Carboxylic Analogues Research Articles

6-Phosphoryl Picolinic Acids as Europium and Terbium Sensitizers

Three 6-phosphoryl picolinic acid (6PPA) derivatives were synthesized and used as europium and terbium sensitizers. Two of the three ligands (6-diethoxyphosphoryl picolinic acid (Hdeppa) and 6-monoethoxyphosphoryl picolinic acid (H(2)meppa)) are water-soluble, once complexed to lanthanide ions, while the third (6-dihydroxyphosphoryl picolinic acid (H(3)dhppa)) forms a precipitate. The stability constants of the phosphoryl-based complexes were found to be higher than the carboxylate analogue (dipicolinic acid, H(2)dpa). The main species are the [LnL(3)] complexes under strict stoichiometric conditions, confirmed by (31)P NMR spectroscopy, mass spectrometry and lifetime analyses. The photophysical measurements reveal that the emission intensity of [Eu(deppa)(3)] is maximal at pH 4.8, whereas for [Eu(meppa)(3)](3-), the optimum pH is observed at 9.0. The lifetimes are all in the millisecond range and have confirmed the absence of water molecules in the first coordination sphere. The emissions of the terbium are always brighter than the corresponding europium within this phosphoryl series. The quantum yields of the phosphoryl containing complexes are lower than the carboxylate analogue ([Ln(dpa)(3)](3-)), except for [Tb(deppa)(3)], which exhibits an interesting quantum yield of 40% in aqueous solution.

ChemInform Abstract: Diastereoselective Michael Addition of Magnesium Amide to O‐(2‐Alkenoyl)TEMPOs and Comparison of Reactivity with Acyl Substituent‐Modified Carboxylic Analogues.

AbstractHighly diastereoselective addition of Mg amides, derived from optically active secondary amines [cf.

A Self-Assembled Two-Dimensional Zwitterionic Structure: H6TSPP Studied on Graphite

Well-defined monolayer islands of protonated meso-tetrakis(4-sulfonatophenyl)porphine (H2[H4TSPP]) self-assembled on highly oriented pyrolytic graphite (HOPG) from 0.75 M HCl solutions are studied in ultrahigh vacuum using scanning tunneling microscopy (STM), orbital-mediated tunneling spectroscopy (OMTS), ultraviolet photoelectron spectroscopy (UPS), and X-ray photoelectron spectroscopy (XPS). HOPG proved to be a superior substrate because it does not form a thin surface chloride in the presence of HCl, as does Au(111). Unlike meso-tetrakis(4-carboxyphenyl)porphine (Hx[HyTCPP]), the carboxylate analog, monolayers are stable on HOPG and can be studied at room temperature without the addition of a second stabilizing compound. Thus, the surface organizational energy for H2[H4TSPP] is significantly stronger than that of Hx[HyTCPP]. This increased interaction is also apparent in the fact that the H2[H4TSPP] monolayer has a much smaller unit cell. It is suggested that sulfonate groups may be more useful than carboxylates for creating self-assembled structures on HOPG. Protonation of the porphyrin nitrogens in the surface species is confirmed by XPS. High-resolution images of single molecule layers show a well-defined deformation of the porphyrin ring, as expected with complete protonation of the central nitrogen atoms. OMTS and UPS were used to identify the HOMO and LUMO of the H2[H4TSPP] monolayer species, and results are contrasted to those of nickel(II) tetraphenylporphyrin (NiTPP). H2[H4TSPP] previously has been shown to form well-defined nanorods on HOPG. I−V curves of single and stacked rods taken by STM are consistent with conduction in a band formed from the LUMO of H2[H4TSPP].

Free Rhodium (II) citrate and rhodium (II) citrate magnetic carriers as potential strategies for breast cancer therapy

BackgroundRhodium (II) citrate (Rh2(H2cit)4) has significant antitumor, cytotoxic, and cytostatic activity on Ehrlich ascite tumor. Although toxic to normal cells, its lower toxicity when compared to carboxylate analogues of rhodium (II) indicates Rh2(H2cit)4 as a promising agent for chemotherapy. Nevertheless, few studies have been performed to explore this potential. Superparamagnetic particles of iron oxide (SPIOs) represent an attractive platform as carriers in drug delivery systems (DDS) because they can present greater specificity to tumor cells than normal cells. Thus, the association between Rh2(H2cit)4 and SPIOs can represent a strategy to enhance the former's therapeutic action. In this work, we report the cytotoxicity of free rhodium (II) citrate (Rh2(H2cit)4) and rhodium (II) citrate-loaded maghemite nanoparticles or magnetoliposomes, used as drug delivery systems, on both normal and carcinoma breast cell cultures.ResultsTreatment with free Rh2(H2cit)4 induced cytotoxicity that was dependent on dose, time, and cell line. The IC50 values showed that this effect was more intense on breast normal cells (MCF-10A) than on breast carcinoma cells (MCF-7 and 4T1). However, the treatment with 50 μM Rh2(H2cit)4-loaded maghemite nanoparticles (Magh-Rh2(H2cit)4) and Rh2(H2cit)4-loaded magnetoliposomes (Lip-Magh-Rh2(H2cit)4) induced a higher cytotoxicity on MCF-7 and 4T1 than on MCF-10A (p < 0.05). These treatments enhanced cytotoxicity up to 4.6 times. These cytotoxic effects, induced by free Rh2(H2cit)4, were evidenced by morphological alterations such as nuclear fragmentation, membrane blebbing and phosphatidylserine exposure, reduction of actin filaments, mitochondrial condensation and an increase in number of vacuoles, suggesting that Rh2(H2cit)4 induces cell death by apoptosis.ConclusionsThe treatment with rhodium (II) citrate-loaded maghemite nanoparticles and magnetoliposomes induced more specific cytotoxicity on breast carcinoma cells than on breast normal cells, which is the opposite of the results observed with free Rh2(H2cit)4 treatment. Thus, magnetic nanoparticles represent an attractive platform as carriers in Rh2(H2cit)4 delivery systems, since they can act preferentially in tumor cells. Therefore, these nanopaticulate systems may be explored as a potential tool for chemotherapy drug development.

Diastereoselective Michael Addition of Magnesium Amide to O-(2-Alkenoyl)TEMPOs and Comparison of Reactivity with Acyl Substituent-Modified Carboxylic Analogues

Abstract O-(2-Alkenoyl)TEMPOs bearing an O–N bond in the acyl substituent are highly reactive in Michael addition of magnesium amide compared with their acyl substituent-modified analogs. Highly diastereoselective addition is achieved to the AlMe3-treated O-(2-alkenoyl)TEMPO as an acceptor with the Mg amide generated from optically active secondary amine.

ChemInform Abstract: Synthesis of C(6)-Carboxylate Analogues of N-Acetylmuramic Acid.

Synthese de 2-acetamido-4-O-acetyl-3-O-[1-carbamoylethyl]-2-deoxy glucopyranuronate de benzyle et de 2-acetamido-4-O-acetyl-2-desoxy-3-O-[1-(methoxycarbonyl)ethyl] glucopyranuronate de benzyle a partir de 2-acetamido-1-O-benzyl-2-desoxy-4,6-O-isopropylidene-glucopyranoside

Evaluation of the fate of perfluoroalkyl compounds in wastewater treatment plants

Recent studies have shown that the wastewater treatment plant (WWTP) is a significant source of perfluoroalkyl compounds (PFCs) in natural water. In this study, 10 PFCs were analyzed in influent and effluent wastewater and sludge samples in 15 municipal, 4 livestock and 3 industrial WWTPs in Korea. The observed distribution pattern of PFCs differed between the wastewater and sludge samples. Perfluorooctane sulfonate (PFOS) was dominant in the sludge samples with a concentration ranging from 3.3 to 54.1 ng/g, whereas perfluorooctanoic acid (PFOA) was dominant in wastewater and ranged from 2.3 to 615 ng/L and 3.4 to 591 ng/L in influent and effluent wastewater, respectively. Principal component analysis (PCA) results provided an explanation for this variation in PFC distribution patterns in the aqueous and sludge samples. The fates of PFCs in the WWTPs were related with the functional groups. The PFOS concentrations tended to decrease after treatment in most WWTPs, whereas PFOA increased. The different fates of PFOA and PFOS in WWTPs were attributed to the higher organic carbon-normalized distribution coefficient of perfluoroalkylsulfonate (PFASs) than that of the carboxylate analog, indicating the preference of PFASs to partition to sludge. Although industrial WWTPs contained high concentration of PFCs, they are not the main source of PFCs in Korean water environment because of their small release amount. WWTPs located in big cities discharged more PFCs, suggesting household sewage is one of the significant sources of PFCs contamination in the environment.

Structure-based design of novel human Pin1 inhibitors (II)

Following the discovery of a novel series of phosphate-containing small molecular Pin1 inhibitors, the drug design strategy shifted to replacement of the phosphate group with an isostere with potential better pharmaceutical properties. The initial loss in potency of carboxylate analogs was likely due to weaker charge–charge interactions in the putative phosphate binding pocket and was subsequently recovered by structure-based optimization of ligand–protein interactions in the proline binding site, leading to the discovery of a sub-micromolar non-phosphate small molecular Pin1 inhibitor.

Remarkable Tuning of the Coordination and Photophysical Properties of Lanthanide Ions in a Series of Tetrazole‐Based Complexes

A series of seven new tetrazole-based ligands (L1, L3-L8) containing terpyridine or bipyridine chromophores suited to the formation of luminescent complexes of lanthanides have been synthesized. All ligands were prepared from the respective carbonitriles by thermal cycloaddition of sodium azide. The crystal structures of the homoleptic terpyridine-tetrazolate complexes [Ln(Li)(2)]NHEt(3) (Ln = Nd, Eu, Tb for i = 1, 2; Ln = Eu for i = 3, 4) and of the monoaquo bypyridine-tetrazolate complex [Eu(H(2)O)(L7)(2)]NHEt(3) were determined. The tetradentate bipyridine-tetrazolate ligand forms nonhelical complexes that can contain a water molecule coordinated to the metal. Conversely, the pentadentate terpyridine-tetrazolate ligands wrap around the metal, thereby preventing solvent coordination and forming chiral double-helical complexes similarly to the analogue terpyridine-carboxylate. Proton NMR spectroscopy studies show that the solid-state structures of these complexes are retained in solution and indicate the kinetic stability of the hydrophobic complexes of terpyridine-tetrazolates. UV spectroscopy results suggest that terpyridine-tetrazolate complexes have a similar stability to their carboxylate analogues, which is sufficient for their isolation in aerobic conditions. The replacement of the carboxylate group with tetrazolate extends the absorption window of the corresponding terpyridine- (approximately 20 nm) and bipyridine-based (25 nm) complexes towards the visible region (up to 440 nm). Moreover, the substitution of the terpyridine-tetrazolate system with different groups in the ligand series L3-L6 has a very important effect on both absorption spectra and luminescence efficiency of their lanthanide complexes. The tetrazole-based ligands L1 and L3-L8 sensitize efficiently the luminescent emission of lanthanide ions in the visible and near-IR regions with quantum yields ranging from 5 to 53% for Eu(III) complexes, 6 to 35% for Tb(III) complexes, and 0.1 to 0.3% for Nd(III) complexes, which is among the highest reported for a neodymium complex. The luminescence efficiency could be related to the energy of the ligand triplet states, which are strongly correlated to the ligand structures.

Synthesis and X-ray structure of platinum(II), palladium(II) and copper(II) complexes with pyridine–pyrazole ligands: Influence of ligands’ structure on cytotoxic activity

The new pyrazole ligand 5-(2-hydroxyphenyl)-3-methyl-1-(2-pyridylo)-1 H-pyrazole-4-phosphonic acid dimethyl ester ( 2a) has been used to obtain a series of platinum(II), palladium(II) and copper(II) complexes ( 3a– 7a) as potential anticancer compounds. The molecular structures of the platinum(II) and copper(II) complexes 3a and 6a have been determined by X-ray crystallography. The cytotoxicity of the phosphonic ligand 2a and its carboxylic analog 2b as well as their complexes has been evaluated on leukemia and melanoma cell lines. Copper(II) complexes were found to be more efficient in the induction of melanoma cell death than the platinum(II) or palladium(II) complexes. Cytotoxic effectiveness of compound 7b against melanoma WM-115 cells was two times better than that of cisplatin. The reaction of compound 5b with 9-methylguanine has been studied.

Studies of Mesomorphic Properties of a Series of Bimetallic Os (III,III) Benzoates and Their Polymeric Axial Pyrazine Adducts

Synthesis, characterization and mesomorphic properties of tetra(alkoxy benzoate)diosminum(III) of the formula Os2(k,l,m-BgOCn)4 (where B is the benzoate group; g is the number of alkoxy chains on the aromatic ring; k, l and m are their positions of attachments; and n is the number of carbon atoms in each alkoxy chain) and their corresponding pyrazine adducts have been carried out. The complexes synthesized are Os2 (3,4,5-B3OCn)4 for n = 2, 10, 16 and 20; Os2(3,4-B2OCn)4 for n = 2, 9, and 14; Os2(3,5-B2OCn)4 for n = 2, 10, 16 and 20; as well as the corresponding adducts[Os2(3,4,5-B3OCn)4px]x for n = 2, 10, 16 and 20; Os2(3,4-B2OCn)4 for n = 2, 9 and 14; Os2(3,5-B2OCn)4 for n = 14, 16 and 19. Full characterization of the compounds were carried out using elemental analyses, 1H NMR and IR. A single crystal X-ray diffraction studies confirmed that the pyrazine adducts prepared via connected metallic centers have a polymeric structure. Diffrential scanning calorimetry (DSC), optical microscopy and XRD studies revealed the liquid-crystalline (LC) properties of most of them as cubic mesophases with melting transition temperatures close or below room temperatures. The mesomorphic character of the pyrazine compounds, compared to the non-mesomorphic aliphatic carboxylate analogues, can be interpreted in terms of the ability of the equatorial ligands to fill the interdimeric space efficiently.

Synthesis and Characterization of Linear Trinuclear Pd, Co, and Pd/Co Pyrazolate Complexes

AbstractA family of dinuclear and linear trinuclear Co/Pd pyrazolate compounds, namely, [Bu4N]2[Co2(μ‐4‐Cl‐3,5‐Me2‐pz)2Cl4] (1), [Bu4N]2[Co2(μ‐4‐Br‐3,5‐Me2‐pz)2Br4] (2), [Bu4N]2[Co2(4‐I‐3,5‐Me2‐pz)2Cl4] (3), [Et4N]2[Pd2Co(4‐Br‐3,5‐Me2‐pz)4Cl4] (4), [Et3NH]4[PdCo2(4‐Br‐3,5‐Me2‐pz)4Cl4][NO3]2 (5), [Et3NH]2[Pd Co2(3‐Me‐5‐Ph‐pz)4Cl4] (6), [Et3NH]2[Pd3(4‐Br‐3,5‐Me2‐pz)4Cl4] (7), and [Co3(3,5‐Me2‐pz)4(3,5‐Me2‐pzH)2(CH3CO2)2] (8) was synthesized. The single‐phase nature of the solids was established by single‐crystal X‐ray diffraction, thermal analysis, and spectroscopic techniques. Moreover, the magnetic behavior is studied and a magnetostructural comparison to the corresponding carboxylate analogues is made. (© Wiley‐VCH Verlag GmbH &amp; Co. KGaA, 69451 Weinheim, Germany, 2008)

Betaine structure and the presence of hydroxyl groups alters the effects on DNA melting temperatures

Betaine lowers the melting temperature of deoxyribonucleic acid (DNA) and decreases its dependence on base composition. The effects of synthetic betaine analogs on the melting of DNA samples with different GC content were measured. Since many polyhydroxy compounds also lower DNA melting temperatures, hydroxyl-substituted betaine analogs were included. Some synthetic sulfonate analogs of betaine lowered the DNA melting temperatures by twice as much at the same molar concentration. They were up to twice as effective at decreasing the base pair dependence. Some carboxylate homologs of betaine, substituted with hydroxyl groups, increased the melting temperature. This effect was greater with low GC content DNA. Sulfonate analogs of betaine with hydroxyl groups usually destabilize the DNA, while their carboxylate analogs stabilize the DNA. Distances between the charges of these synthetic zwitterionic solutes influence the effect on DNA, with the optimum separation being two or three methylene groups. A betaine with two hydroxyl groups on one N-alkyl group had a greater effect than an isomer with two hydroxyl groups on separate N-alkyl substituents. We suggest that the effect of these solutes depends on structuring the hydration water of DNA, as well as interactions with the DNA structure itself.

Identification of ACE pharmacophore in the phosphonopeptide metabolite K-26

The naturally occurring phosphonotripeptide K-26 is a potent angiotensin converting enzyme (ACE) inhibitor containing an α-amino phosphonic acid analogue of tyrosine. Previous studies have demonstrated that canonical peptide analogues of K-26 are micromolar inhibitors of ACE. To ascertain the structure–activity relationships in this class of ACE inhibitory natural products, K-26 and eight analogues were chemically synthesized and evaluated. Phosphonyl substitution was found to be the critical determinant of activity, resulting in a 1500-fold increase in ACE inhibition versus carboxyl analogues. Secondarily, the absolute configuration of the terminal α-amino phosphonate and N-acetylation were found to significantly modulate ACE inhibitory activity.

Synthesis and Thermal Isomerization of Carboxylic and Phosphonic α-Aminoesters Substituted With a Triazole Ring

Thermal isomerization of phosphonic α-aminoesters bearing a 4,5-carboxymethyltriazole ring in α position is described. The results are analyzed by 31P, 1H, and 13C NMR spectroscopy and X-ray crystallography. The same phenomenon is also observed in the case of carboxylic amino acids analogs. It does not occur with triazoles bearing a substituent other than carboxymethyl.

Sorption of Perfluorinated Surfactants on Sediments

The sorption of anionic perfluorochemical (PFC) surfactants of varying chain lengths to sediments was investigated using natural sediments of varying iron oxide and organic carbon content. Three classes of PFC surfactants were evaluated for sorptive potential: perfluorocarboxylates, perfluorosulfonates, and perfluorooctyl sulfonamide acetic acids. PFC surfactant sorption was influenced by both sediment-specific and solution-specific parameters. Sediment organic carbon, rather than sediment iron oxide content, was the dominant sediment-parameter affecting sorption, indicating the importance of hydrophobic interactions. However, sorption also increased with increasing solution [Ca2+] and decreasing pH, suggesting that electrostatic interactions play a role. Perfluorocarbon chain length was the dominant structural feature influencing sorption, with each CF2 moiety contributing 0.50-0.60 log units to the measured distribution coefficients. The sulfonate moiety contributed an additional 0.23 log units to the measured distribution coefficient, when compared to carboxylate analogs. In addition, the perfluorooctyl sulfonamide acetic acids demonstrated substantially stronger sorption than perfluorooctane sulfonate (PFOS). These data should prove useful for modeling the environmental fate of this class of contaminants.

Synthesis and receptor binding affinity of carboxylate analogues of the mannose 6-phosphate recognition marker

The mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) is involved in multiple physiological pathways including targeting of lysosomal enzymes, degradation of IGF2, and cicatrization through TGFβ activation. To target potential therapeutics to this membrane receptor, four carboxylate analogues of mannose 6-phosphate (M6P) were synthesized. Three of them, two isosteric carboxylate analogues and a malonate derivative, showed a binding affinity for the M6P/IGF2R equivalent to or higher than that of M6P. Contrary to M6P, all these analogues were particularly stable in human serum. Moreover, these derivatives did not present any cytotoxic activity against two human cell lines. These analogues represent a new potential for the lysosomal targeting of enzyme replacement therapy in lysosomal diseases or to prevent the membrane-associated activities of the M6P/IGF2R.

From structural properties of the EuIII complex with ethylenediaminetetra(methylenephosphonic acid) (H8EDTMP) towards biomedical applications

Crystals of Eu(III) with ethylenediaminetetra(methylenephosphonic acid) (H(8)EDTMP) and with ethylenediaminetetraacetic acid (H(4)EDTA) have been synthesized in the same experimental conditions and their X-ray analyses have been performed. The EDTMP ligand wraps the Eu(III) ion in a fashion similar to its carboxylic analogue, EDTA, i.e. coordinating through two nitrogen atoms and four oxygen atoms in such a way that only one oxygen atom from each phosphonate group is bonded to the central ion. The coordination sphere is completed by two oxygen atoms of the bidentate carbonate anion in the case of the Eu(III)-EDTMP complex, whereas the inner sphere of the Eu(III)-EDTA crystal is completed by three water molecules. Spectroscopic studies (UV-Vis and (31)P NMR spectra) of Eu(III)-EDTMP solutions at controlled pH showed that the replacement of inner sphere water molecules and/or OH hydroxy groups by a carbonate anion in the Eu(III)-EDTMP complex at physiological pH results in the formation of [Eu(EDTMP)(CO(3))](7-) species which is thermodynamically stable and kinetically inert. The affinity of the carbonate anion towards the Eu(III)-EDTMP species was studied by analysis of f-f intensities and luminescence decay rates. The dissociation constant of the Eu(III)-EDTMP-carbonate complex was found to be approximately 43 mM. The presented results may be helpful in understanding the role played by the (153)Sm(III)-EDTMP complex known as Quadramet in the seeking of metastatic tissue in bones as well as possibly giving some premises for future ligand design of these types of complexes with lanthanide radionuclides.

Copper(II) Complexes of Schiff‐Base and Reduced Schiff‐Base Ligands: Influence of Weakly Coordinating Sulfonate Groups on the Structure and Oxidation of 3,5‐DTBC

AbstractThe copper(II) complexes of the Schiff‐base ligands H2Sams and H2Saes and the reduced Schiff‐base ligands H2Sam and H2Sae formed between salicylaldehyde and aminomethanesulfonic acid or 2‐aminoethanesulfonic acid (taurine) have been synthesized in moderate yields. The solid‐statestructures of the five dinuclear complexes, [Cu2(Sams)2(H2O)2](1), [Cu2(Sam)2(H2O)2]·H2O (2), [Cu2(Saes)2(H2O)2]·2H2O (3), [Cu2(Sae)2]·2H2O (4), and [Cu2(Sae)2(DMF)2]·2DMF (5), have been determined by X‐ray crystallography, showing that the CuII centers have distorted square‐pyramidal geometry. The Schiff‐base copper complexes 1 and 3 have hydrogen‐bonded 2D sheet structures while the reduced Schiff‐base complexes 4 and 5 display a 2D coordination network and a hydrogen‐bonded 2D structure respectively. All these complexes have been investigated for their catecholase activity and activity measurements have been compared with those of dinuclear copper(II) complexes of similar ligands obtained with carboxylate analogues of the corresponding sulfonicacids; these studies show that 4 has significantly higher activity. Further, a strong antiferromagnetic interaction between CuII ions in dimeric complexes 1 [J = –9.04(2) cm–1], 3 [J = –272(4) cm–1), and 4 [J = –237(4) cm–1] has been observed. (© Wiley‐VCH Verlag GmbH &amp; Co. KGaA, 69451 Weinheim, Germany, 2005)

Synthesis and biological activity of M6-P and M6-P analogs on fibroblast and keratinocyte proliferation

A new synthetic route to obtain the carboxylate analog of mannose 6-phosphate (M6-P) is presented. The effects of the M6-P, the carboxylate and two other analogs (the phosphonate and the α,β ethylenic carboxylate) on the proliferation of human keratinocytes and dermal fibroblasts as well as on the proliferation of a murine fibroblast cell line, 3T3-J2 are tested. We observed that M6-P is a potent inhibitor of proliferation of both fibroblasts and keratinocytes. Among its analogs, the phosphonate showed a similar effect on human dermal fibroblasts but not on keratinocytes.