PHOTOSENSITIZATION BY ANTIMALARIAL DRUGS

Abstract The antimalarial drugs, chloroquine, hydroxychloroquine, quinine, quinacrine, amodiaquine and primaquine and the local anaesthetic, dibucaine, were tested for in vitro photosensitizing capability by irradiation with 365 nm UV light in aqueous solutions. The ability of these compounds to photosensitize the oxidation of 2,5-dimethylfuran, histidine, tryptophan or xanthine, and to initiate the free radical polymerization of acrylamide was examined in the pH range 2-12. Chloroquine and hydroxychloroquine show maximal photooxidative behaviour when in the monocation form at pH 9, in contrast to quinine which is extremely efficient as the dication below pH 4. This pattern appears to relate to the fluorescence yield as a function of pH. Chloroquine in the monocation or neutral form was found to undergo dechlorination upon irradiation, and this correlates directly with its ability to initiate photo-polymerization of acrylamide. Quinine also gives rise to small polymerization rates, attributed to photo-ionization in the quinoline ring, yielding a cation radical. Amodiaquine, primaquine and quinacrine do not have significant photochemical activity in aqueous solution. Dibucaine exhibits a strong photosensitizing capability at low pH, similar to quinine.     

In situ ATR-IR investigation of L-lysine adsorption on montmorillonite

The adsorption behavior of lysine on montmorillonite in aqueous solution was investigated by in situ attenuated total reflectance infrared (ATR-IR) spectroscopy. To distinguish the protonation states of α-amino group, side-chain amino group and carboxyl group in lysine structure using ATR-IR spectra (i.e., NH₂ versus and COO⁻ versus COOH), pH-induced spectral changes of dissolved lysine were firstly measured and correlated with the thermodynamically calculated dissociation states of lysine (di-cationic, cationic, zwitterionic and anionic states). The obtained result was applied to interpret the ATR-IR spectra of lysine adsorbed on montmorillonite. We found that the adsorbed lysine was dominantly present as cationic state over the whole range of tested pH (pH = 4.9–9.7). This indicates that the adsorption is mainly driven by electrostatic interaction between the negatively charged montmorillonite surface and positively charged cationic lysine. We also found that lysine interacts with montmorillonite surface through the protonated side-chain amino group. This result suggests that lysine has a preferred vertical orientation, with the side-chain amino group pointing toward the surface.     

Cd spectra of DNP derivatives of aromatic α-amino acids and related compounds: DNP-aromatic rule as a method for determining absolute configuration of chiral amines of RCH(NH2)XAr type

Introduction of an aromatic group to the side-chain functional group or to the α-car?yl group of aliphatic DNP-α-amino acids gives compounds which can be regarded as analogs of aromatic DNP-α-amino acids. DNP-aromatic rule¹ has been proved applicable to these compounds and also to the derivatives of DNP-phenylalanine homologs in which the car?yl group is modified variously. By summarizing the compiled data extension of the DNP-aromatic rule to the DNP-derivatives of chiral amines with a general formula R-CH(NH₂)-XAr is proposed.     

17O-NMR. of Enriched Acetic Acid,Glycine, Glutamic Acid and Aspartic Acid in Aqueous Solution. I. Chemical Shift Studies

The ¹⁷O-NMR. chemical shifts of the enriched amino acids glycine, aspartic acid and glutamic acid were measured in aqueous solution as a function of pH. High magnetic fields are necessary to resolve the α, β- and α, γ-carboxyl resonances of aspartic acid and glutamic acid, respectively. The chemical shifts of acetic acid were measured for comparative reasons. Ionization constants and titration shifts were obtained by nonlinear least-squares fits to one-proton titration curves. The average excitation energy approximation is discussed in terms of the observed changes in ¹⁷O-shielding on deprotonation. No intramolecular association between the α-amino group and the α-carboxyl group in the zwitterionic form is required to explain the high-frequency shift of the carboxylate ion. Also no indication of an intramolecular association between the α-amino group and the side-chain carboxyl groups of aspartic acid or glutamic acid was found.     

Reaction of a cyclic triphosphenium ion with triflic acid and SnX2 (X = Br or Cl): A 31P NMR study

The di‐ium dication formed by triflic acid protonation of the cyclic triphosphenium ion derived from 1,4‐bis‐diphenylphosphinobutane, (dppb), and P₃(X = Br or Cl) decomposes via an acyclic dication bearing a  PHX group; this intermediate is reduced by SnX₂ in the presence of HX to yield a dication with a  PH₂ primary phosphane terminal group, which is comparatively stable. The structure of this species has been unequivocally confirmed by ³¹P solution‐state NMR spectroscopy. © 2007 Wiley Periodicals, Inc. Heteroatom Chem 18:609–612, 2007; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20302     

Reactions of Doubly Ionized Benzene with Nitrogen and Water: A Nitrogen‐Mediated Entry into Superacid Chemistry

Even in the highly diluted gas phase, rather than electron transfer the benzene dication C₆H₆²⁺ undergoes association with dinitrogen to form a transient C₆H₆N₂²⁺ dication which is best described as a ring‐protonated phenyl diazonium ion. Isotopic labeling studies, photoionization experiments using synchrotron radiation, and quantum chemical computations fully support the formation of protonated diazonium, which is in turn a prototype species of superacidic chemistry in solution. Additionally, reactions of C₆H₆²⁺ with background water involve the transient formation of diprotonated phenol and, among other things, afford a long‐lived C₆H₆OH₂²⁺ dication, which is attributed to the hydration product of Hogeveen’s elusive pyramidal structure of C₆H₆²⁺, as the global minimum of doubly ionized benzene. Nitrogen is essential for the formation of the C₆H₆OH₂²⁺ dication in that it mediates the formation of the water adduct, while the bimolecular encounter of the C₆H₆²⁺ dication with water only leads to (dissociative) electron transfer.     

Studies on some radical transfer reactions by entrapping the radicals as polymer end groups. II. Reactions of ȮH radicals with amino acids

The reaction of ?H radicals with a number of aliphatic amino acids has been studied by entrapping the resultant radicals as end groups of poly(methyl methacrylate) that have been detected and estimated by the sensitive dye partition technique. The rate constants of the reaction (in mol^?1 L S^?1) of 7 amino acids at 25°C and at pH 1.00 have been determined as 8.33 × 10⁸ for glycine, 2.56 × 10⁹ for β-alanine, 2.01 × 10⁹ for β-alanine, 3.99 × 10⁹ for 4-amino butyric acid, 7.56 × 10⁹ for (1+) valine, 1.42 × 10¹⁰ for (1?) leucine, and 5.98 × 10¹⁰ for 6-amino caproic acid. Glycine, α-alanine, β-alanine, and 4-amino butyric acid produced radicals that underwent deamination and incorporated only carboxyl-bearing end groups in the polymer. The other amino acids, leucine, valine, and 6-amino caproic acid, produced at least two types of radicals, radicals that underwent deamination and those that remained intact, and incorporated in the polymer both carboxyl- and amine-bearing end groups but in different amounts. The latter type of radicals were about 29% from 6-amino caproic acid, 23% from leucine, and 18% from valine. The change of pH from 0.80 to 2.72 did not produce any significant change in the end group profile of the polymer obtained, indicating no appreciable change in the rate of the reaction of ?H radicals with the simplest amino acid glycine in the pH range studied.     

Intracellular localization of meso-tetraphenylporphine tetrasulphonate probed by time-resolved and microscopic fluorescence spectroscopy.

The effects of solvent pH on spectral properties and fluorescence decay kinetics were investigated in order to characterize the microenvironment of meso-tetraphenylporphine tetrasulphonate (TPPS4) taken up by cells. Steady-state absorption and fluorescence spectra of TPPS4 in buffer solutions of different pH were used to identify a ring protonated species at pH less than or equal to 4. This dictation could also be distinguished from the unprotonated form by its altered fluorescence decay time (3.5 vs. 11.4 ns). In addition, time-resolved spectroscopy gave some evidence of a monocationic species existing at pH 6-9. This was concluded from the occurrence of another component with a decay time of 5 ns. Measurements of the spectral and kinetic properties of the fluorescence emission of single epithelial cells (RR1022) incubated with TPPS4 indicated that the sensitizer was mainly localized in a microenvironment with a pH of 5, a value which occurs intracellularly only within lysosomes. Cells kept in the dark exhibited the characteristic spectra of both the dication and the neutral form. The fluorescence decay showed two components with decay times of 2.6 ns and 10.6 ns. Irradiation of the cells changed the decay times to 4.6 ns and 13.4 ns and the dication fluorescence emission peak vanished, which is in accordance with the results obtained from buffer solutions at pH greater than or equal to 6. Therefore, we deduce that the photodynamic action leads to a rupture of the lysosomes and that the sensitizer is released into the surrounding cytoplasm.     

An ESR study of the copper(II)–glycyl-l-serine and copper(II)–l-seryl-glycine systems by the simultaneous analysis of multi-component isotropic spectra. Formation constants and coordination modes

The formation constants and the isotropic ESR parameters (g-factors, ⁶³Cu, ⁶⁵Cu, ¹⁴N hyperfine coupling constants and relaxation parameters) of the various species were determined by the simultaneous analysis of a series of spectra, taken in a circulating system at various pH and ligand-to-metal concentration ratio. For both systems the new [CuLH]²⁺ complex was identified in acidic solutions. With the glycyl-l-serine ligand below pH 11.5 the same complexes and coordination modes are formed than with simple dipeptides. The side-chain donor group is bound only over pH 11.5 in the complex [CuLH₋₂(OH)]²⁻, where it is deprotonated and substitutes the carboxylate O in the third equatorial site. For the bis complex [CuLH₋₁(L)]⁻ an isomeric equilibrium was shown, where the difference between the isomers was based on which of the donor atoms of the ‘L’ ligand, the peptide O or the amino N, occupies the fourth equatorial position, and which one is coordinated axially. The l-seryl-glycine ligand forms the same species as simple dipeptides and glycyl-l-serine up to pH 8. The only difference is that the axial binding of the alcoholic OH group fairly stabilizes the bidentate equatorial coordination of the ‘L’ ligand through the amino N and peptide O atoms in the [CuL]⁺ complex as well as in the major isomer of the [CuLH₋₁(L)]⁻ complex. For this system we showed that (1) proton loss and the equatorial coordination of the alcoholic OH group occurs at relatively low pH (over pH 8–9), which results in the [CuL₂H₋₂]²⁻ complex with excess ligand, and also the newly identified species [Cu₂L₂H₋₄]²⁻: (2) this process is in competition with the proton loss of a coordinated water molecule. For both systems, the ESR-inactive species [Cu₂L₂H₋₃]⁻ was also shown.     

The pummerer and the thio-claisen–type rearrangements of naphtho[1,8-bc]-1,5-dithiocin monooxide and N-p-tosylsulfilimine

Naphtho[1,8-bc]-1,5-dithiocin N-p-tosylsulfilimine ( 8 ) and monosulfoxide ( 9 ) were prepared. On treatment with conc. H₂SO₄, both the sulfilimine ( 8 ) and sulfoxide ( 9 ) gave the dithia dication which was converted to the sulfoxide by hydrolysis. The H–D exchange reaction of ( 8 ) took place highly regioselectively to afford the monodeuterated ( 8–D ) at the a-position of the N-tosyl group. The Pummerer rearrangement reaction of monooxide ( 9 ) with acetic anhydride gave the a-acetoxy derivative by the dication ( 10b ), while a new thio-Claisen rearrangement of sulfilimine ( 8 ) t-BuOK in CH₂Cl₂ gave 2-allyl-naphtho[1,8-bc]-1,5-dithiole. © John Wiley & Sons, Inc.     

Unusual hydrate stabilization in the two‐dimensional layered structure of quinacrinium bis(2‐carboxy‐4,5‐dichlorobenzoate) tetrahydrate,a proton‐transfer compound of the drug quinacrine

The crystal structure of the hydrated proton‐transfer compound of the drug quinacrine [rac‐N′‐(6‐chloro‐2‐methoxyacridin‐9‐yl)‐N,N‐diethylpentane‐1,4‐diamine] with 4,5‐dichlorophthalic acid, C₂₃H₃₂ClN₃O²⁺·2C₈H₃Cl₂O₄⁻·4H₂O, has been determined at 200 K. The four labile water molecules of solvation in the structure form discrete ...O—H...O—H... hydrogen‐bonded chains parallel to the quinacrine side chain, the two N—H groups of which act as hydrogen‐bond donors for two of the water acceptor molecules. The other water molecules, as well as the acridinium H atom, also form hydrogen bonds with the two anion species and extend the structure into two‐dimensional sheets. Between these sheets there are also weak cation–anion and anion–anion π–π aromatic ring interactions. This structure represents the third example of a simple quinacrine derivative for which structural data are available but differs from the other two in that it is unstable in the X‐ray beam due to efflorescence, probably associated with the destruction of the unusual four‐membered water chain structures.     

COMPLEXING OF RIBOFLAVIN AND ITS 2-SUBSTITUTED ANALOGS WITH ADENOSINE AND OTHER 6-SUBSTITUTED PURINE DERIVATIVES*

Abstract Fluorescence properties of riboflavin and its 2-substituted analogs and the quenching of fluorescence which occurs upon complexing with adenosine and other 6-substituted purine derivatives have been examined at different concentrations of interactants and hydrogen ion. The 6-substituted purines and their ribosides show varying degrees of association with riboflavin. Successive N-alkylation of the 6-amino group of purine ribosides leads to more stable complexing in the order ethyl > methyl > propyl with riboflavin and its analog. These results suggest that such groups, including the 6-amino group of adenine or adenine moiety of FAD, do not directly interact with flavins by hydrophobic or hydrogen bonding. Lowering the pH to above that required to protonate the isoalloxazine system disrupts the intermolecular complexes. Hence, only the unprotonated bases can form such complexes. The 2-substituted aminoriboflavins, as well as FAD, exhibit fluorescence optima upon changing pH. The species involved appear to be a non-fluorescent form with protonated isoalloxazine and amine or adenine portions at low pH, a fluorescent form with only the amine or adenine portions protonated at moderately acid pH, and a non-fluorescent form which is intramolecularly quenched at higher pH. The general electron donating properties of the amines may be the common reason for their quenching of fluorescence in inter- and intramolecular complexes with flavins.     

New chiral polyfunctional cyclobutane derivatives from (−)-verbenone: possible surfactant behaviour

New enantiopure cyclobutane derivatives have been synthesized from a chiral precursor derived from (?)-verbenone. The cyclobutane moiety acts as a chiral platform to afford a γ-amino acid function in a branched side-chain containing an additional stereogenic centre as well as additional C₆ or C₁₆-alkyl chains linked to the ring by means of an amine or an amide function. One of these compounds, obtained as a 1:2 mixture with its TFA salt has been investigated, suggesting behaviour as a good surfactant and its critical micellar concentration has been determined.     

Intercalation behavior of amino acids into Zn-Al-layered double hydroxide by calcination-rehydration reaction

The intercalation of amino acids for the Zn-Al-layered double hydroxide (LDH) has been investigated by the calcination-rehydration reaction at 298 K using mainly phenylalanine (Phe) as a guest amino acid. The Zn-Al oxide precursor prepared by the calcination of Zn-Al-carbonated LDH at 773 K for 2 h was used as the host material. The amount of Phe intercalated by the rehydration was remarkably influenced by the initial solution pH and reached ca. 2.7 times for anion exchange capacity (AEC) of the LDH at neutral and weak alkaline solutions, suggesting that Phe was intercalated as amphoteric ion form into the LDH interlayer. As Phe is intercalated for the LDH as monovalent anion in alkaline solution, the amount of Phe intercalated at pH 10.5 corresponded with AEC of the LDH. The solid products were found to have the expanded LDH structure, which confirmed that Phe was intercalated into the LDH interlayer as amphoteric ion or anion form. The basal spacing, d₀₀₃, of the Phe/LDH was 1.58 nm at pH 7.0 and 0.80 nm at pH 10.5; two kinds of expansion suggested for Phe in the interlayer space as vertical (pH 7.0) and horizontal (pH 10.5) orientations. The intercalation behavior of various amino acids for the LDH was also found to be greatly influenced by the feature of the amino acid side-chain, namely, its carbon-chain length, structure and physicochemical property. In particular, α-amino acids possessing a hydrophobic or negative-charged side-chain were preferentially intercalated for the LDH.     

Gas-phase fragmentation characteristics of benzyl-aminated lysyl-containing tryptic peptides

The fragmentation characteristics of peptides derivatized at the side-chain ε-amino group of lysyl residues via reductive amination with benzaldehyde have been examined using collision-induced dissociation (CID) tandem mass spectrometry. The resulting MS/MS spectra exhibit peaks representing product ions formed from two independent fragmentation pathways. One pathway results in backbone fragmentation and commonly observed sequence ion peaks. The other pathway corresponds to the unsymmetrical, heterolytic cleavage of the C_ζ-N_ε bond that links the benzyl derivative to the side-chain lysyl residue. This results in the elimination of the derivative as a benzylic or tropylium carbocation and a (n − l)⁺-charged peptide product (where n is the precursor ion charge state). The frequency of occurrence of the elimination pathway increases with increasing charge of the precursor ion. For the benzylmodified tryptic peptides analyzed in this study, peaks representing products from both of these pathways are observed in the MS/MS spectra of doubly-charged precursor ions, but the carbocation elimination pathway occurs almost exclusively for triply-charged precursor ions. The experimental evidence presented herein, combined with molecular orbital calculations, suggests that the elimination pathway is a charge-directed reaction contingent upon protonation of the secondary ε-amino group of the benzyl-derivatized lysyl side chain. If the secondary ε-amine is protonated, the elimination of the carbocation is observed. If the precursor is not protonated at the secondary ε-amine, backbone fragmentation persists. The application of appropriately substituted benzyl analogs may allow for selective control over the relative abundance of product ions generated from the two pathways.     

Cyclization reactions of long-lived 10,10-dimethyl-9-phenylethynyl-9,10-dihydrophenanthren-9-yl cation

According to the NMR data, long-lived 10,10-dimethyl-9-phenylethynyl-9,10-dihydrophenanthren-9-ylium in acid medium undergoes cyclization whose direction is determined by the acidity of the medium. The cyclization in HSO₃F-SbF₅ superacid involves the aromatic ring in the phenanthrene core as nucleophilic component and yields 5a,6-dimethyl-4-phenyl-4,5,5a,6-tetrahydroacephenantrylene-4,6-bis(ylium). In trifluoroacetic acid the nucleophilic component is the side-chain phenyl group, and the cyclization product is neutral 8b,14b-dimethyl-8b,14b-dihydrobenzo[g]chrysen-10-yl trifluoroacetate. Both cyclization directions are observed in moderate-strength trifluoromethanesulfonic acid.     

Basicities of some 9-substituted acridine-4-carboxamides: A density functional theory (DFT) calculation

Acid-base properties of drugs are important in understanding the behaviour of these compounds under physiological condition. In order to understand such behaviour the proton affinities of acri-dine 4-carboxamides with substitution (R) at the 9-position are theoretically studied, and considered for the basic sites of both the heterocyclic ring as well as side chain nitrogens. In 9-amino acridine 4-carbox-amide, the -NH₂ group is observed to be an additional basic site. The heterocyclic nitrogen of substituted carboxamides (R =-NH₂, -O-methyl, -O-ethyl, and -O-phenyl) is more basic than the side chain nitrogen, however, side chain nitrogen corresponds to more basic site for some carboxamides (R = -OH and-Cl) and the -NH₂ group represents the least basic site of 9-amino acridine 4-carboxamide. In addition to presenting the basicities of these drugs an indication of another hydrogen-bond between heterocyclic ring N and carboxamide chain O is observed. The difference of basicities with substituents at 9-position are very narrow and carboxamides with substituents at 9-position are found to be suitable for studying intramolecular H-bonds between the heterocyclic N and carboxamide O. The resultant stabilization of a configuration due to such H-bonding is determined     

Crystal Structure Determination of the Pentagonal‐Pyramidal Hexamethylbenzene Dication C6(CH3)62+

In contrast to the well‐known 2‐norbornyl cation, the structure of which was a matter of long debate until its pentacoordinated nature was recently proven by an X‐ray structure, the pentagonal‐pyramidal dication of hexamethylbenzene has received considerably less attention. This species was first prepared by Hogeveen in 1973 at low temperatures in magic acid (HSO₃F/SbF₅), for which he proposed a non‐classical structure (containing a hexacoordinated carbon) based on NMR spectroscopy and reactivity studies, but no X‐ray crystal structure has been reported. C₆(CH₃)₆²⁺ can be obtained through the dissolution of hexamethyl Dewar benzene epoxide in HSO₃F/SbF₅ and crystallized as the SbF₆⁻ salt upon addition of excess anhydrous hydrogen fluoride. The crystal structure of C₆(CH₃)₆²⁺ (SbF₆⁻)₂⋅HSO₃F confirms the pentagonal pyramidal structure of the dication. The apical carbon is bound to one methyl group (distance 1.479(3) Å) and to the five basal carbon atoms (distances 1.694(2)–1.715(3) Å).     

A charge‐transfer salt composed of methyl viologen and hexacyanidoferrate(II)

The methyl viologen dication, used under the name Paraquat as an agricultural reagent, is a well‐known electron‐acceptor species that can participate in charge‐transfer (CT) interactions. The determination of the crystal structure of this species is important for accessing the CT interaction and CT‐based properties. The title hydrated salt, bis(1,1′‐dimethyl‐4,4′‐bipyridine‐1,1′‐diium) hexacyanidoferrate(II) octahydrate, (C₁₂H₁₄N₂)₂[Fe(CN)₆]·8H₂O or (MV)₂[Fe(CN)₆]·8H₂O [MV²⁺ is the 1,1′‐dimethyl‐4,4′‐bipyridine‐1,1′‐diium (methyl viologen) dication], crystallizes in the space group P 2₁/c with one MV²⁺ cation, half of an [Fe(CN)₆]⁴⁻ anion and four water molecules in the asymmetric unit. The Fe^II atom of the [Fe(CN)₆]⁴⁻ anion lies on an inversion centre and has an octahedral coordination sphere defined by six cyanide ligands. The MV²⁺ cation is located on a general position and adopts a noncoplanar structure, with a dihedral angle of 40.32 (7)° between the planes of the pyridine rings. In the crystal, layers of electron‐donor [Fe(CN)₆]⁴⁻ anions and layers of electron‐acceptor MV²⁺ cations are formed and are stacked in an alternating manner parallel to the direction of the −2a + c axis, resulting in an alternate layered structure.