Search results for "HILIC"

Profiling of lipid species by normal-phase liquid chromatography, nanoelectrospray ionization, and ion trap–orbitrap mass spectrometry

2013

Detailed analysis of lipid species can be challenging due to their structural diversity and wide concentration range in cells, tissues, and biofluids. To address these analytical challenges, we devised a reproducible, sensitive, and integrated lipidomics workflow based on normal-phase liquid chromatography-Fourier transform mass spectrometry (LC-FTMS) and LC-ITMS(2) (ion trap tandem mass spectrometry) for profiling and structural analysis of lipid species. The workflow uses a normal-phase LC system for efficient separation of apolar and polar lipid species combined with sensitive and specific analysis powered by a chip-based nanoelectrospray ion source and a hybrid ion trap-orbitrap mass sp…

Molecular mechanism of T-cell protein tyrosine phosphatase (TCPTP) activation by mitoxantrone.

2013

T-cell protein tyrosine phosphatase (TCPTP) is a ubiquitously expressed non-receptor protein tyrosine phosphatase. It is involved in the negative regulation of many cellular signaling pathways. Thus, activation of TCPTP could have important therapeutic applications in diseases such as cancer and inflammation. We have previously shown that the α-cytoplasmic tail of integrin α1β1 directly binds and activates TCPTP. In addition, we have identified in a large-scale high-throughput screen six small molecules that activate TCPTP. These small molecule activators include mitoxantrone and spermidine. In this study, we have investigated the molecular mechanism behind agonist-induced TCPTP activation.…

Thermal- and photoinduced spin-state switching in an unprecedented three-dimensional bimetallic coordination polymer.

2005

The compound {Fe(pmd)[Ag(CN)2][Ag2(CN)3]} (pmd=pyrimidine) was synthesized and characterized. Magnetic, calorimetric and single crystal visible spectroscopic studies demonstrate the occurrence of a two-step high-spin (HS) right arrow over left arrow low-spin (LS) transition. The critical temperatures are T(c1)=185 and T(c2)=148 K. Each step involves approximately 50 % of the iron centers, with the low-temperature step showing a hysteresis of 2.5 K. The enthalpy and entropy variations associated with the two steps are DeltaH(1)=3.6+/-0.4 kJ mol(-1) and DeltaS(1)=19.5+/-3 J K(-1) mol(-1); DeltaH(2)=4.8+/-0.4 kJ mol(-1) and DeltaS(2)=33.5+/-3 J K(-1) mol(-1). Photomagnetic and visible spectros…

Low density lipoproteins and human serum albumin as the carriers of squalenoylated drugs: insights from molecular simulations

2018

We have studied the interaction of three clinically promising squalenoylated drugs (gemcitabine-squalene, adenine-squalene, and doxorubicin-squalene) with low-density lipoproteins (LDL) by means of atomistic molecular dynamics simulations. It is shown that all studied squalenoylated drugs accumulate inside the LDL particles. This effect is promoted by the squalene moiety, which acts as an anchor and drives the hydrophilic drugs into the hydrophobic core of the LDL lipid droplet. Our data suggest that LDL particles could be a universal carriers of squalenoylated drugs in the bloodstream. Interaction of gemcitabine-squalene with human serum albumin (HSA) was also studied by ensemble of dockin…

Binding isotope effects as a tool for distinguishing hydrophobic and hydrophilic binding sites of HIV-1 RT.

2014

The current treatment for HIV-1 infected patients consists of a cocktail of inhibitors, in an attempt to improve the potency of the drugs by adding the possible effects of each supplied compound. In this contribution, nine different inhibitors of HIV-1 RT, one of the three key proteins responsible for the virus replication, have been selected to develop and test a computational protocol that allows getting a deep insight into the inhibitors’ binding mechanism. The interaction between the inhibitors and the protein have been quantified by computing binding free energies through FEP calculations, while a more detailed characterization of the kind of inhibitor–protein interactions is based on …

2020

Electrophilic (het)arenes can undergo reactions with nucleophiles yielding π- or Meisenheimer (σ-) complexes or the products of the SNAr addition/elimination reactions. Such building blocks have only rarely been employed for the design of enzyme inhibitors. Herein, we demonstrate the combination of a peptidic recognition sequence with such electrophilic (het)arenes to generate highly active inhibitors of disease-relevant proteases. We further elucidate an unexpected mode of action for the trypanosomal protease rhodesain using NMR spectroscopy and mass spectrometry, enzyme kinetics and various types of simulations. After hydrolysis of an ester function in the recognition sequence of a weakly…

Regioselective substitution of 6,7-dichloroquinoline-5,8-dione: synthesis and X-ray crystal structure of 4a,10,11-triazabenzo[3,2-a]fluorene-5,6-dion…

2003

6,7-Dichloroquinoline-5,8-dione (1) was reacted with a number of 2-aminopyridine derivatives. Of the several possible products of this reaction, 4a,10,11-triazabenzo[3,2-a]fluorene-5,6-dione (6), produced by condensation and rearrangement, was obtained as the major product, and its structure was subsequently unambigously determined by X-ray crystallographic study. Ortho-quinones were produced via nucleophilic substitution at position C7, which was unexpected, considering that para-quinones were produced via C6 substitution in the reaction between compound 1 and ethyl acetoacetate in our previous work. Such unexpected nucleophilic substitution at C7 provides an effective, yet simple route, t…

In vitro affinities of various halogenated benzamide derivatives as potential radioligands for non-invasive quantification of D(2)-like dopamine rece…

2007

Abstract Benzamide derivatives as radiotracers have played an important role in diagnosing malfunction in dopaminergic neurotransmission. A variety of halogenated and two unsubstituted benzamide derivatives were synthesised and their in vitro affinities to dopaminergic, serotonergic and adrenergic receptors and their lipophilicities were determined. As references IBZM (3), raclopride (4) and FLB457 (5) were tested as well. The two iodinated compounds NAE (27) and NADE (28) displayed Ki values of 0.68 and 14 nM for the D2 receptor. The well-established radiotracers FP (1) and DMFP (2) showed affinities in the same range as did the brominated compounds NABrE (29) and NABrDE (30). The log D7.4…

The introduction of fluorine atoms or trifluoromethyl groups in short cationic peptides enhances their antimicrobial activity

2006

The effect of introducing fluorine atoms or trifluoromethyl groups in either the peptidic chain or the C-terminal end of cationic pentapeptides is reported. Three series of amide and ester peptides were synthesised and their antimicrobial properties evaluated. An enhanced activity was found in those derivatives whose structure contained fluorine, suggesting an increase in their hydrophobicity.

Synthesis and cytotoxicity of 6,11-Dihydro-pyrido- and 6,11-Dihydro-benzo[2,3-b]phenazine-6,11-dione derivatives

2003

6,11-Dihydro-pyrido[2,3-b]phenazine-6,11-diones and 6,11-dihydro-benzo[2,3-b]phenazine-6,11-diones were synthesized from 6,7-dichloro-5,8-quinolinedione and 2,3-dichloro-1,4-naphthoquinone. The study on the cytotoxicity on these products revealed that the pyridophenazinediones, tetracyclic heteroquinone analogues with three nitrogen atoms exhibited a high cytotoxicity on several human tumor cell lines. Compound 9c and 9e showed in vitro antitumor activity comparable or superior to doxorubicin against the human ovarian tumor cells (SK-OV-3) and the human CNS cells (XF 498). The IC(50) value for compound 9e was 0.06 microM against the human CNS cells (XF 498), which was 2.6 times higher than …