEO) database. Subsequently, 50 differentially expressed genes (DEGs) were screened by "limma," and the enrichment analysis of these DEGs revealed that they were associated with neuro-inflammatory-related signaling pathways, including IL-17, TNF, NF-kappa B, etc signaling pathways. Then, CCDC58, CXCL5, EGR1, LOC101929855, SCML1, and THBS1 were screened as biomarkers of DD by the least absolute shrinkage and selection operator (LASSO) analysis. Moreover, Harmaline, Harmine, Quercetin, and Kaempferol were the key chemically active ingredients of Passiflora. Noticeable, THBS1 and Quercetin were connected closely. In addition, the quantitative real-time polymerase chain reaction (qRT-PCR) confirmed that the key biomarkers (EGR1 and THBS1) were significantly lowly expressed in DD samples. In summary, we identified 2 key biomarkers of DD and 4 key chemically active ingredients of Passiflora. The potential mechanism of antidepressant effect of DD associated with neuro-inflammatory responses and neurotransmitter function. These might related to the synergistic activity of its key active ingredients with TNF-α, IL-1β, IL-6, etc, which work with EGR1 and THBS1 to regulate IL-17, NF-kappa B, TNF, etc signaling pathways. These findings might help to deepen the understanding of the mechanism of Passiflora in clinical treatment of DD.

Demonstrating Synergistic Activity of Magnetic Iron Oxide Nano Photocatalyst for C-H Activation in Heterogeneous Phase.

This report describes a dual catalytic approach for the versatile C‒H arylation of arenes under photo-excitation at room temperature. The cooperative catalysis utilizes iron oxide magnetic nanoparticles (which mostly contain Fe3O4 along with some γ-Fe2O3) as the potential photocatalyst, which merges with the Pd-catalyzed C‒H activation cycle for the reductive generation of aryl radical from aryl diazonium salt, revealing its photocatalytic activities. The method is applicable to a wide range of aryl coupling partners and different directing groups, demonstrating excellent productivity, nice co-operativity and recyclability. Adequate control experiments and mechanistic studies assisted in establishing the radical-based mechanism for the C‒H arylation occurring in the heterogeneous phase.

Imidazoles and Quaternary Ammonium Compounds as Effective Therapies against (Multidrug-Resistant) Bacterial Wound Infections.

The rise and spread of antimicrobial resistance complicates the treatment of bacterial wound pathogens, further increasing the need for newer, effective therapies. Azoles such as miconazole have shown promise as antibacterial compounds; however, they are currently only used as antifungals. Previous research has shown that combining azoles with quaternary ammonium compounds yields synergistic activity against fungal pathogens, but the effect on bacterial pathogens has not been studied yet. In this study, the focus was on finding active synergistic combinations of imidazoles and quaternary ammonium compounds against (multidrug-resistant) bacterial pathogens through checkerboard assays. Experimental evolution in liquid culture was used to evaluate the possible emergence of resistance against the most active synergistic combination. Several promising synergistic combinations were identified against an array of Gram-positive pathogens: miconazole/domiphen bromide, ketoconazole/domiphen bromide, clotrimazole/domiphen bromide, fluconazole/domiphen bromide and miconazole/benzalkonium chloride. Especially, miconazole with domiphen bromide exhibits potential, as it has activity at a low concentration against a broad range of pathogens and shows an absence of strong resistance development over 11 cycles of evolution. This study provides valuable insight into the possible combinations of imidazoles and quaternary ammonium compounds that could be repurposed for (topical) wound treatment. Miconazole with domiphen bromide shows the highest application potential as a possible future wound therapy. However, further research is needed into the mode of action of these compounds and their efficacy and toxicity in vivo.

Investigation of the Synergistic Anti-pyretic and Anti-inflammatory Activity of Sonchus wightianus DC, Paracetamol and Indomethacin Combination in Rat Models

Investigation of the Synergistic Anti-pyretic and Anti-inflammatory Activity of Sonchus wightianus DC, Paracetamol and Indomethacin Combination in Rat Models

Boosting the synergistic activation of δ-MnO2 as cathode for aqueous zinc-ion batteries through Ni, Co co-doping

Layered δ-MnO2 is regarded as a promising cathode material for high-performance aqueous zinc-ion batteries (AZIBs) due to the sufficient interlayer spacing for the accommodation and migration of charge carriers. However, the sluggish activation process limits the reversible capacity, thus prevent their application. In this study, Ni-Co co-doped layered δ-MnO2 was designed to enhance ion diffusion capability and cycling stability. The influencing mechanism of Ni and Co on the long activation process are proposed by a comparative analysis between single doping and co-doping approaches. Specifically, the optimized co-doped δ-MnO2 maintained a high specific capacity of 200.2 mAh·g−1 with a capacity retention of 97.40 % after 700 cycles at 1 A·g−1. The co-doping approach exhibited a synergistic effect in suppressing Mn dissolution and enhancing ion diffusion capability. These findings provide new directions on boosting the synergistic activation process of manganese oxide and shed lights on the rational design of low-cost and high-safe batteries.

Synergistic invitro antimicrobial activity of polyherbal combination of Morinda lucida fruit and Pterocarpus santalinoides seed against multi-drug resistant clinical bacterial isolates

Background: Synergistic drug combination has been shown to be a way of bypassing drug resistance and reducing the amounts of antimicrobials consumed. As infections caused by multi-drug resistant organisms (MDROs) continue to pose global threat, it is important to search for new antimicrobial combinations of plant origin that are safe and readily available. The objective of this study is to evaluate the synergistic antimicrobial activity of extracts of Morinda lucida fruit and Pterocarpus santalinoides seed against multi-drug resistant (MDR) bacterial isolates Methodology: Morinda lucida and P. santalinoides fruits were plucked and washed clean, and the fruits of P. santalinoides were deseeded to remove the seeds. They were cut into smaller pieces and dried under shade before being milled into smooth powder and extracted with methanol. The clinical bacterial isolates used were MDR Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus. The phytochemical constituents of the extracts were determined using the standard method. The invitro antimicrobial assay of the extracts was done at a concentration of 50 to 400 mg/ml using the agar well diffusion technique. The minimum inhibitory concentration (MIC) and fractional inhibitory concentration (FIC) of each extract were determined using the Checker-board micro-titration method, and the FIC result obtained for each isolate was used to calculate the fractional inhibitory concentration index (FICI) of the combined extracts. The time kill assay was performed to confirm the synergistic and bactericidal activities from the MIC values obtained. Results: The phytochemical analysis revealed that the extracts of both herbal plants contained alkaloids, phenol, tannin, saponin, glycosides, and terpenoids. The antimicrobial assay results showed that the polyherbal combination of the extracts was active against all the MDR bacterial isolates tested with varying zones of inhibition. The mean inhibition zone diameters of individual M. lucida and P. santalinoides ranged from 18.0±0.9mm to 26.0±1.4mm and 17.0±0.1mm to 24.0±0.2mm respectively, while the MIC ranged from 6.25mg/ml to 12.5mg/ml for M. lucida and 12.5 mg/ml for P. santalinoides. The mean inhibition zone diameter of the polyherbal combination of the two plant extracts ranged from 25.00±00mm to 34.0±0.4mm, which compared favorably with that of levofloxacin control (28.0±0.0mm to 32.00±0.0mm), while their MIC ranged from 0.39mg/ml to 1.56mg/ml. The FIC of M. lucida extract ranged from 0.06mg/ml to 0.25mg/ml while that of P. santalinoides ranged from 0.03mg/ml to 0.13mg/ml. The FICI of combined extracts ranged from 0.09mg/ml to 0.38 mg/ml for all the MDR isolates, which is less than 0.5mg/ml, indicating synergism against all the isolates. The time of kill assay confirmed the synergistic and bactericidal activities with a 3log10 CFU/ml decrease in the number of viable cells within 6 hours of incubation.Conclusion: Our findings showed synergistic antibacterial actions of extracts of M. lucida fruit and P. santalinoides seed against MDR clinical bacterial isolates, comparable to levofloxacin. Combination of these herbal plants may serve as alternative sources of antimicrobial agents for the treatment of infections caused by MDR bacterial pathogens.

Colamine and tartaric acid based innovative antioxidant and anti-spoilage food additive for fish product industry

Background: Fish farming is a vital sector of the global food industry, facing the challenge of developing efficient, chemical-free feeds for high-value fish species. To address this, innovative antimicrobials and antioxidants are crucial. This study explores the antioxidant and anti-spoilage properties of novel N-containing derivatives of natural L-tartaric acid (TA), a safe and widely used food additive. Objectives: Current research is devoted to L-tartrates’ new derivatives’ anti-spoilage and antioxidant potential as an innovative combined feed additive for fish farming. Results: TA Cyclic imide obtaining modified technology was advised. According to the obtained results, TA itself didn’t show antioxidant activity: nevertheless, in combination with new N-containing derivatives, it increased the antioxidant properties of L-ascorbic acid by about 20%. The studied TA amino-derivatives have demonstrated the emphasized activity against the fish-pathogenic Pseudomonas, Streptococcus, and other pathogenic microbes. Conclusions: TA and tartrates, in combination with new N-containing derivatives generated based on the vital compound colamine, have demonstrated several synergic antioxidant activities. They can be recommended for potential application as a cheap and effective alternative to classical anti-spoilage and preservative agents for animal feed production. Also, they showed the prolongation of feed expiration periods. It will significantly increase the quality of final fish products. A further detailed study of toxicological properties of amino derivatives is planned. Keywords: tartaric acid derivative, colamine, antimicrobial, antioxidant, anti-spoilage, feed additive

Synergistic Dual Activation Catalysis by Saccharin‐Based Ionic Liquids for Diastereoselective Synthesis of Ferrocene‐Appended Furopyranones, Furochromenones, and Benzofuranones

ABSTRACTA practical and straightforward strategy for the synthesis of ferrocene appended furopyranone, furochromenone, and benzofuranone via a metal‐free annulation reaction of imidazolium ylide with enone mediated by saccharin‐based ionic liquid has been reported. The mechanistic studies show an approach through synergistic dual activation of enone and imidazolium ylide via cation and anion of ionic liquid, respectively. This operationally simple protocol offers an easy and rapid access to a library of ferrocene appended furopyranone, furochromenone, and benzofuranone in moderate to good yields through the involvement of a six‐membered transition state.

Synergistic bactericidal activity of chlorhexidine loaded on positively charged ionic liquid-protected silver nanoparticles as a root canal disinfectant against Enterococcus faecalis: An ex vivo study

The advancement of nanotechnology and the development of nanocomplexes offer promising solutions to address the limitations in biofilm management within endodontics. Current cleaning and disinfection methods often fail to completely eliminate bacterial biofilms from the complex anatomical structures of root canals, making the invention of new disinfectants or disinfection methods highly relevant. Previously, chlorhexidine-loaded positively charged ionic liquid-protected silver nanoparticles (CHX@AgNPs⁺) were introduced as an innovative root canal irrigation solution, demonstrating significant antibacterial efficacy against Enterococcus faecalis in vitro. This study aimed to further evaluate the antibiofilm activity of CHX@AgNPs⁺ in the root canals of extracted human teeth contaminated with E. faecalis biofilm. Fifty single-rooted human teeth with mature apices were randomly assigned to five experimental groups based on the irrigants used: CHX@AgNPs⁺, AgNPs⁺, 2.5 % NaOCl, 2 % CHX, and normal saline (n = 10 per group). The root canals were contaminated with E. faecalis, and biofilm formation was confirmed. Initial sampling (S1) was performed, followed by mechanical preparation of the root canals using ProTaper F3 files and irrigation with the respective test solutions. Post-instrumentation sampling (S2) was then conducted. The results demonstrated that CHX@AgNPs⁺ exhibited antibiofilm properties comparable to 2.5 % NaOCl, with no significant difference between them. Additionally, CHX@AgNPs⁺ significantly enhanced antimicrobial efficacy compared to CHX alone (P < 0.05), highlighting its potential as an effective root canal disinfectant.

Recent Achievements in Heterogeneous Bimetallic Atomically Dispersed Catalysts for Zn-Air Batteries: A Minireview.

Rechargeable Zn-air batteries (ZABs) hold promise as the next-generation energy-storage devices owing to their affordability, environmental friendliness, and safety. However, cathodic catalysts are easily inactivated in prolonged redox potential environments, resulting in inadequate energy efficiency and poor cycle stability. To address these challenges, anodic active sites require multiple-atom combinations, that is, ensembles of metals. Heterogeneous bimetallic atomically dispersed catalysts (HBADCs), consisting of heterogeneous isolated single atoms and atomic pairs, are expected to synergistically boost the cyclic oxygen reduction and evolution reactions of ZABs owing to their tuneable microenvironments. This minireview revisits recent achievements in HBADCs for ZABs. Coordination environment engineering and catalytic substrate structure optimization strategies are summarized to predict the innovation direction for HBADCs in ZAB performance enhancement. These HBADCs are divided into ferrous and nonferrous dual sites with unique microenvironments, including synergistic effects, ion modulation, electronic coupling, and catalytic activity. Finally, conclusions and perspectives relating to future challenges and potential opportunities are provided to optimise the performance of ZABs.

Selective Functionalization of Alkenes and Alkynes by Dinuclear Manganese Catalysts.

ConspectusAlkenes and alkynes are fundamental building blocks in organic synthesis due to their commercial availability, bench-stability, and easy preparation. Selective functionalization of alkenes and alkynes is a crucial step for the synthesis of value-added compounds. Precise control over these reactions allows efficient construction of complex molecules with new functionalities. In recent decades, second- and third-row precious transition metal catalysts (palladium, platinum, rhodium, ruthenium) have been pivotal in the development of metal-catalyzed synthetic methodology. These metals exhibit excellent catalytic activity and selectivity, enabling efficient synthesis of functionalized organic molecules. However, recovery and reuse of precious metals have long been a challenge in this field. In recent years, exploration of earth-abundant metal-catalyzed organic reactions has interested both academic and industrial researchers. The development of such catalytic systems offers a promising approach to overcome the limitations of precious metal catalysts. For example, manganese is the third most naturally abundant transition metal with minimal toxicity and excellent biocompatibility. It exhibits good catalytic activity in several organic reactions, including C-H bond functionalization, selective reduction, and radical reactions. This Account outlines our recent progress in dinuclear manganese catalysis for selective functionalization of alkenes and alkynes. We have established the elementary manganese(I)-catalysis in transmetalation with R-B(OH)2. This finding has enabled us to apply the catalyst for the selective 1,2-difunctionalization of structurally diverse alkenes and alkynes. Mechanistic studies suggest a double manganese center synergistic activation model, as superior to Mn(CO)5Br in some cases. In addition, we have developed a ligand-tuned metalloradical strategy of dinuclear manganese catalysts (Mn2(CO)10), bridging the gap between the organometallics and radical chemistry, highlighting the unique radical functionalization of alkenes. Interestingly, using the same starting materials, different ligands can deliver completely different products. Meanwhile, a cooperative catalysis strategy involving manganese and other catalysts (e.g., cobalt, iminium) has also been developed and is briefly discussed. For manganese/iminium synergistic catalysis, a new mechanism for migratory insertion and demetalization-isomerization in synergistic HOMO-LUMO activation was disclosed. This strategy expands the application of low-valent manganese catalysts for enantioselective C-C bond-forming reactions. New reaction discovery is outpacing mechanism studies for dinuclear manganese catalysis, and future studies with time-resolved spectroscopy will improve understanding of the mechanism. Based on these intriguing findings, the precise functionalization of alkenes and alkynes by dinuclear manganese catalysts will expedite a novel activation model to enable late-stage functionalization of complex molecules.

Synergistic Effect Antibacterial Activity of The Combination of Andaliman (Zanthoxylum acanthopodium DC) Fruit Essential Oil and Erythromycin against Streptococcus mutans and Streptococcus pyogenes

Background: The concept of synergism is one of the approaches taken to combat the problems related to antibiotic resistance. Objectives: The goal of this study was to determine the synergistic effect of antibacterial activity of a combination of essential oil of Zanthoxylum acanthopodium DC fruit and erythromycin against Streptococcus mutans and Streptococcus pyogenes. Methods: The broth microdilution assay was used to determine the Minimum Inhibitory Concentration (MIC) of Z. acanthpodium DC fruit essential oil and erythromycin. The synergistic effects were assessed using the checkerboard method. Results: MIC value of Z. acanthopodium DC fruit essential oil against both bacteria was 2500 mg/mL. The combination of Z. acanthopodium DC fruit essential oil and erythromycin had a synergistic effect against S. mutans and S. pyogenes with fractional inhibitory concentration index (FICI) values of 0.375 and 0.0872, respectively. Conclusions: These results suggest that a combination of herbal plants and conventional antibiotics could be used as an alternative therapy for bacterial infections.

Efficient degradation of norfloxacin by synergistic activation of PMS with a three-dimensional electrocatalytic system based on Cu-MOF

In this work, Cu-based metal-organic framework material (Cu-MOF) was combined with an electric field to construct a three-dimensional electrocatalytic synergistic activation of peroxymonosulfate sulfate (PMS) system (3D/Cu-MOF/EC/PMS) for the degradation of norfloxacin (NOR). The results show that the synergistic degradation efficiency of the Cu-MOF material with the electric field is enhanced by nearly 64 % relative to the degradation efficiency of the two alone. The quenching experimental and EPR characterization indicates that ROS plays an important role in the degradation process, with O2– playing a dominant role. Finally, the degradation pathway of NOR was explored by DFT study and LC-MS tests, and the toxicity evaluation software (TEST) and CCK-8 cytotoxicity experimental studies demonstrated that the sewage after the degradation of NOR by this system would have little or no effect on human liver cells (L02). This study not only shows that the 3D/Cu-MOF/EC/PMS system can treat the water containing higher concentrations of NOR into a state that is not harmful to the human body but also provides a new idea for the improvement of catalysts that do not have obvious catalytic degradation effects.

The Amount and Pattern of Reciprocal Compensations Predict Performance Stability in a Visually Guided Finger Force Production Task.

Previous work suggests that synergistic activity among motor elements implicated in force production tasks underlies enhanced performance stability associated with visual feedback. A hallmark of synergistic activity is reciprocal compensation, that is, covariation in the states of motor elements that stabilizes critical performance variables. The present study examined if characteristics of reciprocal compensation are indicators of individuals' capacity to respond adaptively to variations in the resolution of visual feedback about criterion performance. Twenty healthy adults (19.25 ± 1.25years; 15 females and five males) pressed two sensors with their index fingers to produce a total target force equivalent to 20% of their maximal voluntary contraction under nine conditions that differed in the spatial resolution of real-time feedback about their performance. By combining within-trial uncontrolled manifold and sample entropy analyses, we quantified the amount and degree of irregularity (i.e.,non-repetitiveness) of reciprocal compensations over time. We found a U-shaped relationship between performance stability and gain. Importantly, this relationship was moderated by the degree of irregularity of reciprocal compensation. Lower irregularity in reciprocal compensation patterns was related to individuals' capacity to maintain (or minimize losses in) performance under changes in feedback resolution. Results invite future investigation into how interindividual variations in reciprocal compensation patterns relate to differences in control strategies supporting adaptive responses in complex, visually guided motor tasks.

219 (PB207): Dual Targeting of BRAF-V600E and Ferroptosis Results in Synergistic Anticancer Activity via Iron Overload and Enhanced Oxidative Stress

219 (PB207): Dual Targeting of BRAF-V600E and Ferroptosis Results in Synergistic Anticancer Activity via Iron Overload and Enhanced Oxidative Stress

Synergistic photocatalytic activity of Bi2O3/g-C3N4/ZnO ternary heterojunction with dual Z-scheme charge transfer towards textile dye degradation

It is clear that a wide range of organic substances, including synthetic textile dyes, have the potential to negatively impact the environment. It is crucial to rationally develop highly effective photocatalysts for the degradation of such type of pollutants. In this regard, a heterostructured photocatalyst comes with enhanced charge separation and extended light absorption ability that improves photocatalytic performance. Therefore, In this study, a Bi2O3/g-C3N4/ZnO (BCNZ) ternary heterojunction photocatalyst was synthesized for the degradation of methylene blue (MB) textile dye.. Thermal polycondensation method was opted to synthesize g-C3N4, while ZnO and Bi2O3 photocatalysts were fabricated using co-precipitation method. Similarly, ternary heterojunction of BCNZ was constructed through co-precipitation method. The ternary heterojunction photocatalyst demonstrated better photodegradation ability due to dual Z-scheme charge transfer route. The dual Z-scheme heterojunction enabled the ternary heterojunction to exhibit enhanced light absorption capabilities with reduced recombination rates as well as enhanced charge separation and migration efficiency (confirmed via transient photocurrent response) that resulted in improved photocatalytic performance. The BCNZ dual Z-scheme photocatalyst displayed 92 % of degradation efficiency which was much higher than that of other (binary and pristine) photocatalysts. Scavenging tests and electron spin resonance spectroscopy revealed the significant role of the •O2−, and •OH radicals in the photodegradation of MB. Furthermore, the reusability test presented good stability and recyclability of the ternary photocatalyst with 80 % degradation efficiency after five catalytic cycles.

SCR-7952, a highly selective MAT2A inhibitor, demonstrates synergistic antitumor activities in combination with the S-adenosylmethionine-competitive or the methylthioadenosine-cooperative protein arginine methyltransferase 5 inhibitors in methylthioadenosine phosphorylase-deleted tumors.

The metabolic enzyme methionine adenosyltransferase 2A (MAT2A) was found to elicit synthetic lethality in methylthioadenosine phosphorylase (MTAP)-deleted cancers, which occur in about 15% of all cancers. Here, we described a novel MAT2A inhibitor, SCR-7952 with potent and selective antitumor effects on MTAP-deleted cancers in both in vitro and in vivo. The cryo-EM data indicated the high binding affinity and the allosteric binding site of SCR-7952 on MAT2A. Different from AG-270, SCR-7952 exhibited little influence on metabolic enzymes and did not increase the plasma levels of bilirubin. A systematic evaluation of combination between SCR-7952 and different types of protein arginine methyltransferase 5 (PRMT5) inhibitors indicated remarkable synergistic interactions between SCR-7952 and the S-adenosylmethionine-competitive or the methylthioadenosine-cooperative PRMT5 inhibitors, but not substrate-competitive ones. The mechanism was via the aggravated inhibition of PRMT5 and FANCA splicing perturbations. These results indicated that SCR-7952 could be a potential therapeutic candidate for the treatment of MTAP-deleted cancers, both monotherapy and in combination with PRMT5 inhibitors.

From the Design of Innovative Ti-Pt Heterometallic Complexes to the Development of Highly Anti-Proliferative Water-Soluble Cationic Titanocenes.

Two innovative early/late Ti-Pt-heterobimetallic complexes were synthesized, characterized, and screened in cell-based assays using several human (SW480 and MDA-MB-231) and murine cancer cell lines (CT26 and EMT6) as well as a non-cancerous cell line (HMEC). The combination of the two metals - titanium(IV) and platinum (IV) - in a single molecule led to a synergistic biological activity (higher anti-proliferative properties than a mixture of each of the corresponding monometallic complexes). This study also investigated the benefits of associating a metal-free terpyridine moiety (with intrinsic biological activity) with a water-soluble titanocene fragment. The present work reveals that these combinations results in water-soluble titanocene compounds displaying an anti-proliferative activity down to the submicromolar level. One of these complexes induced an antitumor effect in vivo in CT26 tumor bearing BALB/C mice. The terpyridine moiety was also used to track the complex in vitro by multiphoton microscopy imaging.