Borophene as an carrier for mercaptopurine drug: electronic study via density-functional theory computations.

CONTEXT: This paper studied MP-B36 interactions through DFT. MP molecules were observed to have a substantial tendency to be adsorbed through their N heads onto B36 at its edge, based on large adsorption energy values. The B atoms at the edges of B36 nanosheets showed higher reactivity than the internal B atoms toward MP. The electronic properties changed upon MP adsorption. The MP-B36 configurations of the highest stability underwent an energy gap reduction of 11-47%. Natural bond orbital (NBO) analysis and molecular electrostatic potential (MEP) analysis were used to evaluate the MP-B36 interaction. METHODS: The configurations were subjected to geometric optimization at the TPSSH/6-31 + G(d) level of theory, at which frequency analysis was carried out to evaluate the stationary points. These configurations were neutral (Q = 0). The electronic properties of MP dramatically changed upon its interaction with B36 nanosheets. The stable configurations underwent an energy gap reduction, suggesting a chemical signal. The MP molecules were observed to be effectively adsorbed onto the B36 edge within aqueous phases. The MP-B36 configurations were estimated to have relatively large dipole moments. This demonstrated that MP-B36 systems were soluble and dispersed within solar media (e.g., water). It was concluded that B36 nanosheets could serve as efficient MP carriers in nanomedical drug delivery applications.

Adsorption behavior of mercaptopurine and 6-thioguanine drugs on the B12N12, AlB11N12 and GaB11N12 nanoclusters, a comparative DFT study.

Lately, drug delivery systems established on nanostructures have become the most proficient to be studied. There are different studies suggested that the BN nanoclusters can be used as drug carriers and transport drugs in the target cell. Therefore, the interactions and adsorption behavior of Mercaptopurine (MC) and 6-thioguanine (TG) as anti-cancer drugs on the B12N12 (BN), AlB11N12 (AlBN) and GaB11N12 (GaBN) nanoclusters were studied by density functional theory (DFT) and quantum mechanics atoms in molecules (QMAIM) methods to find a new drug delivery system. Our results showed strong adsorption obtained in BN-MC/TG and AlBN-MC/TG complexes can be decomposed by the BN and AlBN indicating that these nanostructures are not suitable in drug efficiency of MC and TG drugs. Unlike the BN and AlBN nanoclusters, GaBN significantly makes the MC and TG drugs adsorption energetically favorable. The high solvation energy of GaBN when interacting with MC and TG drugs led it to applicability as nanocarriers for these drugs in the drug delivery systems. Furthermore, GaBN has a short recovery time for MC, and TG drugs desorption compared to BN and AlBN nanoclusters. It is predicted that the MC, and TG drugs over GaBN can be used as a drug delivery system.Communicated by Ramaswamy H. Sarma.

Complexation of uranyl (UO2)2+ with bidentate ligands: XRD, spectroscopic, computational, and biological studies.

Three new uranyl complexes [(UO2)(OAc)2(CMZ)], [(UO2)(OAc)2(MP)] and [(UO2)(OAc)2(SCZ)] were synthesized and characterized by elemental analysis, FT-IR, UV-Vis spectroscopy, powder XRD analysis, and molar conductivity. The IR analysis confirmed binding to the metal ion by the sulfur and ethoxy oxygen atoms in the carbimazole (CMZ) ligand, while in the 6-mercaptopurine (MP) ligand, the sulfur and the N7 nitrogen atom of a purine coordinated binding to the metal ion. The third ligand showed a 1:1 molar ratio and bound via sulfonamide oxygen and the nitrogen of the pyrimidine ring. Analysis of the synthesized complexes also showed that acetate groups had monodentate binding to the (UO22+). Density Functional Theory (DFT) calculations at the B3LYP level showed similar structures to the experimental results. Theoretical quantum parameters predicted the reactivity of the complexes in the order, [(UO2)(OAc)2(SCZ)] > [(UO2)(OAc)2(MP)]> [(UO2)(OAc)2(CMZ)]. DNA binding studies revealed that [(UO2)(OAc)2(SCZ)] and [(UO2)(OAc)2(CMZ)] have the highest binding constant (Kb) among the uranyl complexes. Additionally, strong binding of the MP and CMZ metal complexes to human serum albumin (HSA) were observed by both absorbance and fluorescence approaches. The antibacterial activity of the complexes was also evaluated against four bacterial strains: two gram-negative; Escherichia coli and Klebsiella pneumonia, and two gram-positive; Staphylococcus aureus and Streptococcus mutans. [(UO2)(OAc)2(MP)] had the greatest antibacterial activity against Klebsiella pneumonia, the gram-positive bacteria, with even higher activity than the standard antibiotic. In vitro cytotoxicity tests were also performed against three human cancer lines, and revealed the most cytotoxic complexes to be [(UO2)(OAc)2(SCZ)], which showed moderate activity against a colon cancer cell line. Thus, uranyl addition enhances the antibacterial and anticancer properties of the free ligands.

Recombinant Spider Silk Gels Derived from Aqueous-Organic Solvents as Depots for Drugs.

Hydrogels are widely used in various biomedical applications, as they cannot only serve as materials for biofabrication but also as depots for the administration of drugs. However, the possibilities of formulation of water-insoluble drugs in hydrogels are rather limited. Herein, we assembled recombinant spider silk gels using a new processing route with aqueous-organic co-solvents, and the properties of these gels could be controlled by the choice of the co-solvent. The presence of the organic co-solvent further enabled the incorporation of hydrophobic drugs as exemplarily shown for 6-mercaptopurine. The developed gels showed shear-thinning behaviour and could be easily injected to serve, for example, as drug depots, and they could even be 3D printed to serve as scaffolds for biofabrication. With this new processing route, the formulation of water-insoluble drugs in spider silk-based depots is possible, circumventing common pharmaceutical solubility issues.

Preparation, Characterization, Pharmacokinetic, and Therapeutic Potential of Novel 6-Mercaptopurine-Loaded Oral Nanomedicines for Acute Lymphoblastic Leukemia.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy in children. It requires a long and rigorous course of chemotherapy treatments. 6-Mercaptopurine (6-MP) is one of the primary drugs used in chemotherapy. Unfortunately, its efficacy has been limited due to its insolubility, poor bioavailability and serious adverse effects. To overcome these drawbacks, we constructed 6-mercaptopurine (6-MP)-loaded nanomedicines (6-MPNs) with biodegradable poly(lactide-co-glycolide) (PLGA) to enhance the anticancer efficacy of 6-MP. METHODS: We prepared the 6-MPNs using a double-emulsion solvent evaporation method, characterizing them for the physicochemical properties. We then investigated the plasma, intestinal region and other organs in Sprague Dawley (SD) rats for pharmacokinetics. Additionally, we evaluated its anticancer efficacy in vitro on the human T leukemia cell line Jurkat and in vivo on the ALL model mice. RESULTS: The 6-MPNs were spherical in shape with uniform particle size and high encapsulation efficiency. The in vitro release profile showed that 6-MPNs exhibited a burst release that a sustained release phase then followed. The apoptosis assay demonstrated that 6-MPNs could improve the in vitro cytotoxicity in Jurkat cells. Pharmacokinetics profiles revealed that 6-MPNs had improved oral bioavailability. Tissue distribution experiments indicated that 6-MPNs increased the duodenum absorption of 6-MP, at the same time having a low accumulation of the toxic metabolites of 6-MP. The in vivo pharmacodynamics study revealed that 6-MPNs could prolong the survival time of the ALL model mice. The prepared 6-MPNs, therefore, have superior properties in terms of anticancer efficacy against ALL with reduced systemic toxicity. CONCLUSION: Our nanomedicines provide a promising delivery strategy for 6-MP; they offer a simple preparation method and high significance for clinical translation.

Phosphorene and Na-, Ca-, and Fe-doped phosphorene as candidates for delivery of mercaptopurine and fluorouracil anticancer drugs.

Phosphorene ability for delivery of mercaptopurine and fluorouracil was investigated by the density functional theory (DFT) method. However, the effects of Na, Ca, and Fe as dopants on phosphorene electronic properties such as HOMO and LUMO energies, density of states, chemical potential, electrophilicity index, softness, hardness, and its ability for drug delivery were studied. Natural bond orbital (NBO) analysis was performed. Our findings indicate that metallic dopants can improve the ability of phosphorene. Calcium-doped phosphorene has the greatest adsorption energy.

The critical size of gold nanoparticles for overcoming P-gp mediated multidrug resistance.

Multidrug resistance (MDR) remains a huge obstacle during cancer treatment. One of the most studied MDR mechanisms is P-glycoprotein (P-gp) mediated drug efflux. Based on the three-dimensional structural characteristics of P-gp, gold nanoparticles (AuNPs) with average sizes of 4.1 nm and 5.4 nm were designed for the construction of nanodrug delivery systems (NanoDDSs), with the anticancer molecules 2-(9-anthracenylmethylene)-hydrazinecarbothioamide (ANS) and 6-mercaptopurine (6-MP) modified on the AuNP surfaces through the thiol group. In vitro cytotoxicity results suggested that the larger sized AuNPs can effectively decrease the drug resistance index of MCF-7/ADR cells to ∼2. Verapamil and P-gp antibody competitive experiments, combined with the cellular uptake of AuNPs, indicated that larger NanoDDSs were more conducive to intracellular drug accumulation and thus had improved anticancer activities, due to a size mismatch between the nanoparticles and the active site of P-gp, and, therefore, reduced drug efflux was seen. Measurements of ATPase activity and intracellular ATP levels indicated that the larger nanoparticles do not bind well to P-gp, thus avoiding effective recognition by P-gp. This was further evidenced by the observation that 4.1 nm and 5.4 nm NanoDDS-treated MCF-7/ADR cells showed remarkable differences in energy-related metabolic pathways. Therefore, the critical size of AuNPs for overcoming MDR was identified to be between 4.1 nm and 5.4 nm. This provides a more accurate description of the composite dimension requirements for NanoDDSs that are designed to overcome MDR.

Elucidating the binding mechanism of thione-containing mercaptopurine and thioguanine drugs to small gold clusters.

Density functional theory methods were employed to clarify the adsorption/desorption behaviors of the thione-containing mercaptopurine and thioguanine drugs on the gold surface using both small Au6 and Au8 clusters as model reactants. Structural features, thermodynamic parameters, bonding characteristics, and electronic properties of the resulting complexes were investigated using the Perdew-Burke-Ernzerhof (PBE) and LC-BLYP functionals along with correlation-consistent basis sets, namely cc-pVDZ-PP for gold and cc-pVTZ for non-metals. Computed results show that the drug molecules tend to anchor on the gold cluster at the S atom with binding energies around -34 to -40 kcal/mol (in vacuum) and - 28 to -32 kcal/mol (in aqueous solution). As compared to Au8 , Au6 undergoes a shorter recovery time and a larger change of energy gap that could be converted to an electrical signal for selective detection of the drugs. Furthermore, interactions between the drugs and gold clusters are reversible processes and a drug release mechanism was also proposed. Accordingly, the drugs are able to separate from the gold surface due to either a slight change of pH in tumor cells or the presence of cysteine residues in protein matrices.

Glutathione-responsive nanoscale MOFs for effective intracellular delivery of the anticancer drug 6-mercaptopurine.

A glutathione-triggered drug delivery system (DDS) based on nanoscale metal-organic frameworks (NMOFs) is developed, which features an intracellular redox-responsive release of an anticancer drug. Compared to normal cells, the current NMOF-based DDS has 3-fold higher cytotoxicity to cancer cells, prefiguring its great potential for selective cancer therapy.

Inhibition of Xanthine Oxidase-Catalyzed Xanthine and 6-Mercaptopurine Oxidation by Flavonoid Aglycones and Some of Their Conjugates.

Flavonoids are natural phenolic compounds, which are the active ingredients in several dietary supplements. It is well-known that some flavonoid aglycones are potent inhibitors of the xanthine oxidase (XO)-catalyzed uric acid formation in vitro. However, the effects of conjugated flavonoid metabolites are poorly characterized. Furthermore, the inhibition of XO-catalyzed 6-mercaptopurine oxidation is an important reaction in the pharmacokinetics of this antitumor drug. The inhibitory effects of some compounds on xanthine vs. 6-mercaptopurine oxidation showed large differences. Nevertheless, we have only limited information regarding the impact of flavonoids on 6-mercaptopurine oxidation. In this study, we examined the interactions of flavonoid aglycones and some of their conjugates with XO-catalyzed xanthine and 6-mercaptopurine oxidation in vitro. Diosmetin was the strongest inhibitor of uric acid formation, while apigenin showed the highest effect on 6-thiouric acid production. Kaempferol, fisetin, geraldol, luteolin, diosmetin, and chrysoeriol proved to be similarly strong inhibitors of xanthine and 6-mercaptopurine oxidation. While apigenin, chrysin, and chrysin-7-sulfate were more potent inhibitors of 6-mercaptopurine than xanthine oxidation. Many flavonoids showed similar or stronger (even 5- to 40-fold) inhibition of XO than the positive control allopurinol. Based on these observations, the extremely high intake of flavonoids may interfere with the elimination of 6-mercaptopurine.

Simple hydrothermal approach for synthesis of fluorescent molybdenum disulfide quantum dots: Sensing of Cr3+ ion and cellular imaging.

Nowadays, fluorescent molybdenum disulfide quantum dots (MoS2 QDs) have proven to be potential candidates in the sensing and bioimaging areas owing to their exceptional intrinsic characteristics. Here, a simple hydrothermal strategy was explored for the preparation of MoS2 QDs using ammonium heptamolybdate and 6-mercaptopurine (6-MP) as precursors. The emission peak of MoS2 QDs was significantly quenched in the presence Cr3+ ion due to the selective surface chemistry on the surfaces of MoS2 QDs. The designed fluorescent MoS2 QDs showed a linear fluorescence quenching response with increasing concentration of Cr3+ ion (0.1-10 µM), allowing to detect Cr3+ ion even at 0.08 µM. This fluorescent MoS2 QDs were utilized for the quantification of Cr3+ ion in real samples (water and biological samples). Interestingly, the synthesized MoS2 QDs exhibited negligible cytotoxicity on NRK cells and acted as good candidates for imaging of Trichoderma viride fungal cells.

A bio-responsive 6-mercaptopurine/doxorubicin based "Click Chemistry" polymeric prodrug for cancer therapy.

A novel bio-responsive co-delivery system based on Poly(DEA)-b-Poly(ABMA-co-OEGMA) (PDPAO, prepared by reversible addition-fragmentation chain transfer (RAFT) polymerization) copolymers was constructed for enhanced cellular internalization and effective combination therapy. Reduction-sensitive 6-mercaptopurine (6MP) based prodrug and pH-sensitive doxorubicin (DOX) based prodrug were grafted onto PDPAO by an azide-alkyne "Click Chemistry" reaction to acquire a pH/reduction-sensitive polymeric prodrug (PDPAO@imine-DOX/cis-6MP), which was able to self-aggregate to form polymeric micelles (M(DOX/6MP)) with an average particle size of 116 ± 2 nm in the water. The resultant micelles could maintain a stable sphere structure and show stability with a small particles' dispersion index in the blood. Importantly, it has been observed that the pH-sensitive surface charge-conversion accompanied pH-triggered DOX release in the biomimetic extracellular acidic environment of tumor tissue and a rapid dual-drug release triggered by pH and GSH in the intracellular environment. The in vitro evaluation of micelles on human cervical cancer (HeLa) and human promyelocytic leukemia (HL-60) cells showed an enhanced cellular uptake because of charge-conversion and exhibited a higher cell-killing performance. Moreover, the graft ratio of DOX and 6MP showed the ability to adjust the cytotoxicity; the micelles with a graft ratio of 2: 1 (M(DOX2/6MP)) displayed the higher cellular inhibition on either HeLa (combination index (CI) = 0.62) or HL-60 (CI = 0.35) cells. Overall, this novel dual-drug-conjugated delivery system might have important potential applications for combination therapy of cancer.

Cycloplatinated(II) Derivatives of Mercaptopurine Capable of Binding Interactions with HSA/DNA.

In this study, two new bis-cyclometalated Pt(II) complexes, [Pt(C^N)(S^N)] [S^N = deprotonated 6-mercaptopurine (6-MP) and C^N = deprotonated 2-phenylpyridine (ppy), 2a; C^N = deprotonated benzo[h]quinoline (bhq), 2b], are synthesized by the reaction of [PtR(SMe2)(C^N)] (R = Me or p-MeC6H4) with 1 equiv of 6-mercaptopurine (6-HMP) at room temperature. The complexes are fully characterized using 1H and 13C NMR spectroscopies, electrospray ionization mass spectrometry, and elemental analysis. Biomolecular interaction of complex 2a with human serum albumin (HSA) is studied by fluorescence, UV-vis, and circular dichroism (CD) spectroscopies. The binding constants (Kb) and number of binding sites (n) are evaluated using the Stern-Volmer equation. The intrinsic fluorescence of protein is quenched by a static quenching mechanism, with a binding constant of Kb ∼ 105 reflecting a high affinity of complex 2a for HSA. The thermodynamic parameters (ΔH°, ΔG°, and ΔS°) indicate that the interaction is a spontaneous process and hydrophobic forces play a main role in the reaction. The displacement experiments demonstrate that the reactive binding sites of HSA to complex 2a are mainly located within its hydrophobic cavity in subdomain IIA (site I). Synchronous fluorescence spectra reveal that complex 2a affected the microenvironment of tryptophan-214 residues in subdomain IIA of HSA. In the case of interaction of complex 2b and HSA, because of overlapping of the emission spectra of complex 2b with HSA, chemometric approaches are applied. The results indicate significant interaction between the tryptophan residue of HSA and complex 2b. Moreover, the binding of Pt(II) complexes 2a and 2b causes a reduction of the α-helix content of HSA, as obtained by far-UV CD spectroscopy. The average binding distance (r) between Pt(II) complexes and HSA is obtained by Förster's resonance energy-transfer theory. Also, a molecular docking simulation reveals that π-π-stacking and hydrophobic interactions between these complexes and HSA are significant. Furthermore, the interactions of platinum complexes, 2, with calf-thymus DNA (CT-DNA) are investigated. The UV-vis results and ethidium bromide competitive studies support an intercalative interaction of both Pt(II) complexes with DNA. The new complexes 2 are also screened for anticancer activities. The results show that complexes 2 exhibit significant anticancer activity against the K562 (chronic myelogenous leukemia) cell line.

Discovery of New Inhibitors of Transforming Growth Factor-Beta Type 1 Receptor by Utilizing Docking and Structure-Activity Relationship Analysis.

The transforming growth factor-beta (TGF-ß) plays an important role in pathological fibrosis and cancer transformation. Therefore, the inhibition of the TGF-ß signaling pathway has therapeutic potential in the treatment of cancer. In this study, the binding modes between 47 molecules with a pyrrolotriazine-like backbone structure and transforming growth factor-beta type 1 receptor (TßR1) were simulated by molecular docking using Discovery Studio software, and their structure-activity relationships were analyzed. On the basis of the analysis of the binding modes of ligands in the active site and the structure-activity relationships, 29,254 new compounds were designed for virtual screening. According to the aforementioned analyses and Lipinski's rule of five, five new compounds (CQMU1901-1905) with potential activity were screened through molecular docking. Among them, CQMU1905 is an attractive molecule composed of 5-fluorouracil (5-FU), 6-mercaptopurine (6-MP), and 5-azacytosine. Interestingly, 5-FU, 6-MP, and 5-azacytidine are often used as anti-metabolic agents in cancer treatment. Compared with existing compounds, CQMU1901-1905 can interact with target proteins more effectively and have good potential for modification, making them worthy of further study.

Mechanisms of NT5C2-Mediated Thiopurine Resistance in Acute Lymphoblastic Leukemia.

Relapse remains a formidable challenge for acute lymphoblastic leukemia (ALL). Recently, recurrent mutations in NT5C2 were identified as a common genomic lesion unique in relapsed ALL and were linked to acquired thiopurine resistance. However, molecular mechanisms by which NT5C2 regulates thiopurine cytotoxicity were incompletely understood. To this end, we sought to comprehensively characterize the biochemical and cellular effects of NT5C2 mutations. Compared with wild-type NT5C2, mutant proteins showed elevated 5'-nucleotidase activity with a stark preference of thiopurine metabolites over endogenous purine nucleotides, suggesting neomorphic effects specific to thiopurine metabolism. Expression of mutant NT5C2 mutations also significantly reduced thiopurine uptake in vitro with concomitant increase in efflux of 6-mercaptopurine (MP) metabolites, plausibly via indirect effects on drug transporter pathways. Finally, intracellular metabolomic profiling revealed significant shifts in nucleotide homeostasis induced by mutant NT5C2 at baseline; MP treatment also resulted in global changes in metabolomic profiles with completely divergent effects in cells with mutant versus wild-type NT5C2. Collectively, our data indicated that NT5C2 mutations alter thiopurine metabolism and cellular disposition, but also influence endogenous nucleotide homeostasis and thiopurine-induced metabolomic response. These complex mechanisms contributed to NT5C2-mediated drug resistance in ALL and pointed to potential opportunities for therapeutic targeting in relapsed ALL.

Compatibility of Baclofen, Carvedilol, Hydrochlorothiazide, Mercaptopurine, Methadone Hydrochloride, Oseltamivir Phosphate, Phenobarbital, Propranolol Hydrochloride, Pyrazinamide, Sotalol Hydrochloride, Spironolactone, Tacrolimus Monohydrate, Ursodeoxycholic Acid, and Vancomycin Hydrochloride Oral Suspensions Compounded with SyrSpend SF pH4.

Compounded liquid medication is frequently required in children to allow easy dose adjustment and overcome swallowing difficulties. The objective of this study was to evaluate the stability of oral suspensions compounded with SyrSpend SF PH4 and the commonly used active pharmaceutical ingredients baclofen 2.0 mg/mL, carvedilol 5.0 mg/mL, hydrochlorothiazide 2.0 mg/mL, mercaptopurine 10.0 mg/mL, methadone hydrochloride 10.0 mg/mL, oseltamivir phosphate 6.0 mg/mL, phenobarbital 9.0 mg/mL and 15.0 mg/mL, propranolol hydrochloride 0.5 mg/mL and 5.0 mg/mL, pyrazinamide 100.0 mg/mL, spironolactone 2.0 mg/mL and 2.5 mg/mL, sotalol hydrochloride 5.0 mg/mL, tacrolimus monohydrate 0.5 mg/mL, ursodeoxycholic acid 20.0 mg/mL, and vancomycin hydrochloride 25.0 mg/mL. Suspensions were compounded with raw powders, except for mercaptopurine, pyrazinamide, and sotalol hydrochloride, which were made from commercial tablets. Stability was assessed by measuring the percentage recovery at 0 (baseline), 60 days, and 90 days after compounding for suspensions made with raw powders, which were stored at 2ÅãC to 8ÅãC. The stability of tablets, which were stored at 2ÅãC to 8ÅãC and 20ÅãC to 25ÅãC, was assessed by measuring the percentage recovery at 0 (baseline), 7 days, 14 days, 30 days, 60 days, and 90 days. Active pharmaceutical ingredients quantification was performed by ultraviolet high-performance liquid chromatography via a stability-indicating method. Given the percentage of recovery of the active pharmaceutical ingredients within the suspensions, the beyond-use date of the final products (active pharmaceutical ingredients + vehicle) was at least 90 days for all suspensions in the conditions tested. This suggests that SyrSpend SF PH4 is suitable for compounding active pharmaceutical ingredients from different pharmacological classes.

A novel multi stimuli-responsive PEGylated hybrid gold/nanogels for co-delivery of doxorubicin and 6­mercaptopurine.

The clinical applications of anticancer drugs are restricted due to the incomplete delivery to the cancerous tissue and the numerous drug resistance mechanisms involved in malignant cells. In this regard, stimuli-responsive nanomaterials offer a promising prospect to deal with these concerns. In the present study, ternary responsive hybrid gold/nanogels (Au/NGs) were synthesized as a new nanoplatform to simultaneously carry two anticancer drugs, i.e., doxorubicin (DOX) and 6-mercaptopurine (MP). For this purpose, these drugs were successfully loaded (the loading capacity of 23% and 11%, respectively) into the hybrid Au/NGs by electrostatic interaction (DOX) and AuS bonds (MP). The triggered drug release ability of hybrid Au/NGs was assessed by comparing the environments of simulated physiological and tumor tissue. The incorporation of disulfide bond linkers, pH sensitive, and thermosensitive polymeric segments endowed the NGs with an excellent property in reducing acidic and hyperthermia environments, which greatly facilitates drug release in tumor cells. Intracellular tracking of DOX@MP-Au/NGs confirmed efficient accumulation and cellular uptake of developed NGs and the cytotoxicity studies showed a pronounced tumor inhibition compared with free DOX@MP. It was concluded that the new ternary-responsive NGs have great potential for co-delivery of DOX and MP and can be used in efficient cancer therapy.

Preparation of strongly fluorescent water-soluble dithiothreitol modified gold nanoclusters coated with carboxychitosan, and their application to fluorometric determination of the immunosuppressive 6-mercaptopurine.

Water-soluble and non-aggregating gold nanoclusters (AuNCs) were obtained by modification of the AuNCs with dithiothreitol (DTT) and then coating them with carboxylated chitosan. This process remarkably enhances the dispersibility of DTT-coated AuNCs in water. The resulting AuNCs, on photoexcitation at 285 nm, display strong red emission with a maximum at 650 nm and a 23% quantum yield. Fluorescence is strongly and selectively suppressed in the presence of 6-mercaptopurine (6-MP). Photoluminescence drops linearly in the 0.1-100 µM 6-MP concentration range, and the detection limit of this assay is 0.1 µM. Other features of the modified AuNCs include a decay time of 8.56 µs, a 365 nm Stokes shift, good colloidal stability, ease of chemical modification, and low toxicity. Conceivably, these NCs may find a range of applications in biological imaging and optical sensing. Graphical abstract Highly fluorescent and water-soluble gold nanoclusters (AuNCs) were obtained by modification of the AuNCs with dithiothreitol (DTT) and then coating them with carboxylated chitosan (CC). The resulting CC/DTT-AuNCs were used for sensitive and selective detection of 6-mercaptopurine.

Analytical and clinical validation of an LC-MS/MS method to measure thiopurine S-methyltransferase activity by quantifying d3-6-MMP.

BACKGROUND: Identification of patients with thiopurine S-methyltransferase (TPMT) deficiency prior to thiopurine drug therapy has become routine clinical practice worldwide. To measure TPMT activity, traditional radiochemical assays have been replaced by chromatographic methods. METHOD: Inspired by the increasing number of isotope labelled sources that may be of benefit for the TPMT assay, a new LC-MS/MS method for TPMT activity was developed and validated. Isotope labelled d3-S-adenosyl-l-methionine (d3-SAM) was selected for the enzymatic methylation of mercaptopurine during sample incubation; d3-6-methylmercaptopurine (d3-6-MMP) with d2-2, 8-hypoxanthine as the internal standard was quantified to ascertain individual TPMT activity. RESULTS: The validation of the analytical part of this method showed good linearity (coefficient of determination 0.9999 in the range of 1-500 ng/mL) with the intra-and inter-day impression CV% between 7.6% and 9.1% and 3.7% and 9.2%, respectively. Recovery ranged from 94.9% to 112.3%. The specificity of the enzymatic reaction was validated by using 108 clinical check samples. After compared with traditional radiochemical assay and genotype results, all homozygous and heterozygous deficiency clinical checks fitted into the nominal groups, inter-batch and intra-batch impression CV% were between 2.3% and 9.7%. CONCLUSION: With the inclusion of isotope labelled substrate, interfering non-enzymatic methylation no longer results in potential false assignment of abnormal patients. Furthermore, the method can be applied to patients who have already been prescribed thiopurine drugs. This new LC-MS/MS is therefore a favourable clinical routine application to test TPMT activity, as it shows excellent performance in identifying patients with TPMT deficiency.

Role of 6-Mercaptopurine in the potential therapeutic targets DNA base pairs and G-quadruplex DNA: insights from quantum chemical and molecular dynamics simulations.

The theoretical studies on DNA with the anticancer drug 6-Mercaptopurine (6-MP) are investigated using theoretical methods to shed light on drug designing. Among the DNA base pairs considered, 6-MP is stacked with GC with the highest interaction energy of -46.19 kcal/mol. Structural parameters revealed that structure of the DNA base pairs is deviated from the planarity of the equilibrium position due to the formation of hydrogen bonds and stacking interactions with 6-MP. These deviations are verified through the systematic comparison between X-H bond contraction and elongation and the associated blue shift and red shift values by both NBO analysis and vibrational analysis. Bent's rule is verified for the C-H bond contraction in the 6-MP interacted base pairs. The AIM results disclose that the higher values of electron density (ρ) and Laplacian of electron density (∇2ρ) indicate the increased overlap between the orbitals that represent the strong interaction and positive values of the total electron density show the closed-shell interaction. The relative sensitivity of the chemical shift values for the DNA base pairs with 6-MP is investigated to confirm the hydrogen bond strength. Molecular dynamics simulation studies of G-quadruplex DNA d(TGGGGT)4 with 6-MP revealed that the incorporation of 6-MP appears to cause local distortions and destabilize the G-quadruplex DNA.