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Aliphatic hydroxamic acids (HA) with varying numbers of carbon atoms, C2, C6, C8, C10, C12 and C17, and corresponding Fe(II), Fe(III), Ni(II), Cu(II) and Zn(II) complexes have been synthesized and characterized by various methods, including structural determination by single crystal X-ray diffraction and theoretical calculations. The biological activities of HA and their complexes have been assessed on a panel of pathogens, including eight bacteria strains and one fungus. The C12 aliphatic HA displayed the lowest minimum inhibitory concentrations (MIC) towards several microbial strains and a selective antifungal activity. This antifungal selectivity was further improved considering the Ni(II), Cu(II) and Zn(II) complexes of C12 HA showed higher IC50 values, thus less impact on the SiHa human cell line viability. This work warrants further investigation to understand the underlying mechanism of action and potential biological applications of HA and the derived metal complexes.

Ruthenium (Ru) and osmium (Os) complexes are of sustained interest in cancer research and may be alternative to platinum-based therapy. We detail here three new series of ruthenium and osmium complexes, supported by physico-chemical characterizations, including time-dependent density functional theory, a combined experimental and computational study on the aquation reactions and the nature of the metal-arene bond. Cytotoxic profiles were then evaluated on several cancer cell lines although with limited success. Further investigations were, however, performed on the most active series using a genetic approach based on RNA interference and highlighted a potential multi-target mechanism of action through topoisomerase II, mitotic spindle, HDAC and DNMT inhibition., info:eu-repo/semantics/published

Toll-like receptors (TLRs) are proteins that act as the sentinels of mammalian cells by detecting bacteria and viruses motifs such as the phospholipid lipopolysaccharides (LPS) from Gram-negative bacterial membrane, among others. Bacteria like Vibrio cholerae, when grow in phosphate-depleted medium are unable to produce LPS and other phospholipids and therefore increase the synthesis of ornithine lipids (OLs) to keep membrane integrity and survival. We found that, although the huge structural differences between OL and LPS, our immune system is still able to detect OL and trigger immune response through TLR4 and the non-canonical Nucleotide-binding domain and leucine-rich repeat-containing pyrin protein 3 (NLRP3) inflammasome. Similar to LPS, OL induced TLR4-dependent tumor necrosis factor (TNF)-α secretion and Nuclear Factor (NF)-κB activation and therefore also elicited the priming of the NLRP3 inflammasome. Moreover, incubation of macrophages with OL causes caspase-dependent cleavage of gasdermin D (GSDMD) and consequent K+ efflux-dependent NLRP3 activation and interleukin (IL)-1β secretion.Results abstract (if needed)In bone-marrow derived murine macrophages (BMDM) from wild type mice, OLs induced hallmarks of NF-κB activation such as TNF-α secretion and the expression of pro-IL-1β and NLRP3. OL induced NF-κB activation dependent on TLR4 as demonstrated by the NF-κB activation measured in HEK293 reporting cells expressing uniquely TLR4 and by the decrease of TNF-α secretion in macrophages caused by antibodies blocking TLR4. OLs also induced IL-1β secretion dependent on cellular K+ efflux and NLRP3/caspase-1 inflammasome, as it was blocked by specific inhibitors and absent on Nlrp3−/−, Pycard−/− or Casp1/11−/− macrophages.

Smart materials represent an elegant class of (macro)-molecules endowed with the ability to react to chemical/physical changes in the environment. Herein, we prepared new photo responsive azobenzenes possessing halogen bond donor groups. The X-ray structures of two molecules highlight supramolecular organizations governed by unusual noncovalent bonds. In azo dye I-azo-NO2, the nitro group is engaged in orthogonal H···O···I halogen and hydrogen bonding, linking the units in parallel undulating chains. As far as compound I–azo–NH–MMA is concerned, a non-centrosymmetric pattern is formed due to a very rare I···π interaction involving the alkene group supplemented by hydrogen bonds. The Cambridge Structural Database contains only four structures showing the same I···CH2=C contact. For all compounds, an 19F-NMR spectroscopic analysis confirms the formation of halogen bonds in solution through a recognition process with chloride anion, and the reversible photo-responsiveness is demonstrated upon exposing a solution to UV light irradiation. Finally, the intermediate I–azo–NH2 also shows a pronounced color change due to pH variation. These azobenzenes are thereby attractive building blocks to design future multi-stimuli responsive materials for highly functional devices.

Smart materials represent an elegant class of (macro)-molecules endowed with the ability to react to chemical/physical changes in the environment. Herein, we prepared new photo responsive azobenzenes possessing halogen bond donor groups. The X-ray structures of two molecules highlight supramolecular organizations governed by unusual noncovalent bonds. In azo dye I-azo-NO2, the nitro group is engaged in orthogonal H···O···I halogen and hydrogen bonding, linking the units in parallel undulating chains. As concern parent I-azo-NH-MMA, a non-centrosymmetric pattern is formed due to a very rare I···π interaction involving the alkene group supplemented by hydrogen bonds. The Cambridge Structural Database contains only four structures with the same I···CH2=C contact. For all compounds, a 19F NMR spectroscopic analysis confirms the formation of halogen bonds in solution through a recognition process with chloride anion, and the reversible photo-responsiveness is demonstrated upon exposing a solution to UV light irradiation. Finally, intermediate I-azo-NO2 also shows a pronounced color change due to pH variation. These azobenzenes are thereby attractive building blocks to design multi-stimuli responsive materials for highly functional devices.

The heme enzyme myeloperoxidase (MPO) participates in innate immune defense mechanism through formation of microbicidal reactive oxidants. However, evidence has emerged that MPO-derived oxidants contribute to propagation of inflammatory diseases. Because of the deleterious effects of circulating MPO, there is a great interest in the development of new efficient and specific inhibitors. Here, we have performed a novel virtual screening procedure, depending on ligand-based pharmacophore modeling followed by structure-based virtual screening. Starting from a set of 727842 compounds, 28 molecules were selected by this virtual method and tested on MPO in vitro. Twelve out of 28 compounds were found to have an IC50 less than 5 μM. The best inhibitors were 2-(7-methoxy-4-methylquinazolin-2-yl)guanidine (28) and (R)-2-(1-((2,3-dihydro-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-5-fluoro-1H-benzo[d]imidazole (42) with IC50 values of 44 and 50 nM, respectively. Studies on the mechanism of inhibition suggest that 28 is the first potent mechanism-based inhibitor and inhibits irreversibly MPO at nanomolar concentration., SCOPUS: ar.j, info:eu-repo/semantics/published

The formation of multi-stimuli responsive polymers exhibiting magnetic, pH and light sensitivity is reported. After quaternization of tertiary amines along poly(2-(N,N-dimethylamino) ethyl methacrylate) (PDMAEMA) with varied alkyl and benzyl halides, a series of tetrahalogenoferrate(III) salts were obtained by anion metathesis, conferring tailored and high magnetic responses. Experimental and theoretical Raman analyses allowed one to distinguish between the different magnetic anions present in the materials. This strategy was then implemented to the formation of multi-responsive compounds, by using random copolymers that incorporate various amounts of DMAEMA (∼40, 65 and 80%) and diazobenzene units. Partial or total quaternization of the dimethylamino end groups (10, 50 and 100%) followed by magnetic anion exchange afforded the magnetic-responsive copolymers, as evidenced by their magnetic susceptibility. Free ternary amino groups and diazobenzene moieties further brought pH and light sensitivity, giving rise to triple-stimuli responsive materials. This simple and rapid procedure offers the opportunity to fine tune the magnetic properties of remotely controlled smart devices.

The implementation of dynamic combinatorial libraries allowed the determination of highly active reversible and irreversible inhibitors of myeloperoxidase (MPO) at the nanomolar level. Docking experiments highlighted the interaction between the most active ligands and MPO, and further kinetic studies defined the mode of inhibition of these compounds. Finally, in vivo evaluation showed that one dose of irreversible inhibitors is able to suppress the activity of MPO after inducing inflammation.

Inhaled chemotherapy for the treatment of lung tumors requires that drug delivery systems improve selectivity for cancer cells and tumor penetration and allow sufficient lung residence. To this end, we developed solid lipid nanoparticles (SLN) with modified surface properties. We successfully synthesized a new folate-grafted copolymer of polyethylene glycol (PEG) and chitosan, F-PEG-HTCC, with a PEG-graft ratio of 7% and a molecular weight range of 211-250 kDa. F-PEG-HTCC-coated, paclitaxel-loaded SLN were prepared with an encapsulation efficiency, mean diameter, and zeta potential of about 100%, 250 nm, and +32 mV, respectively. The coated SLN entered folate receptor (FR)-expressing HeLa and M109-HiFR cells in vitro and M109 tumors in vivo after pulmonary delivery. The coated SLN significantly decreased the in vitro half-maximum inhibitory concentrations of paclitaxel in M109-HiFR cells (60 vs 340 nM, respectively). We demonstrated that FR was involved in these improvements, especially in M109-HiFR cells. After pulmonary delivery in vivo, the coated SLN had a favorable pharmacokinetic profile, with pulmonary exposure to paclitaxel prolonged to up to 6 h and limited systemic distribution. Our preclinical findings therefore demonstrated the positive impact of the coated SLN on the delivery of paclitaxel by inhalation.

Besides the numerous advantages of a chemotherapy administered by the inhalation route for lung cancer therapy, dry powder for inhalation (DPI) offers many advantages compared to other techniques and seems to be a technique that is well-adapted to an anticancer treatment. DPI formulations were developed using the cytotoxic drug temozolomide and a new folate-grafted self-assembling copolymer, a conjugate of three components, folate-polyethylene glycol-hydrophobically-modified dextran (F-PEG-HMD). F-PEG-HMD was synthesized using carbodiimide-mediated coupling chemistry in three main steps. F-PEG-HMD was characterized by 1H-NMR, mass spectrometry and thermal analysis. F-PEG-HMD presented a critical micellar concentration in water of 4x10-7 M. F-PEG-HMD nanomicelles were characterized by a trimodal particle size distribution with Z-average diameter of 83±1 nm in water. Temozolomide-loaded nanomicelles were prepared by solubilization of F-PEG-HMD in the presence of temozolomide. Temozolomide solubility in water was increased in the presence of F-PEG-HMD (2-fold increase in molar solubility) which could potentially lead to increased local concentrations in the tumor site. The temozolomide-loaded F-PEG-HMD nanomicelles were characterized by a Z-average diameter of ~50 to ~60 nm, depending on the F-PEG-HMD concentration used. The nanomicelles were then spray-dried to produce dry powders. Temozolomide remained stable during all the formulation steps, confirmed by similar in vitro anticancer properties for the DPI formulations and a raw temozolomide solution. Two of the developed DPI formulations were characterized by good aerodynamic properties (with a fine particle fraction of up to 50%) and were able to release the F-PEG-HMD nanomicelles quickly in aqueous media. Moreover, in vitro, the two DPI formulations showed wide pulmonary deposition in the lower respiratory tract where adenocarcinomas are more often found. The present study, therefore, shows that F-PEG-HMD-based dry powders for inhalation could constitute an interesting drug delivery system able to release nanomicelles that are useful in adenocarcinomas that overexpress folate receptors.

The heme enzyme myeloperoxidase (MPO) participates in innate immune defense mechanism through formation of microbicidal reactive oxidants. However, evidence has emerged that MPO-derived oxidants contribute to the propagation of inflammatory diseases. Because of the deleterious effects of circulating MPO, there is a great interest in the development of new efficient and specific inhibitors. The implementation of dynamic combinatorial libraries allowed to obtain several compounds derived from aromatic hydrazone with high activity on MPO. These inhibitors were found to be reversible and irreversible MPO inhibitors at the nanomolar level. Docking experiments highlighted the interaction between the most active ligands and MPO, and further kinetic studies defined the mode of inhibition of these compounds. In vivo evaluation in rats injected by carrageenan showed that one dose of irreversible inhibitors is able to suppress the activity of MPO after inducing inflammation. On the other hand, paroxetine and p-aminobenzoic acid hydrazide are irreversible MPO inhibitors. The hydrazide group was identified as responsible for the irreversible activity. In addition, hydroxamic acid derivatives are good reversible inhibitors and the hydroxamate group is very similar to the hydrazide one in electronic density and ability to make bonds. Thus, starting from paroxetine, benzoic acid hydrazide, and hydroxamic acid, a new series of compounds has been designed and synthesized. These compounds have shown very high activity on MPO with IC50 of 12-900 nM. Investigations on the mechanism of action has demonstrated that these compounds are irreversible MPO inhibitors. To see if these inhibitors impair the innate immunity, the effect of the compounds were tested on the neutrophils. The results showed that these inhibitors inhibit only the released MPO into the extracellular fluids. Finally, hydrazide and hydrazine derivatives were tested as anti-bacterial agents. Surprisingly, all hydrazone derivatives showed high activity against Gram (-) bacteria and low activity on Gram (+). In contrast, hydrazide derivatives showed very high potency against Gram (+) but no effect was found on Gram (-).

Due to its production of potent antimicrobial oxidants including hypochlorous acid, human myeloperoxidase (MPO) plays a critical role in innate immunity and inflammatory diseases. Thus MPO is an attractive target in drug design. (Aminoalkyl)fluoroindole derivatives were detected to be very potent MPO inhibitors; however, they also promote inhibition of the serotonin reuptake transporter (SERT) at the same concentration range. Via structure-based drug design, a new series of MPO inhibitors derived from 3-alkylindole were synthesized and their effects were assessed on MPO-mediated taurine chlorination and low-density lipoprotein oxidation as well as on inhibition of SERT. The fluoroindole compound with three carbons in the side chain and one amide group exhibited a selectivity index of 35 (Ki/IC50) with high inhibition of MPO activity (IC50 = 18 nM), whereas its effect on SERT was in the micromolar range. Structure-function relationships, mechanism of action, and safety of the molecule are discussed.

A new method for the synthesis of 15N-labeled chiral beta-diamines from a common precursor, either optically pure amino acids or anti-beta-amino alcohols, is reported. The two diastereomeric series of vicinal diamines are produced through the nucleophilic ring opening of activated chiral aziridines. 15N was introduced by means of [15N]-benzylamine, prepared from 15NH4Cl. The final compounds are highly valuable because [1H-15N] NMR is considered a powerful tool for studying the chemical properties of platinum-based complexes., SCOPUS: ar.j, info:eu-repo/semantics/published

Metal complexes have been the subject of numerous investigations in oncology but, despite the plethora of newly synthesized compounds, their precise mechanisms of action remain generally unknown or, for the best, incompletely determined. The continuous development of efficient and sensitive techniques in analytical chemistry and molecular biology gives scientists new tools to gather information on how metal complexes can be effective toward cancer. This review focuses on recent findings about the anticancer mechanism of action of metal complexes and how the ligands can be used to tune their pharmacological and physicochemical properties.

Human myeloperoxidase (MPO) plays an important role in innate immunity but also aggravates tissue damage by oxidation of biomolecules at sites of inflammation. As a result from a recent high-throughput virtual screening approach for MPO inhibitors, bis-2,2'-[(dihydro-1,3(2H,4H) pyrimidinediyl)bis(methylene)]phenol was detected as a promising lead compound for inhibition of the MPO-typical two-electron oxidation of chloride to hypochlorous acid (IC50 = 0.5 μM). In the present pharmacomodulation study, 37 derivatives of this lead compound were designed and synthesized driven by comprehensive docking studies and the impact on the chlorination activity of MPO. We describe the structural requirements for optimum (i) binding to the heme periphery and (ii) inhibition capacity. Finally, the best three inhibitors (bis-arylalkylamine derivatives) were probed for interaction with the MPO redox intermediates Compound I and Compound II. Determined apparent bimolecular rate constants together with determination of reduction potential and nucleophilicity of the selected compounds allowed us to propose a mechanism of inhibition. The best inhibitor was found to promote the accumulation of inactive form of MPO-Compound II and has IC50 = 54 nM, demonstrating the successful approach of the drug design. Due to the similarity of ligand interactions between MPO and serotonine transporter, the selectivity of this inhibitor was also tested on the serotonin transporter providing a selectivity index of 14 (KiSERT/IC50MPO).

The electrodimerisation of acroleine on a zinc-copper couple in the presence of acetic acid gives 1,5-hexadiene-3,4-diol 5 in 76% yield, the ratio meso/dl being 60/40. Gas chromatographic analysis of the reaction mixture reveals the presence of threo- and erythro-1-hexene-3,4-diol and of the mono- and di-acetates (meso/dl) of 4, especially when large quantities of acetic acid are used. Optimum conditions are described in order to minimize these side-reactions. Starting from 4, two new routes to 1,3,5-hexatriene 1 has been developped, namely by treating the bistosylate derivative of 4 with sodium iodide in 2-(2-ethoxy-ethoxy) ethanol (adaptation of Linstead's reaction) and by a modification of Corey's method, where 4 is treated with N′, N′-thiocarbonyl-diimidazole and the resulting cyclic thiocarbonate decomposed in triphenylphosphite. Hexatriene is obtained respectively in 52 and 47% overall yield, the cis/trans ratios being 10/90 and 20/80. Although these reaction schemes appear to be non-stereospecific, they constitute two new valuable methods to cis-1,3,5-hexatriene.

The bromination of 1,5‐hexadiyne at ‐40° in chloroformic solution gives 1,2,5,6‐tetrabromo‐1,5‐hexadiene (5) with a yield of 948; at higher temperatures (e. g. ‐15°), bromination of the double bonds occurs. The stereochemistry of (5) has been studied by N. M. R. ‐spectroscopy; the ratio of cis to trans double bonds (defined with respect to the two bromine atoms) is shown to be 1/9. When (5) is treated repeatedly with N‐bromo‐succinimide (NBS) in CCl4 solution, 1,1, 2,5, 6,6‐hexabromo‐2,4‐hexadiene (7) (trans, trans or cis, cis) is formed, implying a double allylic bromine migration; this structure is assigned on the basis of U. V.‐ and N. M. R.‐ evidence, in comparison with the spectroscopic properties of 1,2,3‐tribromopropene. Treatment of (7) with zinc powder in ethanol produces mainly trans‐1,5‐hexadiyne‐3‐ene (yield 57%), together with a small amount (2,8%) of the cis‐derivative. Copyright © 1974 Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim

Proton and carbon-13 chemical shifts and coupling constants of 6-mercapto-2-pyridinecarboxylic acid and its seven methylated derivatives are reported. Substituent effects are discussed Les deplacements chimiques et les constants de couplage en RMN-1H et -13C de l'acide mercapto-6 pyridinecarboxylique-2 et de ses sept derives methyles ont ete releves. Les effets de substituent sont discutes.

The carbon-13 NMR spectra of β-aminothiols and disulfides related to nor-and pseudonorthiophedrine (N-CH3; N-C2H5; N-iC3H7 and N-tC4H9) and the series of the corresponding thiazolidine from paraformaldehyde were obtained. Their study allowed the differentiation of the diastereomers in these three series.

The synthesis of various diastereoisomeric (±) H4a,H9a‐trans,H9,H9a‐cis‐ (VIII) and H4a,H9a‐trans, H9,H9a‐trans‐2,3,4,4a,9,9a‐hexahydro‐9‐phenyl‐1H‐indeno[1,2‐b]pyrazines (IX) is described, using as key step for piperazine ring formation an alkoxyphosphonium salt. Compound IXa was prepared as a putative serotonin reuptake inhibitor. Copyright © 1995 Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim

Proton and carbon-13 chemical shifts and coupling constants of 2-mercapto-4-pyridinecarboxylic acid, 4-mercapto-2-pyridinecarboxylic acid and their seven respective methylated derivatives are reported. Substituent effects are discussed.

The condensation of (1R,2S) or (1S, 2S)‐N,N′‐dimethyl‐1‐phenylpropane‐1,2‐diamines with aldehydes gives respectively two diastereomeric 2‐alkyl‐1,3,4‐trimethyl‐5‐phenylimidazolidines. At thermodynamical equilibrium the major isomer in the erythro series is this one where the substituents at position 2 and 4 are ”cis“. In the threo series, the major isomer has the substituents at position 2 and 4 ”trans“. Copyright © 1990 Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim

A qualitative and quantitative study of the constituents of quinoline yellow (C.I. 47005) in several samples is presented here. The isolation through preparative ion pairs HPLC of these constituents, followed by a spectroscopic examination (UV-visible, IR, 1H - NMR) and by a study which compares them to synthesized derivatives, shows that quinoline yellow commercial samples contain chiefly disodic salts of 2-(2′-quinolyl) 1, 3-indandione sulfonic acids sulfonated respectively on 5,6′ and 5,8′ positions. Some samples contain also important quantities of the last mentioned compound methylated on 6′ position. Une etude qualitative et quantitative des constituants du jaune de quinoleine (C.I. 47005) dans plusieurs echantillons, est presentee. L'isolement de ces composes par CLHP preparative d'appariement d'ions, suivi d'un examen spectroscopique (UV-visible, IR, RMN- H) et d'une etude comparative de derives synthetises, montre que les echantillons commerciaux du jaune de quinoleine contiennent principalement des sels disodiques des acides (quinoleinyl-2′)-2 indanedione-1,3 sulfoniques respectivement sulfones en positions 5,6′ et 5,8′. Certains echantillons renferment, en outre, des quantites importantes du second derive methyle en position 6′.

Carbon-13 nuclear magnetic resonance spectra of some sulfonated 2-(2′-quinolyl)-1, 3-indanedione dyes have been reported and fully assigned. Les spectres RMN-13C de quelques colorants (quinoleinyl-2′)-2 indanedione-1, 3 sulfones ont ete etudies. Une attribution totale des signaux est proposee.

1H- and 13C-NMR studies of mono- and diacetylated-erythro- and threo-2-alkylamino-1-phenylpropan-1-ols, C6H5CHOHCHNHRCH3 (R = H, CH3, C2H5 and i-C3H7) show that the series exhibit Z/E isomerism about the C-N amide bond. The Z/E ratio increases in the monoacetylated series CH3 < C2H5 < i-C3H7 indicating that the hydrogen bond between the hydroxylic proton and the carbonyl function of the amide is in the case of the isopropyl substituent favoured. In the diacetylated series, where an hydrogen bond is not possible, the Z/E ratio is respectively in the erythro and threo series about 3 and 1. The progressive increase of the volume of the substituent N-alkyl modifies the conformational equilibrium about the C1-C2 and N-C2 bonds. In the Z configuration, the conformer Z-s-syn where the proton H-2 is syn with the N-alkyl substituent predominates.

The synthesis of various diastereoisomeric (±) trans-(VIII) and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[1,2-b] pyrazines (IX) is described, using as key step for piperazine ring formation an alkoxyphosphonium salt. Compound VIIIa was prepared as a potential serotonin reuptake inhibitor.

We report the first spectroscopic (NMR) evidences of macroscopic orientation of benzene in C60⋅4C6H6 solvate at room temperature. Unusually strong transcient oscillations have been observed in proton-carbon cross-polarization and cross-polarization inversion experiments for a static sample. This provides detailed geometrical information about macroscopically oriented benzene in C60 solvate.

Myeloperoxidase (MPO) is an important target for drug design because of its contributing role in many inflammatory syndromes such as atherosclerosis, rheumatoid arthritis, end-stage renal disease or neurodegeneration. Rational drug design assisted by virtual screening is an interesting tool to design new chemical entities that could inhibit MPO. After a high throughput virtual screening of a database, bis-2,2′-[(dihydro-1,3(2H,4H)-pyrimidinediyl)bis(methylene)]phenol was chosen as a starting hit and we used different strategies of chemical synthesis to perform pharmacomodulation described by the three following approaches: I) changing the position of the two nitrogen atoms in the hexahydropyrimidine cycle leading to piperazine derivatives, II) omitting one nitrogen atom in the hexahydropyrimidine leading to piperidine derivatives, III) opening the cycle of hexahydropyrimidine and keeping one nitrogen atom in the aliphatic chain leading to alkylamine derivatives. This led to 30 compounds that have been assessed in an in vitro inhibition MPO test. We found that the alkylamine compounds were active but to a lesser extent than the starting hit. Exception for propylamine derivatives with a phenyl cycle should be noticed. As indolic compounds have demonstrated interesting inhibiting properties, we combined indole ring with thephenolhydropyrimidine structure which led to compounds more active than the hit. Among them, propylamine derivatives were new MPO inhibitors with a nanomolar IC50. Kinetics studies for the most potent inhibitors were conducted and reflected a fast reaction with compound I (MPO-Porphyrin•+-Fe(IV)=O) resulting in the accumulation of compound II (MPO-Porphyrin-Fe(IV)=O). Structure-activity relationship will be discussed to highlight the chemical group of interest in the interaction with MPO.

1R-(-)-myrtenal was tested as a chiral derivatising agent for the determination of the enantiomeric purity of aliphatic primary amines, beta-aminoalcohols, beta-diamines and alpha-amino-acids. Derivatisation procedure consists in mixing one equivalent each of the amine and 1R-(-)-myrtenal directly into the nuclear magnetic resonance (NMR) tube before addition of the appropriate deuterated solvent and, for alpha-amino-acids, one equivalent of NaOH was added to neutralise the acidic function. Diastereoisomeric imines were completely formed after 12 h and analysed by 1H-NMR except for N-methyl beta-diamines for which imidazolidines were obtained. The method gave satisfactory results only for alpha- and beta-arylalkylamines for which CDCl(3) could be advantageously replaced by C(6)D(6) or pyridine-d(5) in order to increase the difference between the chemical shifts. The main advantage of the procedure is its simplicity as it does not involve steps such as activation, heating, solvent evaporation and isolation of the product. Its limitations are the limited series of compounds susceptible to be analysed and the small difference between the chemical shifts of the diastereoisomeric imines obtained.

A series of 4-amino-piperidine containing molecules have been synthesized and structure-affinity relationship toward the M3-muscarinic receptor has been investigated. Chemical modulations provided molecules with K(i) for the human M3-R up to 1 nM with variable selectivity (3- to 40-fold) over the human M2-R. Compounds 2 (pA(2)=8.3, 8.6) demonstrates in vitro on guinea pig bladder and ileal strips potent anticholinergic properties and tissue selectivity.

Cordia gilletii De Wild (Boraginaceae), a medicinal plant used against infectious diseases in the Democratic Republic of Congo, was investigated for direct and indirect antimicrobial properties. On one hand, the methanol extract is active against many pathogenic bacteria, including resistant strains. Its bio-guided fractionation led to the isolation of ferulaldehyde; this compound showed antimicrobial and antioxidant properties that may support the activity we observed for the methanol extract and some of the traditional uses of C. gilletii. On the other hand, the n-hexane extract of root barks possesses indirect antimicrobial properties, enhancing the activity of antibiotics against methicillin-resistant Staphylococcus aureus (MRSA). The fractionation of this extract led to the isolation of lupeol, which decreases the minimum inhibitory concentration of several antibiotics (4 to 8 fold) against MRSA and contributes to the effects observed for the raw n-hexane extract.

Objectives Major depressive disorder (MDD) is accompanied with an imbalance in the immune system and cardiovascular impairments, such as atherosclerosis. Several mechanisms have been pointed out to underlie this rather unexpected association, and among them the activity of myeloperoxidase (MPO). The aim of our study was to find compounds that inhibit both MPO and serotonin transporter (SERT) for treating MDD associated with cardiovascular diseases. Methods SERT inhibition was assessed with measuring of [3H]-serotonin uptake using HEK-293 MSR cells. MPO inhibition was determined by taurine chloramine test on 3-(aminoalkyl)-5-fluoroindole derivatives and on clinically relevant antidepressants. All kinetic measurements were performed using a temperature-controlled stopped-flow apparatus (model SX-18 MV). Promising lead compounds were docked onto SERT 3D structure modelled using the LeuT structure complexed to tryptophan (PDB code 3F3A). Their toxicological profile was also assessed. Key findings 3-(aminoalkyl)-5-fluoroindole derivative with 5 carbons on the side chain and paroxetine showed the best activity on both MPO and SERT at the nanomolar range. Paroxetine was found to be the first irreversible MPO inhibitor at nanomolar concentrations. Conclusions Our results put forward the first hybrid molecule (compound 25) and drug (paroxetine) that can be especially used in MDD associated with inflammatory syndrome.

Structural and motional features of C 60 · 4C 6 H 6 solvate has been investigated by high-resolution 13 C solid-state NMR spectroscopy. 13 C line shape analysis of the cross-polarization spectrum for the static sample at 293 K shows an unusual motional restriction of benzene molecules in this solvate. The existence of highly anisotropic motion of benzene fraction is visualized also by the detection of important homo and heteronuclear dipolar interactions. 13 C magic-angle spinning spectra reveal a complex character of the C 60 NMR signal composed of three components with slightly different isotropic chemical shifts indicating the existence of magnetically nonequivalent positions or sites.

Platinum-based drugs have been used for several decades to treat various cancers successfully. Cisplatin is the original compound in this class; it cross-links DNA, resulting in cell cycle arrest and cell death via apoptosis. Cisplatin is effective against several tumor types but exhibits toxic side effects; in addition, tumors often develop resistance. An original in vitro approach is proposed to determine whether platinum-based research compounds are good candidates for further study by comparing them to marketed drugs using FTIR spectroscopy and the COMPARE analysis from the NCI. Both methods can produce fingerprints and highlight differences between the compounds, classifying the candidates and revealing promising derivatives.

The in vitro growth inhibitory effects of 27 bufadienolides and eight degradation products, with two cardenolides (ouabain and digoxin) chosen as reference compounds, were analyzed by means of an MTT colorimetric assay in six human and two mouse cancer cell lines. A structure−activity analysis was then performed to highlight the most important substituents relating to the in vitro growth inhibitory activity of bufadienolides in cancer cells. Thus, the current study revealed that various bufadienolides, including gamabufotalin rhamnoside (1a), bufotalin (2a), and hellebrin (3a), displayed higher growth inhibitory activities for various human cancer cell lines when compared to ouabain and digoxin. Gamabufotalin rhamnoside (1a) was the only compound that displayed growth inhibitory effects of

Monomethoxypoly(ethylene glycol)-N-succinimide carbonate (SC-PEG) was used to prepare PEG-lysozyme, PEG-papaya proteinase III, PEG-catalase, and PEG-lactoperoxidase conjugates. SC-PEG produced extensively modified enzymes under mild conditions (pH 7.0; 25°C) within a couple of hours. PEG-enzyme conjugates showed equal or even greater specific activity provided that low-molecularweight substrates were used to evaluate the biological activities. However, papaya proteinase III and lysozyme lost their proteolytic and bacteriolytic activities, respectively, on conjugation with PEG. This was most probably because of steric factors, since no drastic conformational changes could be detected after conjugation of these enzymes with PEG chains. Unlike these enzymes, the secondary structures of the two hemoproteins were somewhat affected by the covalent attachment of PEG chains as shown by FTIR experiments. These results confirmed the potential usefulness of SC-PEG, for which a novel route of synthesis making use ofN,N′-disuccinimidyl carbonate was described.

18-β-Glycyrrhetinic acid (GA; 1) and many of its derivatives are cytotoxic in cancer cells. The current study aims to characterize the anticancer effects of 17 novel 1 derivatives. On the basis of these studies, N-(2-{3-[3,5-bis(trifluoromethyl)phenyl]ureido}ethyl)-glycyrrhetinamide (6b) appeared to be the most potent compound, with IC(50)in vitro growth inhibitory concentrations in single-digit micromolarity in a panel of 8 cancer cell lines. Compound 6b is cytostatic and displays similar efficiency in apoptosis-sensitive versus apoptosis-resistant cancer cell lines through, at least partly, the inhibition of the activity of a cluster of a dozen kinases that are implicated in cancer cell proliferation and in the control of the actin cytoskeleton organization. Compound 6b also inhibits the activity of the 3 proteolytic units of the proteasome. Compound 6b thus represents an interesting hit from which future compounds could be derived to improve chemotherapeutic regimens that aim to combat cancers associated with poor prognoses.

The importance of reactive drug metabolites in the pathogenesis of drug-induced toxicity has been investigated since the early 1950s, mainly to reveal the link between toxic metabolites and chemical carcinogenesis. This review mainly focuses on biologically active compounds, which generate reactive quinone methide (QM) intermediates either directly or after bioactivation. Several examples of anticancer drugs acting through the generation of QM electrophiles are given. The use of those drugs for chemotherapeutic purposes is also discussed. The key feature of those QM-generating drugs is their reactivity toward specific nucleophilic biological targets. Modulation of their reactivity represents a challenge for medicinal chemists because, depending on the reactivity of these QM intermediates, their interaction with critical proteins can alter the function of these key proteins and induce a wide variety of responses with functional consequences. Among the possible consequences, antiproliferative effects could be exploited for chemotherapeutic purposes. Information on how such QM-generating drugs can affect individual target proteins and their functional consequences are required to help the medicinal chemist in the design of more specific QM-generating molecules for chemotherapeutic use., Journal Article, SCOPUS: re.j, info:eu-repo/semantics/published

Carbonylimidazol-l-yl-mPEG is obtained quantitatively by reacting methoxypoly(ethyleneglycol) (mPEG) with 1.1 Eq of N,N′-carbonyldiimidazole in the presence of a stoechiometric amount of 4-dimethyl-aminopyridine used as hypernucleophilic acylation catalyst. Carbonylimidazol-l-yl-mPEG is quite stable in aqueous solutions with half-lives up to 70 h in pHs ranging from 6.0 to 7.0 at 25‡C. From reactivity studies toward amines with various nucleophilic strengths, it is suggested that carbonylimidazol-l-yl-mPEG may be best used to modify α-amino terminal function of proteins selectively or to introduce amino function on PEG chains.

Oxidized low-density lipoproteins (LDLs) accumulate in the vascular wall and promote local inflammation, which contributes to the progression of the atheromatous plaque. The key role of myeloperoxidase (MPO) in this process is related to its ability to modify APO B-100 in the intima and at the surface of endothelial cells. A series of 3-(aminoalkyl)-5-fluoroindole analogues was designed and synthesized by exploiting the structure-based docking of 5-fluorotryptamine, a known MPO inhibitor. In vitro assays were used to study the effects of these compounds on the inhibition of MPO-mediated taurine chlorination and oxidation of LDLs. The kinetics of the interaction between the MPO redox intermediates, Compounds I and II, and these inhibitors was also investigated. The most potent molecules possessed a 4- or 5-carbon aminoalkyl side chain and no substituent on the amino group. The mode of binding of these analogues and the mechanism of inhibition is discussed with respect to the structure of MPO and its halogenation and peroxidase cycles., Journal Article, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published

Platinum complexes remain widely used to combat various types of cancers. Three platinum complexes, cisplatin, carboplatin and oxaliplatin, are marketed for various oncological purposes. Additionally, nedaplatin, lobaplatin and heptaplatin have gained regionally limited approval for oncology purposes. Furthermore, various platinum derivatives are currently under clinical trials. More than 40 years after their discovery, however, the precise mechanism of action of platinum antitumor complexes remains elusive, partly because these compounds display numerous intracellular targets. Structure-activity-relationship analyses are therefore difficult to conduct to optimize the synthesis of novel platinum derivatives. The aim of the present study is to illustrate the potential of using Fourier Transform Infrared (FTIR) analyses to monitor the cellular modifications induced by the new platinum derivatives that we have synthesized. We show in the present study the advantages of combining an in vitro assay to determine the IC50 growth inhibition concentrations of a series of compounds belonging to a given chemical series and FTIR analyses carried out at the IC50 concentrations for each compound to identify potential hits within this series of compounds. The original pharmacological approach proposed here could, therefore, avoid large-scale pharmacological experiments to find hits within a given chemical series.

In order to regulate simultaneously the biosynthesis and the transport of natural polyamines, the synthesis of a series of N-methylated analogues of N,N1-Bis(benzyl)-alkanediamines (propanediamine and butanediamine) was achieved and the cytotoxicity of these compounds on the P388D1 cell line was determined. Experiments were conducted in a growth culture medium 20 microM of 2-mercaptoethanol or 0.1 mM of aminoguanidine. Their cytotoxic effects were compared to those obtained under the same conditions with natural polyamines known as toxic compounds at high concentrations. The IC50 of each compound was found very similar for all experimental conditions (IC50 approximately 150 microM) at the opposite of spermidine and spermine which were less toxic (IC50 > 500 microM) when cells were grown in the presence of aminoguanidine (a specific inhibitor of fetal calf serum's PAO). The DL-difluoromethylornithine (DFMO) and MDL 72527DA, two well known inhibitors of ornithine decarboxylase (ODC) and Polyamine Oxidase (PAO) respectively, had no toxicity on the P388D1 cells compared to our compounds. Our most toxic compound was N1,N4-Bis(benzyl)-N1,N4-bis(methyl)-1,4-butanediamine (6) with an IC50 of 127 +/- 3 microM (in culture medium alone). The synthesis of the beta-aminothioether derivative of N-benzylputrescine (11) and the beta-aminothiol derivative of N-benzylspermidine (13) were also related. The Compound 11 was tested against the P388D1 cells, and did not show any cytotoxic effect. The N-methyl derivatives should give the advantage to be used at low concentrations than those used to test the DFMO.

Amorphous solid dispersions of dipyridamole were prepared by the solvent method using Eudragit S and RL as carriers in order to obtain controlled release dosage forms. When Eudragit S was used the release of dipyridamole from the solid dispersion particles was inhibited at low pH, but remarkably improved at neutral or alkaline pH values which correspond to the pH of polymer dissolution. In contrast, the dissolution of the active drug in acidic media was neither slowed down nor delayed when Eudragit RL was used as the carrying polymer. The striking difference between the drug release profiles of the two coprecipitates seemed to be caused by some interaction between Eudragit S and dipyridamole. The mechanism of this interaction was further investigated using various spectroscopic methods (UV, infrared, 1H- and 13C-NMR). The existence of preferential hydrogen bonding between the carboxylic functions of the polymer and some of the nitrogen atoms of dipyridamole was clearly demonstrated.

A series of 33 novel divanillates and trivanillates were synthesized and found to possess promising cyto-static rather than cytotoxic properties. Several compounds under study decreased by >50% the activity of Aurora A, B, and C, and WEE1 kinase activity at concentrations