Hydroxyethyl Piperazine Research Articles

Novel aloe emodin–hydroxyethyl piperazine hybrid dihydrochloride induces oral cancer CAL-27 cells apoptosis through ROS production, DNA damage and mitochondrial pathways

Novel aloe emodin–hydroxyethyl piperazine hybrid dihydrochloride induces oral cancer CAL-27 cells apoptosis through ROS production, DNA damage and mitochondrial pathways

A buffering fluorogenic probe for real-time lysosomal pH monitoring

Real-time monitoring of lysosomal pH is critical for understanding lysosome-related biological processes and diseases, but few lysosome probes can achieve this response effectively. Therefore, it is essential to develop pH-sensitive probes with better performance. In this study, we designed and synthesized a lysosome-targeting “buffering fluorogenic probe” (Lyso-BFP) by introducing a salicylamide group to naphthalimide for buffering strategy and a hydroxyethyl piperazine unit to target lysosome as well as specific pH response. Lyso-BFP demonstrated excellent photostability, pH specificity, and responsiveness to lysosomal acidification in living cells, thanks to its well-suit pKa. Density functional theory calculation revealed that Lyso-BFP’s excellent pH sensing performance resulted from the inhibition of the photo-induced electron transfer (PET) process from hydroxyethyl piperazine to the naphthalimide moiety after the piperazine ring’s protonation at low pH. Remarkably, Lyso-BFP allowed for wash-free imaging and long-term real-time monitoring of lysosome pH changes based on its off-on fluorescence behavior and buffer strategy. With its superior pH selectivity and real-time pH monitoring capability, Lyso-BFP holds great potential in the diagnosis of lysosome-related disease, and the design concept of this fluorogenic probe provides a new perspective for real-time tracking of cell organelles.

In silico repurposing of CNS drugs for multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune neurodegenerative disease affecting numerous people worldwide. While the relapsing subtypes of MS are to some extent treatable, the disease remains incurable leading to progressive disability. Limited efficacy of current small molecule drugs necessitates development of efficient and safe MS medications. Accordingly, drug repurposing is an invaluable strategy that recognizes new targets for known drugs especially in the field of poorly addressed therapeutic areas. Drug discovery largely depends on the identification of potential binding molecules to the intended biomolecular target(s). In this regard, current study was devoted to in silico repurposing of 263 small molecule CNS drugs to achieve superior binders to some MS-related targets. On the basis of molecular docking scores, thioxanthene and benzisothiazole-based antipsychotics could be identified as potential binders to sphingosine-1-phosphate lyase (S1PL) and cyclophilin D (CypD). Tightest interaction modes were observed for zuclopenthixol-S1PL (ΔGb -7.96kcal/mol) and lurasidone-CypD (ΔGb -8.84kcal/mol) complexes. Molecular dynamics (MD) simulations proved the appropriate and stable accommodation of top-ranked drugs inside enzyme binding sites during 100ns. Hydroxyethyl piperazine of zuclopenthixol and benzisothiazole of lurasidone flipped inside the binding pocket to interact with adjacent polar and apolar residues. Solvent accessible surface area (SASA) fluctuations confirmed the results of binding trajectory analysis and showed that non-polar hydrophobic interactions played significant roles in acquired stabilities. Our results on lurasidone binding pattern were interestingly in accordance with previous reports on X-ray structures of other norbornane maleimide derivatives as CypD inhibitors. According to this, Asn144, Phe102 and Phe155 served as important residues in providing stable binding pose of lurasidone through both exo and endo conformations. Although experimental results are necessary to be achieved, the outcomes of this study proposed the potentiality of some thioxanthene and benzisothiazole-based antipsychotics for binding to S1PL and CypD, respectively, as MS-related targets.

Design, synthesis, heme binding and density functional theory studies of isoindoline-dione-4-aminoquinolines as potential antiplasmodials.

Aim:WHO Malaria report 2017 estimated 216 million cases of malaria and 445,000 deaths worldwide, with 91% of deaths affecting the African region.Results/methodology:Microwave promoted the synthesis of cycloalkyl amine substituted isoindoline-1,3-dione-4-aminoquinolines was urbanized for evaluating their antiplasmodial activities. Compound with the optimum combination of propyl chain length and hydroxyethyl piperazine proved to be the most potent among the synthesized scaffolds against chloroquine-resistant W2 strain of Plasmodium falciparum with an IC50 value of 0.006 μM. Heme-binding along with density functional theory studies were further carried out in order to delineate the mechanism of action of the most active compound.Conclusion:The synthesized scaffold can act as a therapeutic template for further synthetic modifications toward the search for a new antimalarial agent.

Photophysical, electrochemical and flexible organic resistive switching memory device application of a small molecule: 7,7-bis(hydroxyethylpiperazino) dicyanoquinodimethane

Abstract Utilization of Hydroxyethyl piperazine in a straightforward reaction with tetracyanoquinodimethane (TCNQ) produced a unique multifunctional molecular material 7,7-bis(Hydroxyethyl piperazino)dicyanoquinodimethane (BHEPDQ) exhibiting fluorescence, electrochemical property and capability of organic resistive switching (RS) memory device application. Obtained molecular material has been characterized by various spectroscopic and single crystal X-ray diffraction techniques. Fluorescence decay study in solid revealed single excited state conformation with life time ~1.26 ns. The energy levels were derived from the cyclic voltammetry and the electrochemical band gap was found to be 2.76 eV, good agreement with the theoretical band gap (2.75 eV). Flexible Al/BHEPDQ/ITO/PET RS non-volatile memory device was fabricated and different electrical performances were tested, which demonstrated excellent switching property. The SET/RESET voltage was found to be 2.26 V/– 2.88 V and the device offered high retention without any distortion. The effect of convex (upward bend) and concave (downward bend) bending on the resistive switching behavior of the same device was also investigated. The devices on a flexible platform under the application of a strain through different bending conditions exhibit no degradation on the electrical properties and the obtained results also matched well with the device under no stress, demonstrates its high reliability and ability for practical flexible electronic applications. The memory operations were also explained employing a proposed band diagram and transport studies were explicated to have the better insight of the obtained electrical performances. This work offers a new approach towards the realization of a novel organic material and its integration for efficient flexible memory device applications.

A pH-triggered charge reversal and self-fluorescent micelle as a smart nanocarrier for doxorubicin controlled release

A novel pH-sensitive charge reversal and self-fluorescent polymeric micelle is designed and synthesized successfully. The smart micelle is prepared based on MPEG-polyurethane multi-block copolymer, which is synthesized by polycondensation, with 1, 4-bis (hydroxyethyl) piperazine (HEP) and hydroxyl-sulfamethazine (Hydroxyl-SM) as pH-sensitive molecules and fluorescein isothiocyanate (FITC) as fluorescent segment. The resulting MPEG-polyurethane multi-block copolymer is examined by 1H–NMR, UV-vis spectra, fluorescence spectra and an acid-base titration. Moreover, the diameter, morphology and cytotoxicity of obtained polymer micelle are measured by dynamic light scattering (DLS), transmission electron microscopy (TEM) and MTT assay. The results indicate that the micelle has a small diameter of less than 200 nm and can remain unchanged within two weeks. Zeta-potential measurement shows that the negative charge of micelle can switch into positive charge as the pH value decreasing from 9.0 to 3.0. Subsequently, the fluorescence intensity decreases significantly with the reducing of pH values. The MTT assay shows the low cytotoxicity and good biocompatibility of the MPEG-polyurethane polymeric micelles. Finally, doxorubicin (DOX) is loaded into micelles to detect in vitro release behavior. The drug loaded micelles show a faster release behavior at pH 5.0 than that at pH 7.4. Therefore, the pH-sensitive charge reversal and self-fluorescent micelle can be a potential smart carrier for delivery and controlled release of protein drug.

A sensitive colorimetric and ratiometric chemosensor for trivalent metal cations.

A novel hydroxyethyl piperazine functionalized cyanine derivative was designed and synthesized. It presents selective colorimetric as well as ratiometric absorption responses to trivalent metal cations (Cr(3+), Fe(3+) and Al(3+)) over a variety of divalent and monovalent metal cations in 3:7 ethanol-water solution. Detection limits of this method for Cr(3+), Fe(3+) and Al(3+) were 3.99μM, 4.30μM and 1.85μM, respectively. The recognition mechanism was attributed to the protonation of the organic probe, which blocked the photoinduced electron transfer (PET) process. In addition, the sensor was also successfully applied to the determination of Cr(3+) in prepared samples.

Fluorescein-based chromo-fluorescent probe for zinc in aqueous solution: Spirolactam ring opened or closed?

A fluorescein derivative, sensor 1, was synthesized and characterized. It shows 50nm bathochromic shifts (from 346 to 400nm) with a change of solution color and a large increase in the fluorescence intensity upon binding zinc in 1:1 ethanol–hydroxyethyl piperazine ethanesulfonic acid buffer (v/v, pH 7.2) solution. It was demonstrated that changes are not due to the ring opening of the fluorescein spirolactam. The formation of 1–Zn2+ complex or fluorescein dianion adduct at higher pH was further confirmed by mass spectrometry. The fluorescein based molecular probe showed Zn2+ induced absorption and emission changes but does not undergo spirolactam ring opening (reversible) whereas ring opening (irreversible) and hydrolysis take place in alkaline pH region. Confocal microscopy experiments showed that 1 can be used for detection of Zn2+ levels (∼30μM) within living cells.

Propylene Glycol-Linked Amino Acid/Dipeptide Diester Prodrugs of Oleanolic Acid for PepT1-Mediated Transport: Synthesis, Intestinal Permeability, and Pharmacokinetics

In our previous studies, ethylene glycol-linked amino acid diester prodrugs of oleanolic acid (OA), a Biopharmaceutics Classification System (BCS) class IV drug, designed to target peptide transporter 1 (PepT1) have been synthesized and evaluated. Unlike ethylene glycol, propylene glycol is of very low toxicity in vivo. In this study, propylene glycol was used as a linker to further compare the effect of the type of linker on the stability, permeability, affinity, and bioavailability of the prodrugs of OA. Seven diester prodrugs with amino acid/dipeptide promoieties containing L-Val ester (7a), L-Phe ester (7b), L-Ile ester (7c), D-Val-L-Val ester (9a), L-Val-L-Val ester (9b), L-Ala-L-Val ester (9c), and L-Ala-L-Ile ester (9d) were designed and successfully synthesized. In situ rat single-pass intestinal perfusion (SPIP) model was performed to screen the effective permeability (P(eff)) of the prodrugs. P(eff) of 7a, 7b, 7c, 9a, 9b, 9c, and 9d (6.7-fold, 2.4-fold, 1.24-fold, 1.22-fold, 4.15-fold, 2.2-fold, and 1.4-fold, respectively) in 2-(N-morpholino)ethanesulfonic acid buffer (MES) with pH 6.0 showed significant increase compared to that of OA (p < 0.01). In hydroxyethyl piperazine ethanesulfonic acid buffer (HEPES) of pH 7.4, except for 7c, 9a, and 9d, P(eff) of the other prodrugs containing 7a (5.2-fold), 7b (2.0-fold), 9b (3.1-fold), and 9c (1.7-fold) exhibited significantly higher values than that of OA (p < 0.01). In inhibition studies with glycyl-sarcosine (Gly-Sar, a typical substrate of PepT1), P(eff) of 7a (5.2-fold), 7b (2.0-fold), 9b (3.1-fold), and 9c (2.3-fold) had significantly reduced values (p < 0.01). Compared to the apparent permeability coefficient (P(app)) of OA with Caco-2 cell monolayer, significant enhancement of the P(app) of 7a (5.27-fold), 9b (3.31-fold), 9a (2.26-fold), 7b (2.10-fold), 7c (2.03-fold), 9c (1.87-fold), and 9d (1.39-fold) was also observed (p < 0.01). Inhibition studies with Gly-Sar (1 mM) showed that P(app) of 7a, 9b, and 9c significantly reduced by 1.3-fold, 1.6-fold, and 1.4-fold (p < 0.01), respectively. These results may be attributed to PepT1-mediated transport and their differential affinity toward PepT1. According to the permeability and affinity, 7a and 9b were selected in the pharmacokinetic studies in rats. Compared with group OA, C(max) for group 7a and 9b was enhanced to 3.04-fold (p < 0.01) and 2.62-fold (p < 0.01), respectively. AUC(0→24) was improved to 3.55-fold (p < 0.01) and 3.39-fold (p < 0.01), respectively. Compared to the ethylene glycol-linked amino acid diester prodrugs of OA in our previous work, results from this study revealed that part of the propylene glycol-linked amino acid/dipeptide diester prodrugs showed better stability, permeability, affinity, and bioavailability. In conclusion, propylene glycol-linked amino acid/dipeptide diester prodrugs of OA may be suitable for PepT1-targeted prodrugs of OA to improve the oral bioavailability of OA.

Temperature- and pH-responsive nanoparticles of biocompatible polyurethanes for doxorubicin delivery

A series of temperature- and pH-responsive polyurethanes based on hexamethylene diisocyanate (HDI) and 4,4'-diphenylmethane diisocyanate (MDI) were synthesized by a coupling reaction with bis-1,4-(hydroxyethyl) piperazine (HEP), N-methyldiethanolamine (MDEA) and N-butyldiethanolamine (BDEA), respectively. The chemical structure, molecular weight, thermal property and crystallization properties were characterized by Fourier transform infrared (FT-IR) spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, gel permeation chromatography (GPC), differential scanning calorimetry (DSC) and X-ray diffraction (XRD) spectroscopy. The resulting polyurethanes were then used to prepare nanoparticles either by direct dispersion method or dialysis method. Their pH and temperature responsibilities were evaluated by optical transmittance and size measurement in aqueous media. Interestingly, HDI-based and MDI-based polyurethanes exhibited different pH and temperature responsive properties. Nanoparticles based on HDI-HEP and HDI-MDEA were temperature-responsive, while MDI-based biomaterials were not. All of them showed pH-sensitive behavior. The possible responsive mechanism was investigated by (1)H NMR spectroscopy. The cytotoxicity of the polyurethanes was evaluated using methylthiazoletetrazolium (MTT) assay in vitro. It was shown that the HDI-based polyurethanes were non-toxic, and could be applied to doxorubicin (DOX) encapsulation. The experimental results indicated that DOX could be efficiently encapsulated into polyurethane nanoparticles and uptaken by Huh-7 cells. The loaded DOX molecules could be released from the drug-loaded polyurethane nanoparticles upon pH and temperature changes, responsively.

PH- and temperature-sensitive multiblock copolymer hydrogels composed of poly(ethylene glycol) and poly(amino urethane)

A series of novel pH- and temperature-responsive multiblock copolymers (poly(PEG/HEP urethane)) consisting of poly(ethylene glycol) (PEG) and poly(amino urethane) (PAU) were synthesized, and their physicochemical properties were studied. The amphiphilic block copolymers were synthesized from PEG, 1,4-bis(hydroxyethyl) piperazine (HEP) and 1,6-diisocyanato hexamethylene (HDI) in the presence of dibutyltin dilaurate as a catalyst. The resulting polymers were examined by FT-IR, 1H and 13C NMR spectroscopies and gel permeation chromatography (GPC). The solution properties of the copolymers were studied by turbidity measurement and fluorescence spectroscopy. The copolymers showed a pH-dependent soluble–insoluble transition in diluted aqueous solutions. The concentrated polymer solutions exhibited a thermo-induced sol–gel–sol phase transition at pH 6.8–7.4. The gel window covers the physiological conditions. After a subcutaneous injection of the multiblock copolymer solution into mice, a transparent and soft gel was formed immediately. The in vitro release of a model anticancer drug, chlorambucil, persisted over 2 weeks under physiological conditions.

Synthesis, characterization and biological screening of some new pyridine derivatives

2- Amino substituted benzothiazole 2 1-12 and p-acetamidobenzenesulfonyl chloride 1 were used to prepare N'-(p-anilinosulfonamido)substitutedbenzothiazole 4 1-12 using mixture of pyridine and acetic anhydride which formed (N-acetyl pyridinium) an electrophilic complex which facilitated condensation to give desired product by removal of HCl. 2-[N 4 -(N 2 -(7-(Substitutedanilino)benzothiazolyl)sulfanilamido)amino]pyridine-3-carboxylic acid 6 1-12 were synthesized from 2-chloropyridine-3-carboxylic acid 5 and 4 1-12 in 2-ethoxy cthanol using Cu-powder and K 2 CO 3 . 2-[N 4 -{N 2 -(7-Substitutedanilino)-benzothiazolyl)sulfanilamido}amino]-3-[N 1 -{4'-(2-hydroxyethyl)piperazinyl}carbonyl]pyridine 9 1-12 have been synthesized by the condensation of 6 1―32 and 2―hydroxyethyl piperazine 8 for new amide derivatives via acid chloride 7 1―12.

Cadmium is acutely toxic for murine hepatocytes: effects on intracellular free Ca2+ homeostasis

We studied cadmium toxicity in murine hepatocytes in vitro. Cadmium effects on intracellular free Ca(2+) concentration ([Ca(2+)](i)) were assayed, using a laser scanning confocal microscope with a fluorescent probe, Fluo-3/AM. The results showed that administration of cadmium chloride (CdCl(2), 5, 10, 25 microM) resulted in a dose-dependent decrease of hepatocyte viability and an elevated aspartate aminotransferase (AST) activity in the culture medium (p<0.05 for 25 microM CdCl(2) vs. control). Significant increases of lactate dehydrogenase (LDH) activities in 10 and 25 microM CdC1(2)-exposed groups were observed (p<0.05 and p<0.01, respectively). A greatly decreased albumin content and a more malondialdehyde (MDA) formation also occurred after CdC1(2) treatment. The Ca(2+) concentrations in the culture medium of CdCl(2)-exposed hepatocytes were significantly decreased, while [Ca(2+)](i) appeared to be significantly elevated (p<0.05 or p<0.01 vs. control). We found that in Ca(2+)-containing hydroxyethyl piperazine ethanesulfonic acid-buffered salt solution (HBSS) only, CdCl(2) elicited [Ca(2+)](i) increases, which comprised an initially slow ascent and a strong elevated phase. However, in Ca(2+)-containing HBSS with addition of 2-aminoethoxydiphenyl borane (2-APB), CdCl(2) caused a mild [Ca(2+)](i) elevation in the absence of an initial rise phase. Removal of extracellular Ca(2+) showed that CdCl(2) induced an initially slow [Ca(2+)](i) rise alone without being followed by a markedly elevated phase, but in a Ca(2+)-free HBSS with addition of 2-APB, CdCl(2) failed to elicit the [Ca(2+)](i) elevation. These results suggest that abnormal Ca(2+) homeostasis due to cadmium may be an important mechanism of the development of the toxic effect in murine hepatocytes. [Ca(2+)](i) elevation in acutely cadmium-exposed hepatocytes is closely related to the extracellular Ca(2+) entry and an excessive release of Ca(2+) from intracellular stores.