Aptamer based hybrid monolithic pipette tips supported by melamine sponge for enrichment of proteins.

BACKGROUND: The convenient preparation and application of functionalized organic-inorganic hybrid monolithic materials have obtained substantial interest in the pretreatment of complex samples by solid-phase extraction (SPE). Compared to the in-tube solid-phase microextraction in fused-silica capillaries, micro SPE in plastic pipette tips have fascinating merits for the easily operated enrichment of trace target analytes from biological samples. However, the poor compatibility of organic-inorganic hybrid monoliths with plastics leads to the rare appearance of commercial hybrid monolithic pipette tips (HMPTs). Therefore, how to synthesize the organic-inorganic hybrid monolithic materials with better extraction performance in plastic pipette tips becomes a challenge. RESULTS: We develop a facile and cheap strategy to immobilize organic-inorganic hybrid monoliths in pipette tips. Melamine sponge was employed as the supporting skeleton to in situ assemble amine- and thiol-bifunctionalized hybrid monolithic material via "one pot" in a pipette tip, and gold nanoparticles (GNPs) and thiol-modified aptamer against human α-thrombin were sequentially attached to the hybrid monolith within the HMPTs. The average coverage density of the aptamer with GNPs as an intermediary reached as high as 818.5 pmol µL-1. The enriched thrombin concentration was determined by a sensitive enzymatic chromogenic assay with the limit of detection of 2 nM. The extraction recovery of thrombin at 10 nM in human serum was 86.1 % with a relative standard deviation of 6.1 %. This proposed protocol has been applied to the enrichment and determination of thrombin in real serum sample with strong anti-interference ability, low limit of detection and high recovery. SIGNIFICANCE: The amine- and thiol-bifunctionalized HMPTs prepared with sponge as the skeleton frame provided a novel substrate material to decorate aptamers for efficient enrichment of proteins. This enlightens us that we can take advantage of the tunability of sponge assisted HMPTs to produce and tailor a variety of micro SPE pipette tips for broader applications on the analysis of trace targets in complex biological, clinic and environmental samples.

Advances in the Synthesis of Bioorthogonal Reagents: s-Tetrazines, 1,2,4-Triazines, Cyclooctynes, Heterocycloheptynes, and trans-Cyclooctenes.

Aligned with the increasing importance of bioorthogonal chemistry has been an increasing demand for more potent, affordable, multifunctional, and programmable bioorthogonal reagents. More advanced synthetic chemistry techniques, including transition-metal-catalyzed cross-coupling reactions, C-H activation, photoinduced chemistry, and continuous flow chemistry, have been employed in synthesizing novel bioorthogonal reagents for universal purposes. We discuss herein recent developments regarding the synthesis of popular bioorthogonal reagents, with a focus on s-tetrazines, 1,2,4-triazines, trans-cyclooctenes, cyclooctynes, hetero-cycloheptynes, and -trans-cycloheptenes. This review aims to summarize and discuss the most representative synthetic approaches of these reagents and their derivatives that are useful in bioorthogonal chemistry. The preparation of these molecules and their derivatives utilizes both classical approaches as well as the latest organic chemistry methodologies.

The activity of pyrazolo[4,3-e][1,2,4]triazine and pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine sulphonamide derivatives in monolayer and spheroid breast cancer cell cultures.

In the last decade, an increasing interest in compounds containing pyrazolo[4,3-e][1,2,4]triazine moiety is observed. Therefore, the aim of the research was to synthesise a novel sulphonyl pyrazolo[4,3-e][1,2,4]triazines (2a, 2b) and pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine sulphonamide derivatives (3a, 3b) to assess their anticancer activity. The MTT assay showed that 2a, 2b, 3a, 3b have stronger cytotoxic activity than cisplatin in both breast cancer cells (MCF-7 and MDA-MB-231) and exhibited weaker effect on normal breast cells (MCF-10A). The obtained results showed that the most active compound 3b increased apoptosis via caspase 9, caspase 8, and caspase 3/7. It is worth to note that compound 3b suppressed NF-κB expression and promoted p53, Bax, and ROS which play important role in activation of apoptosis. Moreover, our results confirmed that compound 3b triggers autophagy through increased formation of autophagosomes, expression of beclin-1 and mTOR inhibition. Thus, our study defines a possible mechanism underlying 3b-induced anti-cancer activity against breast cancer cell lines.

Functionalization of Siloxanes with Arynes Generated from o-Triazenylarylboronic Acids.

Herein, we report the functionalization of polyhedral oligosilsesquioxanes (POSS) and related siloxanes with arynes. Using o-triazenylarylboronic acids as aryne precursors and silica gel as the activator, the transformation of siloxane bearing various arynophilic moieties on the side chains was achieved with high yields without touching the siloxane core. This method was applied to the conjugation of POSS and pharmaceutical cores using an aryne derived from the synthetic intermediate of cabozantinib. Furthermore, orthogonal dual functionalization of POSS was realized by combining the aryne reaction with Huisgen cyclization.

Melamine sponges incorporated azo-linked porous organic polymer as adsorbent for extraction and determination of six B vitamins using pipette tip micro solid-phase extraction.

A novel azo-linked porous organic polymer (AL-POP) was synthesized from caffeic acid and benzidine via an azo-coupling reaction and characterized by FTIR, SEM-EDS, BET, TGA, XRD and zeta potential analysis. AL-POPs were incorporated into melamine sponges and used for pipette tip micro solid-phase extraction (PT-MSPE) of six types of B vitamins (including thiamine, riboflavin, nicotinamide, pyridoxine, folic acid, and cyanocobalamin). After extraction, the samples were analyzed using high performance liquid chromatography-diode array detection (HPLC-DAD) system. The effect of AL-POP composition on the extraction efficiency (EE) of vitamins was investigated and benzidine to caffeic acid mol ratio of 1.5, 3.35 mmol of NaNO2, and reaction time of 8 h were selected as optimum conditions. The efficiency of the extraction process was improved by optimizing various parameters such as the amount of sorbent, pH and ionic strength of the sample, sample volume, number of sorption and desorption cycles, type of wash solvent, and type and volume of eluent solvent. Linearity (R2≥0.9987), Limit of detection (LOD) (11.88-18.97 ng/mL), limit of quantification (LOQ) (39.62-63.23 ng/mL), and enrichment factor (EF) (1.27-4.31) were obtained using calibration curves plotted under optimum conditions. Recovery values of these six B vitamins in the spiked multivitamin syrup samples varied from 80.01% to 108.35%, with a relative standard deviation (RSD) below 5.44%. Eventually, the optimized method was successfully used to extract and quantify the B vitamins in multivitamin syrup and non-alcoholic beer.

Co-delivery of Plinabulin and Tirapazamine boosts anti-tumor efficacy by simultaneously destroying tumor blood vessels and killing tumor cells.

It is imperative to optimize chemotherapy for heightened anti-tumor therapeutic efficacy. Unrestrained tumor cell proliferation and sustained angiogenesis are pivotal for cancer progression. Plinabulin, a vascular disrupting agent, selectively destroys tumor blood vessels. Tirapazamine (TPZ), a hypoxia-activated prodrug, intensifies cytotoxicity in diminishing oxygen levels within tumor cells. Despite completing Phase III clinical trials, both agents exhibited modest treatment efficiency due to dose-limiting toxicity. In this study, we employed methoxy poly(ethylene glycol)-b-poly(D,L-lactide) (mPEG-b-PDLLA) to co-deliver Plinabulin and TPZ to the tumor site, concurrently disrupting blood vessels and eliminating tumor cells, addressing both symptoms and the root cause of tumor progression. Plinabulin was converted into a prodrug with esterase response (PSM), and TPZ was synthesized into a hexyl chain-containing derivative (TPZHex) for effective co-delivery. PSM and TPZHex were co-encapsulated with mPEG-b-PDLLA, forming nanodrugs (PT-NPs). At the tumor site, PT-NPs responded to esterase overexpression, releasing Plinabulin, disrupting blood vessels, and causing nutritional and oxygen deficiency. TPZHex was activated in response to increased hypoxia, killing tumor cells. In treating 4T1 tumors, PT-NPs demonstrated enhanced therapeutic efficacy, achieving a 92.9 % tumor suppression rate and a 20 % cure rate. This research presented an innovative strategy to enhance synergistic efficacy and reduce toxicity in combination chemotherapy.

Fabrication of melamine formaldehyde/graphene oxide composite for efficient static and dynamic adsorption of lead ions from aqueous medium.

The present work discusses the synthesis, characterization, and environmental applications of graphene oxide (GO), melamine formaldehyde resin (MF), and melamine formaldehyde/graphene oxide composite (MGO) for the efficient removal of Pb2+ from aqueous medium via batch and column procedures. TGA, XRD, TEM, zeta potential, nitrogen adsorption/desorption, ATR-FTIR, and other characterization techniques revealed that MGO is characterized by a greater surface area (609 m2/g), total pore volume (1.0106 cm3/g), pHPZC (6.5), and the presence of various surface chemical functional groups. The synthesized solid adsorbents were used in both static and dynamic adsorption processes to remove Pb2+, with varying application parameters such as pH, starting concentration, adsorbent dosage, and shaking time in the case of static adsorption method. While through the column adsorption process the effects of column bed height, flow rate, and starting Pb2+ were taken into consideration. Results of the batch adsorption demonstrated that MGO had the highest Langmuir adsorption capacity (201.5 mg/g), and the adsorption fit the nonlinear Langmuir adsorption model and Elovich kinetic models. The adsorption of Pb2+ onto all prepared solid materials is endothermic, spontaneous, and physical in nature, as demonstrated by thermodynamic studies. Column adsorption of Pb2+ well fitted by Thomas and Yoon Nelson nonlinear adsorption models. MGO showed a maximum column adsorption capacity of 168 mg/g when applying 4 cm, 15 mL/min, and 150 mg/L as bed height, flow rate, and initial Pb2+, respectively. With only a 12.6% reduction in its adsorption capacity, column regeneration showed that MGO exhibited a high degree of reusability even after five cycles of adsorption/desorption studies.

A novel sponge composite of chitosan-sodium tripolyphosphate-melamine for anionic dye Orange II removal.

Since the potential carcinogenic, toxic and non-degradable dyes trigger serious environmental contamination by improper treatment, developing novel adsorbents remains a major challenge. A novel high efficiency and biopolymer-based environmental-friendly adsorbent, chitosan­sodium tripolyphosphate-melamine sponge (CTS-STPP-MS) composite, was prepared for Orange II removing with chitosan as raw material, sodium tripolyphosphate as cross-linking agent. The composite was carefully characterized by SEM, EDS, FT-IR and XPS. The influence of crosslinking conditions, dosage, pH, initial concentration, contacting time and temperature on adsorption were tested through batch adsorption experiments. CTS-STPP-MS adsorption process was exothermic, spontaneous and agreed with Sips isotherm model accompanying the maximum adsorption capacity as 948 mg∙g-1 (pH = 3). Notably, the adsorption performance was outstanding for high concentration solutions, with a removal rate of 97 % in up to 2000 mg∙L-1 OII solution (100 mg sorbent dosage, 50 mL OII solution, pH = 3, 289.15 K). In addition, the adsorption efficiency yet remained 97.85 % after 5 repeated adsorption-desorption cycles. The driving force of adsorption was attributed to electrostatic attraction and hydrogen bonds which was proved by adsorption results coupled with XPS. Owing to the excellent properties of high-effective, environmental-friendly, easy to separate and regenerable, CTS-STPP-MS composite turned out to be a promising adsorbent in contamination treatment.

A nimble strategy for enabling bioderived flame retardants with strikingly enhanced interfacial compatibility in poly (lactic acid) composites.

The utilization of bioderived flame retardants in biodegradable poly (lactic acid) (PLA) has profound practical implications for extending the widespread application of PLA composites and protecting the environment. Nevertheless, there are still certain challenges that require prompt attention, especially the ineffectiveness of bio-based flame retardants and their deterioration of the mechanical properties of PLA. This work introduced triglycidyl isocyanurate (TGIC), which has multiple epoxy functions, into the self-assembly process of phytic acid (PA) and chitosan (CS). The epoxy-modified bioderived flame retardant PA@CS-TGIC (PCT) was well dispersed in the PLA matrix and had a strong interfacial adhesion, while also TGIC had a synergistic char-forming effect. By compounding epoxy-modified ammonium polyphosphate (MAPP), 3%PCT/MAPP-PLA composites may reach a LOI value of 28.8 % and UL-94 V-0 rating. Simultaneously, the melting droplets had been considerably reduced. Tensile strength of the 3%PCT/MAPP-PLA composites was 67.0 MPa, 10.8 % higher than that of pure PLA. This work paves a new avenue for the development of PLA composites with robust mechanical and flame retardant properties.

A magnetic imprinted polymer nano-adsorbent with embedded quantum dots and mesoporous carbon for the microextraction of triazine herbicides.

A magnetic molecularly imprinted polymer (MMIP) adsorbent incorporating amino-functionalized magnetite nanoparticles, nitrogen-doped graphene quantum dots and mesoporous carbon (MIP@MPC@N-GQDs@Fe3O4NH2) was fabricated to extract triazine herbicides from fruit juice. The embedded magnetite nanoparticles simplified the isolation of the adsorbent from the sample solution. The N-GQDs and MPC enhanced adsorption by affinity binding with triazines. The MIP layer provided highly specific recognition sites for the selective adsorption of three target triazines. The extracted triazines were determined by high-performance liquid chromatography (HPLC) coupled with diode-array detection (DAD). The developed method exhibited linearity from 1.5 to 100.0 µg L-1 with a detection limit of 0.5 µg L-1. Recoveries from spiked fruit juice samples were in the range of 80.1- 108.4 %, with a relative standard deviation of less than 6.0 %. The developed MMIP adsorbent demonstrated good selectivity, high extraction efficiency, ease of fabrication and use, and good stability.

A nanogold sensor test for tire wear chemicals based on the plasmon ruler approach.

The release of tire wear substances in the environment is raising concerns about potential impacts on aquatic ecosystems. The purpose of this study was to develop a quick and inexpensive screening test for the following tire wear substances: 6-phenylphenyldiamine quinone (6-PPD quinone), hexamethoxymethylmelamine (HMMM), 1-3-diphenylguanidine (1,3-DPG), and melamine. A dual strategy consisting of nanogold (nAu) signal intensity and the plasmonic ruler principle was used based on the spectral shift from the unaggregated free-form nAu from 525 nm to aggregated nAu at higher wavelengths. The shift in resonance corresponded to the relative sizes of the tire wear substances at the surface of nAu: 6-PPD (560 nm), HMMM (590 nm), 1,3-DPG (620 nm), and melamine (660 nm) in a concentration-dependent manner. When present in mixtures, a large indiscriminate band between 550 and 660 nm with a maximum corresponding to the mean intermolecular distance of 0.43 nm from the tested individual substances suggests that all compounds indiscriminately interacted at the surface of nAu. An internal calibration methodology was developed for mixtures and biological extracts from mussels and biofilms and revealed a proportional increase in absorbance at the corresponding resonance line for each test compound. Application of this simple and quick methodology revealed the increased presence of melamine and HMMM compounds in mussels and biofilms collected at urban sites (downstream city, road runoffs), respectively. The data also showed that treated municipal effluent decreased somewhat melamine levels in mussels.

Oligo-Adenine and Cyanuric Acid Supramolecular DNA-Based Hydrogels Exhibiting Acid-Resistance and Physiological pH-Responsiveness.

Expanding the functions and applications of DNA by integrating noncanonical bases and structures into biopolymers is a continuous scientific effort. An adenine-rich strand (A-strand) is introduced as functional scaffold revealing, in the presence of the low-molecular-weight cofactor cyanuric acid (CA, pKa 6.9), supramolecular hydrogel-forming efficacies demonstrating multiple pH-responsiveness. At pH 1.2, the A-strand transforms into a parallel A-motif duplex hydrogel cross-linked by AH+-H+A units due to the protonation of adenine (pKa 3.5). At pH 5.2, and in the presence of coadded CA, a helicene-like configuration is formed between adenine and protonated CA, generating a parallel A-CA triplex cross-linked hydrogel. At pH 8.0, the hydrogel undergoes transition into a liquid state by deprotonation of CA cofactor units and disassembly of A-CA triplex into its constituent components. Density functional theory calculations and molecular dynamics simulations, supporting the structural reconfigurations of A-strand in the presence of CA, are performed. The sequential pH-stimulated hydrogel states are rheometrically characterized. The hydrogel framework is loaded with fluorescein-labeled insulin, and the pH-stimulated release of insulin from the hydrogel across the pH barriers present in the gastrointestinal tract is demonstrated. The results provide principles for future application of the hydrogel for oral insulin administration for diabetes.

Modulation of Electron Transfer Branches by Atrazine and Triazine Herbicides in Photosynthetic Reaction Centers.

Quinone analogue molecules, functioning as herbicides, bind to the secondary quinone site, QB, in type-II photosynthetic reaction centers, including those from purple bacteria (PbRC). Here, we investigated the impact of herbicide binding on electron transfer branches, using herbicide-bound PbRC crystal structures and employing the linear Poisson-Boltzmann equation. In contrast to urea and phenolic herbicides [Fufezan, C. Biochemistry 2005, 44, 12780-12789], binding of atrazine and triazine did not cause significant changes in the redox-potential (Em) values of the primary quinone (QA) in these crystal structures. However, a slight Em difference at the bacteriopheophytin in the electron transfer inactive branch (HM) was observed between the S(-)- and R(+)-triazine-bound PbRC structures. This discrepancy is linked to variations in the protonation pattern of the tightly coupled Glu-L212 and Glu-H177 pairs, crucial components of the proton uptake pathway in native PbRC. These findings suggest the existence of a QB-mediated link between the electron transfer inactive HM and the proton uptake pathway in PbRCs.

Rapid detection of melamine by DNA Walker mediated SERS sensing technique based on signal amplification function.

A new method is proposed for detecting typical melamine dopants in food using surface-enhanced Raman scattering (SERS) biosensing technology. Melamine specific aptamer was used as the identification probe, and gold magnets (AuNPs@MNPs) and small gold nanoparticles (AuNPs@MBA) were used as the basis for Raman detection. The Raman signal of the detection system can directly detect melamine quantitatively. Under optimized conditions, the detection of melamine was carried out in the low concentration range of 0.001-500 mg/kg, the enhancement factor (EF) was 2.3 × 107, and the detection limit was 0.001 mg/kg. The method is sensitive and rapid, and can be used for the rapid detection of melamine in the field environment.

Design, Synthesis, Formulation, and Bioevaluation of Trisubstituted Triazines as Highly Selective mTOR Inhibitors for the Treatment of Human Breast Cancer.

The aberrant activation of the PI3K/mTOR signaling pathway is implicated in various human cancers. Thus, the development of inhibitors targeting mTOR has attracted considerable attention. In this study, we used a structure-based drug design strategy to discover a highly potent and kinase-selective mTOR inhibitor 24 (PT-88), which demonstrated an mTOR inhibitory IC50 value of 1.2 nM without obvious inhibition against another 195 kinases from the kinase profiling screening. PT-88 displayed selective inhibition against MCF-7 cells (IC50: 0.74 µM) with high biosafety against normal cells, in which autophagy induced by mTOR inhibition was implicated. After successful encapsulation in a lipodisc formulation, PT-88 demonstrated favorable pharmacokinetic and biosafety profiles and exerted a large antitumor effect in an MCF-7 subcutaneous bearing nude mice model. Our study shows the discovery of a highly selective mTOR inhibitor using a structure-based drug discovery strategy and provides a promising antitumor candidate for future study and development.

Low-cost pyrolysis of biomass-derived nitrogen-doped porous carbon: Chlorella vulgaris replaces melamine as a nitrogen source.

Porous carbon generated from biomass has a rich pore structure, is inexpensive, and has a lot of promise for use as a carbon material for energy storage devices. In this work, nitrogen-doped porous carbon was prepared by co-pyrolysis using bagasse as the precursor and chlorella as the nitrogen source. ZnCl2 acts as both an activator and a nitrogen fixer during activation to generate pores and reduce nitrogen loss. The thermal weight loss experiments showed that the pyrolysis temperatures of bagasse and chlorella overlap, which created the possibility for the synthesis of nitrogen-rich biochar. The optimum sample (ZBC@C-5) possessed a surface area of 1508 m2g-1 with abundant nitrogen-containing functional groups. ZBC@C-5 in the three-electrode system exhibited 244.1F/g at 0.5A/g, which was extremely close to ZBC@M made with melamine as the nitrogen source. This provides new opportunities for the use of low-cost nitrogen sources. Furthermore, the devices exhibit better voltage retention (39%) and capacitance retention (96.3%). The goal of this research is to find a low cost, and effective method for creating nitrogen-doped porous carbon materials with better electrochemical performance for highly valuable applications using bagasse and chlorella.

Design, in silico study, synthesis and evaluation of hybrid pyrazole substituted 1,3,5-triazine derivatives for antimalarial activity.

OBJECTIVES: Malaria is a significant global health challenge, particularly in Africa, Asia, and Latin America, necessitating immediate investigation into innovative and efficacious treatments. This work involves the development of pyrazole substituted 1,3,5-triazine derivatives as antimalarial agent. METHODS: In this study, ten compounds 7(a-j) were synthesized by using nucleophilic substitution reaction, screened for in silico study and their antimalarial activity were evaluated against 3D7 (chloroquine-sensitive) strain of P. falciparum. KEY FINDING: The present work involves the development of hybrid trimethoxy pyrazole 1,3,5-triazine derivatives 7 (a-j). Through in silico analysis, four compounds were identified with favorable binding energy and dock scores. The primary focus of the docking investigations was on the examination of hydrogen bonding and the associated interactions with certain amino acid residues, including Arg A122, Ser A108, Ser A111, Ile A164, Asp A54, and Cys A15. The IC50 values of the four compounds were measured in vitro to assess their antimalarial activity against the chloroquine sensitive 3D7 strain of P. falciparum. The IC50 values varied from 25.02 to 54.82 µg/mL. CONCLUSION: Among the ten derivatives, compound 7J has considerable potential as an antimalarial agent, making it a viable contender for further refinement in the realm of pharmaceutical exploration, with the aim of mitigating the global malaria load.

Premise setting for sustainable developing adsorption in environmental remediation using graphitic carbon nitride@agar-derived porous carbon composite.

In the adsorption process for wastewater treatment, the adsorbent plays an important role. A composite adsorptive material composed of graphitic carbon nitride and agar-derived porous carbon (CNPC) was fabricated from simple precursors (melamine, thiourea, and agar) and through a facile procedure with different melamine and thiourea ratios. Characterization of CNPC proved a successful formation of a porous structure consisting of mesopores and macropores, wherein CNPC holds distinctive electrochemical (lowered resistance and higher specific capacity) and photochemical properties (lowered bandgap to 2.33 eV) thanks to the combination of graphitic carbon nitride (CN) and agar-derived porous carbon (PC). Inheriting the immanent nature, CNPC was subjected to the adsorption of methylene blue (MB) dye in an aqueous solution. The highest adsorption capacity was 133 mg/g for CNPC-4 which was prepared using a melamine to thiourea ratio of 4:4 - equivalent to the removal rate of 53.2 % and following the pseudo-I-order reaction rate. The effect of pH points out that pH 7 and 9 were susceptible to maximum removal and pretreatment is not required while the optimal ratio of 7.5 mg of MB and 30 mg of material was also determined to yield the highest performance. Furthermore, the reusability of the material for three consecutive cycles was evaluated based on two methods pyrolysis at 200 °C and photocatalytic degradation by irradiation under visible light. In general, the photocatalytic regeneration pathway is more ample and efficient than pyrolysis in terms of energy efficiency (saving energy over 10 times) and adsorption capacity stability. As a whole, the construction of accessible regenerative and stable adsorbent could be a venturing step into the sustainable development spearhead for industries.

Design, synthesis, and biological evaluation of some 2-(3-oxo-5,6-diphenyl-1,2,4-triazin-2(3H)-yl)-N-phenylacetamide hybrids as MTDLs for Alzheimer's disease therapy.

Inspite of established symptomatic relief drug targets, a multi targeting approach is highly in demand to cure Alzheimer's disease (AD). Simultaneous inhibition of cholinesterase (ChE), ß secretase-1 (BACE-1) and Dyrk1A could be promising in complete cure of AD. A series of 18 diaryl triazine based molecular hybrids were successfully designed, synthesized, and tested for their hChE, hBACE-1, Dyrk1A and Aß aggregation inhibitory potentials. Compounds S-11 and S-12 were the representative molecules amongst the series with multi-targeted inhibitory effects. Compound S-12 showed hAChE inhibition (IC50 value = 0.486 ± 0.047 µM), BACE-1 inhibition (IC50 value = 0.542 ± 0.099 µM) along with good anti-Aß aggregation effects in thioflavin-T assay. Only compound S-02 of the series has shown Dyrk1A inhibition (IC50 value = 2.000 ± 0.360 µM). Compound S-12 has also demonstrated no neurotoxic liabilities against SH-SY5Y as compared to donepezil. The in vivo behavioral studies of the compound S-12 in the scopolamine- and Aß-induced animal models also demonstrated attanuation of learning and memory functions in rats models having AD-like characteristics. The ex vivo studies, on the rat hippocampal brain demonstrated reduction in certain biochemical markers of the AD brain with a significant increase in ACh level. The Western blot and Immunohistochemistry further revealed lower tau, APP and BACE-1 molecular levels. The drosophilla AD model also revealed improved eyephenotype after treatment with compound S-12. The molecular docking studies of the compounds suggested that compound S-12 was interacting with the ChE-PAS & CAS residues and catalytic dyad residues of the BACE-1 enzymes. The 100 ns molecular dynamics simulation studies of the ligand-protein complexed with hAChE and hBACE-1 also suggested stable ligand-protein confirmation throughout the simulation run.

Design, Synthesis, Docking Studies and Molecular Dynamics Simulation of New 1,3,5-Triazine Derivatives as Anticancer Agents Selectively Targeting Pancreatic Adenocarcinoma (Capan-1).

On the basis of remarkable anticancer profile of s-triazine nucleus, a new series of 2-methoxy-4-(3-morpholino-5-(arylamino)phenoxy)benzaldehyde derivatives 11 a-u was prepared and evaluated for in vitro antiproliferative activity against eight diverse human cancer cell lines (Capan-1, HCT-116, LN229, NCI-H460, DND-41, HL-60, K562 and Z138). Compounds 11 o, 11 r and 11 s were the most potent anticancer agents on pancreatic adenocarcinoma (Capan-1) cell line with IC50 value of 1.4, 5.1 and 5.3 µM, respectively, while compounds 11 f, 11 g, 11 k, 11 l and 11 n displayed selective activity against the pancreatic adenocarcinoma (Capan-1) cell line with IC50 values of 7.3-11.5 µM. These results indicate that derivative 11 o may serve as a promising lead compound for the ongoing development of novel antiproliferative agents. The docking studies were conducted to predict the interactions of derivative 11 o with putative protein targets in pancreatic adenocarcinoma (Capan-1) cell line, specifically the prenyl-binding protein PDEδ. Furthermore, the analysis of the molecular dynamics simulation results demonstrated that complex 11 o promoted a higher stability to the prenyl-binding protein PDEδ.