The sulfonamide-zinc ion interaction, performing a key role in various biological contexts, is the focus of the present study, with the aim of elucidating ligation motifs in zinc complexes of sulfa ...drugs, namely sulfadiazine (SDZ) and sulfathiazole (STZ), in a perturbation-free environment. To this end, an approach is exploited based on mass spectrometry coupled with infrared multiple photon dissociation (IRMPD) spectroscopy backed by quantum chemical calculations. IR spectra of Zn(H
O+SDZ-H)
and Zn(H
O+STZ-H)
ions are consistent with a three-coordinate zinc complex, where ZnOH
binds to the uncharged sulfonamide via N(heterocycle) and O(sulfonyl) donor atoms. Alternative prototropic isomers Zn(OH
)(SDZ-H)
and Zn(OH
)(STZ-H)
lie 63 and 26 kJ mol
higher in free energy, respectively, relative to the ground state Zn(OH)(SDZ)
and Zn(OH)(STZ)
species and do not contribute to any significant extent in the sampled population.
The study of Pt(IV) antitumor prodrugs able to circumvent some drawbacks of the conventional Pt(II) chemotherapeutics is the focus of a lot of attention. This paper reports a thorough study based on ...experimental methods (reduction kinetics, electrochemistry, tandem mass spectrometry and IR ion spectroscopy) and quantum–mechanical DFT calculations on the reduction mechanism of cisplatin-based Pt(IV) derivatives having two hydroxido (
1
), one hydroxido and one acetato (
2
), or two acetato ligands (
3
) in axial position. The biological reductants glutathione and ascorbic acid were taken into consideration. The presence of a hydroxido ligand resulted to play an important role in the chemical reduction with ascorbic acid, as verified by
15
N-NMR kinetic analysis using
15
N-enriched complexes. The reactivity trend (
1
>
2
>
3
) does not reflect the respective reduction peak potentials (
1
<
2
<
3
), an inverse relationship already documented in similar systems. Turning to a simplified environment, the Pt(IV) complexes associated with a single reductant molecule (corresponding to the encounter complex occurring along the reaction coordinate in bimolecular reactions in solution) were characterized by IR ion spectroscopy and sampled for their reactivity under collision-induced dissociation (CID) conditions. The complexes display a comparable reduction reactivity ordering as that observed in solution. DFT calculations of the free energy pathways for the observed fragmentation reactions provide theoretical support for the CID patterns and the mechanistic hypotheses on the reduction process are corroborated by the observed reaction paths. The bulk of these data offers a clue of the intricate pathways occurring in solution.
Graphic abstract
The binding motifs in the halide adducts with tyrosine (Tyr + X
, X = Cl, Br, I) have been investigated and compared with the analogues with 3-nitrotyrosine (nitroTyr), a biomarker of protein ...nitration, in a solvent-free environment by mass-selected infrared multiple photon dissociation (IRMPD) spectroscopy over two IR frequency ranges, namely 950-1950 and 2800-3700 cm
. Extensive quantum chemical calculations at B3LYP, B3LYP-D3 and MP2 levels of theory have been performed using the 6-311++G(d,p) basis set to determine the geometry, relative energy and vibrational properties of likely isomers and interpret the measured spectra. A diagnostic carbonyl stretching band at ∼1720 cm
from the intact carboxylic group characterizes the IRMPD spectra of both Tyr + X
and nitroTyr + X
, revealing that the canonical isomers (maintaining intact amino and carboxylic functions) are the prevalent structures. The spectroscopic evidence reveals the presence of multiple non-covalent forms. The halide complexes of tyrosine conform to a mixture of plane and phenol isomers. The contribution of phenol-bound isomers is sensitive to anion size, increasing from chloride to iodide, consistent with the decreasing basicity of the halide, with relative amounts depending on the relative energies of the respective structures. The stability of the most favorable phenol isomer with respect to the reference plane geometry is in fact 1.3, -2.1, -6.8 kJ mol
, for X = Cl, Br, I, respectively. The change in π-acidity by ring nitration also stabilizes anion-π interactions yielding ring isomers for nitroTyr + X
, where the anion is placed above the face of the aromatic ring.
Pantothenic acid, also called vitamin B5, is an essential nutrient involved in several metabolic pathways. It shows a characteristic preference for interacting with Ca(II) ions, which are abundant in ...the extracellular media and act as secondary mediators in the activation of numerous biological functions. The bare deprotonated form of pantothenic acid, panto-H
, its complex with Ca(II) ion, Ca(panto-H)
, and singly charged micro-hydrated calcium pantothenate Ca(panto-H)(H
O)
adduct have been obtained in the gas phase by electrospray ionization and assayed by mass spectrometry and IR multiple photon dissociation spectroscopy in the fingerprint spectral range. Quantum chemical calculations at the B3LYP(-D3) and MP2 levels of theory were performed to simulate geometries, thermochemical data, and linear absorption spectra of low-lying isomers, allowing us to assign the experimental absorptions to particular structural motifs. Pantothenate was found to exist in the gas phase as a single isomeric form showing deprotonation on the carboxylic moiety. On the contrary, free and monohydrated calcium complexes of deprotonated pantothenic acid both present at least two isomers participating in the gas-phase population, sharing the deprotonation of pantothenate on the carboxylic group and either a fourfold or fivefold coordination with calcium, thus justifying the strong affinity of pantothenate for the metal.
Kinetically inert platinum(IV) complexes are receiving growing attention as promising candidates in the effort to develop safe and valid alternatives to classical square-planar Pt(II) complexes ...currently used in antineoplastic therapy. Their antiproliferative activity requires intracellular Pt(IV)–Pt(II) reduction (activation by reduction). In the present work, a set of five Pt(IV) complexes has been assayed using mass spectrometry–based techniques, i.e., collision-induced dissociation (CID), and IR multiple photon dissociation (IRMPD) spectroscopy, together with ab initio theoretical investigations. Breakdown and reduction mechanisms are observed that lead to Pt(II) species. Evidence is found for typically transient Pt(III) intermediates along the dissociation paths of isolated, negatively charged (electron-rich) Pt(IV) prodrug complexes.
As regioisomers/bioisosteres of 1a, a 4-phenylbenzamide tranylcypromine (TCP) derivative previously disclosed by us, we report here the synthesis and biological evaluation of some ...(hetero)arylbenzoylamino TCP derivatives 1b-6, in which the 4-phenyl moiety of 1a was shifted at the benzamide C3 position or replaced by 2- or 3-furyl, 2- or 3-thienyl, or 4-pyridyl group, all at the benzamide C4 or C3 position. In anti-LSD1-CoREST assay, all the meta derivatives were more effective than the para analogues, with the meta thienyl analogs 4b and 5b being the most potent (IC
50
values = 0.015 and 0.005 μM) and the most selective over MAO-B (selectivity indexes: 24.4 and 164). When tested in U937 AML and prostate cancer LNCaP cells, selected compounds 1a,b, 2b, 3b, 4b, and 5a,b displayed cell growth arrest mainly in LNCaP cells. Western blot analyses showed increased levels of H3K4me2 and/or H3K9me2 confirming the involvement of LSD1 inhibition in these assays.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
: LSD1 is a lysine demethylase highly involved in initiation and development of cancer. To design highly effective covalent inhibitors, a strategy is to fill its large catalytic cleft by designing ...tranylcypromine (TCP) analogs decorated with long, hindered substituents. We prepared three series of TCP analogs, carrying aroyl‐ and arylacetylamino (1 a–h), Z‐amino acylamino (2 a–o), or double‐substituted benzamide (3 a–n) residues at the C4 or C3 position of the phenyl ring. Further fragments obtained by chemical manipulation applied on the TCP scaffold (compounds 4 a–i) were also prepared. When tested against LSD1, most of 1 and 3 exhibited IC50 values in the low nanomolar range, with 1 e and 3 a,d,f,g being also the most selective respect to monoamine oxidases. In MV4‐11 AML and NB4 APL cells compounds 3 were the most potent, displaying up to sub‐micromolar cell growth inhibition against both cell lines (3 a) or against NB4 cells (3 c). The most potent compounds in cellular assays were also able to induce the expression of LSD1 target genes, such as GFI‐1b, ITGAM, and KCTD12, as functional read‐out for LSD1 inhibition. Mouse and human intrinsic clearance data highlighted the high metabolic stability of compounds 3 a, 3 d and 3 g. Further studies will be performed on the new compounds 3 a and 3 c to assess their anticancer potential in different cancer contexts.
Some TCP for LSD: Lysine specific demethylase 1 (LSD1) is heavily involved in the initiation and progression of cancer. Through an X‐ray‐driven drug discovery process, we identified some tranylcypromine (TCP)‐based compounds 1–4. Among them, 1–3 were found to be active against LSD1 in the sub‐micromolar/low nanomolar range. When tested in MV4‐11 AML and NB4 APL cells, 3 a and 3 c were the most potent to arrest proliferation and induced target genes under the control of LSD1 in cells. These compounds will be further validated in different cancer contexts.
Infrared multiple photon dissociation (IRMPD) spectroscopy allows for the derivation of the vibrational fingerprint of molecular ions under tandem mass spectrometry (MS/MS) conditions. It provides ...insight into the nature and localization of posttranslational modifications (PTMs) affecting single amino acids and peptides. IRMPD spectroscopy, which takes advantage of the high sensitivity and resolution of MS/MS, relies on a wavelength specific fragmentation process occurring on resonance with an IR active vibrational mode of the sampled species and is well suited to reveal the presence of a PTM and its impact in the molecular environment. IRMPD spectroscopy is clearly not a proteomics tool. It is rather a valuable source of information for fixed wavelength IRMPD exploited in dissociation protocols of peptides and proteins. Indeed, from the large variety of model PTM containing amino acids and peptides which have been characterized by IRMPD spectroscopy, specific signatures of PTMs such as phosphorylation or sulfonation can be derived. High throughput workflows relying on the selective fragmentation of modified peptides within a complex mixture have thus been proposed. Sequential fragmentations can be observed upon IR activation, which do not only give rise to rich fragmentation patterns but also overcome low mass cutoff limitations in ion trap mass analyzers. Laser-based vibrational spectroscopy of mass-selected ions holding various PTMs is an increasingly expanding field both in the variety of chemical issues coped with and in the technological advancements and implementations.
Thyroid hormones are biologically active small molecules responsible for growth and development regulation, basal metabolic rate, and lipid and carbohydrate metabolism. Liquid chromatography mass ...spectrometry (LC–MS) can be used to quantify thyroid hormones blood level with high speed and selectivity, aiming to improve the diagnosis and treatment of the severe pathological conditions in which they are implicated, i.e., hypo- and hyperthyroidism. In this work, the gas-phase behavior of the isomeric thyroid hormones triiodothyronine (T3) and reverse triiodothyronine (rT3) in their deprotonated form was studied at a molecular level using MS-based techniques. Previously reported collision-induced dissociation experiments yielded distinct spectra despite the high structural similarity of the two compounds, suggesting different charge sites to be responsible. Infrared multiple photon dissociation spectroscopy on T3-H− and rT3-H− was performed, and the results were interpreted using DFT and MP2 calculations, assessing the prevalence of T3 in the carboxylate form and rT3 as a phenolate isomer. The different deprotonation sites of the two isomers were also found to drive their ion-mobility behavior. In fact, T3-H− and rT3-H− were successfully separated. Drift times were correlated with collisional cross section values of 209 and 215 Å2 for T3-H− and rT3-H−, respectively. Calculations suggested the charge site to be the main parameter involved in the different mobilities of the two anions. Finally, bare T3-H− and rT3-H− were made to react with neutral acetylacetone and trifluoroacetic acid, confirming rT3 to be more acidic than T3 in agreement with the calculated gas-phase acidities of T3 and rT3 equal to 1345 and 1326 kJ mol–1, respectively.
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