Synthesis, molecular modeling and preliminary biological evaluation of a set of 3-acetyl-2,5-disubstituted-2,3-dihydro-1,3,4-oxadiazole as potential antibacterial, anti-Trypanosoma cruzi and antifungal agents

A series of 3-acetyl-2,5-disubstituted-2,3-dihydro-1,3,4-oxadiazole derivatives was synthesized and their activity screened in vitro against Staphylococcus aureus, Trypanosoma cruzi, and Candida albicans. The bioactivity was expressed as minimum inhibitory concentration (MIC) for S. aureus strains, and as fifty-percent inhibitory concentration (IC(50)) of parasite population growth for T. cruzi. A molecular modeling approach was performed to establish qualitative relationships regarding the biological data and the compounds' physicochemical properties. The 5-(4-OC(4)H(9)Ph, 5l), and 5-(4-CO(2)CH(3)Ph, 5o) derivatives were the most active compounds for S. aureus ATCC 25923 (MIC=1.95-1.25 μg/mL) and T. cruzi (IC(50)=7.91 μM), respectively. Also, a preliminary evaluation against C. albicans involving some compounds was performed and the 5-(4-CH(3)Ph, 5e) derivative was the most active compound (MIC=3.28-2.95 μg/mL). In this preliminary study, all synthesized 3-acetyl-2,5-disubstituted-2,3-dihydro-1,3,4-oxadiazole derivatives were active against all microorganisms tested.     

Light-harvesting function of carotenoids in photo-synthesis: the roles of the newly found 1(1)Bu- state

This minireview article highlights the energetics and the dynamics of the 1(1)B(u)(-) and 3(1)A(g)(-) states of carotenoids discovered very recently. Those "hidden" covalent states have been revealed by measurements of resonance-Raman excitation profiles of crystalline carotenoids. The dependence of the energies of the low-lying singlet states, including the 1(1)B(u)(+), 3(1)A(g)(-), 1(1)B(u)(-), and 2(1)A(g)(-) states, on the number of conjugated double bonds (n) is in agreement with the extrapolation of those state energies calculated by Tavan and Schulten for shorter polyenes (P. Tavan and K. Schulten, Journal of Chemical Physics, 1986, vol. 85, pp. 6602-6609). It has also been shown that the internal-conversion processes among those singlet states take place in accord with the state ordering, i.e., 1(1)B(u)(+) --> 1(1)B(u)(-) --> 2(1)A(g)(-) --> 1(1)A(g)(-) (the ground state) for carotenoids having n = 9 and 10, whereas 1(1)B(u)(+) --> 3(1)A(g)(-) --> 1(1)B(u) (-) --> 2(1)A(g)(-) --> 1(1)A(g)(-) for carotenoids having n = 11-13. Radiative transitions of 1(1)B(u)(+) --> 2(1)A(g)(-) and 1(1)B(u)(-) --> 2(1)A(g)(-) as well as a branching into the triplet manifold of 1(1)B(u)(-) --> 1(3)A(g) --> 1(3)B(u) have also been found. Those low-lying singlet states of all-trans carotenoids can facilitate multiple channels of singlet-energy transfer to bacteriochlorophyll in the LH2 antenna complexes of purple photosynthetic bacteria. Thus, the newly found 1(1)B(u)(-) and 3(1)A(g)(-) states of carotenoids need to be incorporated into the picture of carotenoid-to-bacteriochlorophyll singlet-energy transfer.     

Two-dimensional kinetic analysis suggests nonsequential gating of mechanosensitive channels in Xenopus oocytes

Xenopus oocytes express mechanosensitive (MS(XO)) channels that can be studied in excised patches of membrane with the patch-clamp technique. This study examines the steady-state kinetic gating properties of MS(XO) channels using detailed single-channel analysis. The open and closed one-dimensional dwell-time distributions were described by the sums of 2-3 open and 5-7 closed exponential components, respectively, indicating that the channels enter at least 2-3 open and 5-7 closed kinetic states during gating. Dependency plots revealed that the durations of adjacent open and closed intervals were correlated, indicating two or more gateway states in the gating mechanism for MS channels. Maximum likelihood fitting of two-dimensional dwell-time distributions to both generic and specific models was used to examine gating mechanism and rank models. A kinetic scheme with five closed and five open states, in which each closed state could make a direct transition to an open state (two-tiered model) could account for the major features of the single-channel data. Two-tiered models that allowed direct transitions to subconductance open states in addition to the fully open state were also consistent with multiple gateway states. Thus, the gating mechanism of MS(XO) channels differs from the sequential (linear) gating mechanisms considered for MS channels in bacteria, chick skeletal muscle, and Necturus proximal tubule.     

Conformational properties of branched RNA fragments in aqueous solution

The conformational properties of branched trinucleoside diphosphates ACC, ACG, AGC, AGG, AUU, AGU, AUG, ATT, GUU, and aAUU [XYZ = X(2'p5'Y)3'p5'Z] have been studied in aqueous solution by nuclear magnetic resonance (1H, 13C), ultraviolet absorption, and circular dichroism. It is concluded from these studies that the purine ring of the central residue (X; e.g., adenosine) forms a base-base stack exclusively with the purine or pyrimidine ring of the 2'-nucleotidyl unit (Y; 2'-residue). The residue attached to the central nucleoside via the 3'-5'-linkage (Z; 3'-residue) is "free" from the influence of the other two heterocyclic rings. The ribose rings of the central nucleoside and the 2'- and 3'-residues exist as equilibrium mixtures of C2'-endo (2E)-C3'-endo (3E) conformers. The furanose ring of the central nucleoside (e.g., A) when linked to a pyrimidine nucleoside via the 2'-5'-linkage shows a higher preference for the 2E pucker conformation (e.g., AUG, AUU, ACG, ca. 80%) than those linked to a guanosine nucleoside through the same type of bond (AGU, AGG, AGC, ca. 70%). This indicates some correlation between nucleotide sequence and ribose conformational equilibrium. The 2E-3E equilibrium of 2'-pyrimidines (Y) shows significant, sometimes exclusive, preference (70-100%) for the 3E conformation; 3'-pyrimidines and 2'-guanosines have nearly equal 2E and 3E rotamer populations; and the ribose conformational equilibrium of 3'-guanosines shows a preference (60-65%) for the 2E pucker. Conformational properties were quantitatively evaluated for most of the bonds (C4'-C5', C5'-O5', C2'-O2', and C3'-O3') in the branched "trinucleotides" AUU and AGG by analysis of 1H-1H, 1H-31P, and 13C-31P coupling constants. The C4'-C5' bond of the adenosine units shows a significant preference for the gamma + conformation. The dominant conformation about C4'-C5' and C5'-O5' for the 2'-and 3'-nucleotidyl units is gamma + and beta t, respectively, with larger gamma + and beta t rotamer populations for the 2'-unit. The increased conformational purity in the 2'-residue, compared to the 3'-residue, is ascribed to the presence of an ordered (adenine----2'-residue) stacked state. The favored rotamers about C3'-O3' and C2'-O2' are epsilon- and epsilon'-, respectively. The conformational features of AUU and AGG were compared to those of their constitutive dimers A3'p5'G, A2'p5'G, A3'p5'U, and A2'p5'U and monomers 5'pG and 5'pU.     

Unusual spectroscopic and electrochemical properties of the 2[4Fe-4S] ferredoxin of Thauera aromatica

A reduced ferredoxin serves as the natural electron donor for key enzymes of the anaerobic aromatic metabolism in the denitrifying bacterium Thauera aromatica. It contains two [4Fe-4S] clusters and belongs to the Chromatium vinosum type of ferredoxins (CvFd) which differ from the "clostridial" type by a six-amino acid insertion between two successive cysteines and a C-terminal alpha-helical amino acid extension. The electrochemical and electron paramagnetic resonance (EPR) spectroscopic properties of both [4Fe-4S] clusters from T. aromatica ferredoxin have been investigated using cyclic voltammetry and multifrequency EPR. Results obtained from cyclic voltammetry revealed the presence of two redox transitions at -431 and -587 mV versus SHE. X-band EPR spectra recorded at potentials where only one cluster was reduced (greater than -500 mV) indicated the presence of a spin mixture of S = (3)/(2) and (5)/(2) spin states of one reduced [4Fe-4S] cluster. No typical S = (1)/(2) EPR signals were observed. At lower potentials (less than -500 mV), the more negative [4Fe-4S] cluster displayed Q-, X-, and S-band EPR spectra at 20 K which were typical of a single S = (1)/(2) low-spin [4Fe-4S] cluster with a g(av) of 1.94. However, when the temperature was decreased stepwise to 4 K, a magnetic interaction between the two clusters gradually became observable as a temperature-dependent splitting of both the S = (1)/(2) and S = (5)/(2) EPR signals. At potentials where both clusters were reduced, additional low-field EPR signals were observed which can only be assigned to spin states with spins of >(5)/(2). The results that were obtained establish that the common typical amino acid sequence features of CvFd-type ferredoxins determine the unusual electrochemical properties of the [4Fe-4S] clusters. The observation of different spin states in T. aromatica ferredoxin is novel among CvFd-type ferredoxins.     

Studies on electronic structures and related properties of [Ru(bpy)2(dpq)] and its 9,9′-substituted derivates with DFT method

Studies on electronic structures and related properties of [Ru(bpy)₂(dpq)]²⁺ and its 9,9′-substituted derivates are carried out using DFT method at B3LYP/LanL2DZ level. The substituent effects caused by the electron-pushing group (OH) and the electron-withdrawing groups (F) on the electronic structures and its related properties, e.g. the energies and components of some frontier molecular orbitals, the spectral properties, and the net charge populations of some main atoms of the complexes, etc. have been investigated. The computational results show that: first, the substituents have some important effects on the first excited state properties. Both electron-withdrawing group (F) and the electron-pushing group (OH) can all activate the main ligand and passivate the co-ligands in the first excited states of [Ru(bpy)₂(9,9′-2R-dpq)]²⁺, and both can lead to a little red shift in the electronic ground bands of the substitutive derivates, respectively, in particular, the electron-pushing group (OH) can lead to that more. Secondly, the most negative charges are populated on N1 or N5, and the next most negative charges are populated on C8 among all atoms of aromatic ring skeleton. In addition, the substituents have slight effects on coordination-bond lengths of complexes. The above theoretical results should be important to further inquire into the interaction mechanism between the complexes and DNA active units from the interactions between molecular orbitals, or from the interactions between atomic charges.     

Comparative study of the g=4.1 EPR signals in the S(2) state of photosystem II

The Mn(4) complex which is involved in water oxidation in photosystem II is known to exhibit three types of EPR signals in the S(2) state, one of the five redox states of the enzyme cycle: a multiline signal (spin 1/2), signals at g5 (spin 5/2) and a signal at g=4.1 (or g=4.25). The g=4.1 signal could be generated under two distinct sets of conditions: either by illumination at room temperature or at 200 K in certain experimental conditions (g4(S) signal) or by near-infrared illumination between approximately 77 and approximately 160 K of the S(2)-multiline state (g4(IR) signal). The two g=4.1 signals arise from states which have quite different stability in terms of temperature. In the present work we have compared these two signals in order to test if they originate from the same or from different chemical origins. The microwave power saturation properties of the two signals measured at 4.2 K were found to be virtually identical. Their temperature dependencies measured at non-saturating powers were also identical. The presence of Curie law behavior for the g4(S) and g4(IR) signals indicates that the states responsible for both signals are ground states. The orientation dependence, anisotropy and resolved hyperfine structure of the two g4 signals were also found to be virtually indistinguishable. We have been unable to confirm the behavior reported earlier indicating that the g4(S) signal is an excited state, nor were we able to confirm the presence of signal from a higher excited state in samples containing the g4(S), nor a radical signal in samples containing the g4(IR). These findings are best interpreted assuming that the two signals have a common origin i.e. a spin 5/2 ground state arising from a magnetically coupled Mn-cluster of 4 Mn ions.     

The effect of (2''-5'') and (3''-5'') phosphodiester linkages on conformational and stacking properties of cytidylyl-cytidine in aqueous solution.

Conformational properties of (2'-5') and (3'-5') CpC have been determined by proton magnetic resonance spectroscopy at 220 MHz. The ribose ring structures are predominantly 3E with the exception of the ring from the 2'-phosphate fragment of C(2'-5')pC which exhibits an 2E pucker. Bases are oriented anti with respect to the ribose and the conformations about C4'-C5', C5'-O5', C3'-O3' (C2'-O2') are gg, g'g', and g+ in equilibrium g-, respectively. The dimers exist as mixtures of stacked (g+g+ and g-g- about the P-O(C) bonds) and unstacked species at 20 degrees C. Stacking is estimated to be 35% in both dimers.     

High-affinity agonist binding correlates with efficacy (intrinsic activity) at the human serotonin 5-HT2A and 5-HT2C receptors: evidence favoring the ternary complex and two-state models of agonist action

Many modern models of receptor-G protein function assume that there is a direct relationship between high-affinity agonist binding and efficacy. The validity of this assumption has been recently questioned for the serotonin 5-HT2A receptor. We examined the intrinsic activities of various ligands in activating phosphoinositide hydrolysis and measured their respective binding affinities to the high- and low-affinity states of the 5-HT2C (VNV isoform) and 5-HT(2A) receptors. Ligand binding affinities for the high-affinity state of the receptors were determined using 1-(4-[125I]iodo-2,5-dimethoxyphenyl)2-aminopropane, whereas [3H]mesulergine and N-[3H]methylspiperone were used, in the presence of excess guanine nucleotide [guanosine 5'-O-(3-thiotriphosphate)], to define binding to the low-affinity state of the 5-HT2C and 5-HT2A receptors, respectively. Antagonists labeled the high- and low-affinity states of each receptor with comparable affinities. Previously identified inverse agonists of the 5-HT2C receptor behaved as silent antagonists in our systems even when the receptor was overexpressed at a relatively high density. In contrast, the ability of agonists to bind differentially to the high- and low-affinity states of the 5-HT2A and 5-HT2C receptors was highly correlated (r2 = 0.86 and 0.96, respectively) with their intrinsic activities. These data suggest that high-affinity agonist states can account for agonist efficacy at human 5-HT2A or 5-HT2C receptors without the need for considering additional transition or active states of the receptor-ligand complex. The procedure described herein may expedite drug discovery efforts by predicting intrinsic activities of ligands solely from ligand binding assays.     

In Vitro antifungal activity of 2-(4-substituted phenyl)-3(2H)-isothiazolones

The in vitro antifungal activity of several N2-phenyl-3(2H)-isothiazolones substituted at C4 of the phenyl moiety with heterocyclic nucleus or groups of different physico-chemical properties against four human pathogenic fungi was determined by broth macrodilution method; results were compared with those obtained with itraconazole and ketoconazole. These isothiazolones showed moderate to high activity against some or all tested strains and in comparison with the reference drugs, 5-chloro-2-(4-nitrophenyl)isothiazol-3-one (1g), 5-chloro-2-phenylisothiazol-3-one (1c), 4-[4-(5-chloro-3-oxo-3H-isothiazol-2-yl)phenyl]-1,4-dihydrotriazol-5-one (1s) and 2-(4-nitrophenyl)isothiazol-3-one (2g) against Aspergillus niger, 5-chloro-2-(4-nitrophenyl)isothiazol-3-one (1g) and 4-[4-(5-chloro-3-oxo-3H-isothiazol-2-yl)phenyl]piperazine-1-carboxamide (1q) against Trichophyton mentagrophytes had comparable activity, compounds 1g and 2g showing higher activity against Microsporum canis. Antifungal activity was favored by the presence of chlorine at C5 of the isothiazolone and/or the presence of nitro group or heterocyclic nucleus at C4 of the phenyl ring and proper hydrophilicity of the molecule.     

Ab initio study of polar and non-polar aprotic solvents effects on some 3-hydroxychromones and 3-hydroxyquinolones derivatives

The photophysical properties of some 3-hydroxychromones (3-HC) and 3-hydroxyquinolones (3-HQ) derivatives are investigated in polar and non-polar aprotic solvents using the TDDFT method and the PCM formalism. In acetonitrile and n-hexane, 2–(2-benzothienyl)-3-HC) (BTHC), 2-furyl-3-HQ (FHQ), and 1-methyl-2-furyl-3-HQ (MFHQ) have exhibited dual emission bands due to the excited state intramolecular proton transfer (ESIPT) reaction, leading to a single excited tautomer form. Our results indicate a very high BTHC light absorption efficiency and radiative rate constant. A charge transfer (CT) analysis suggests that the chromone moiety acts as an acceptor group while quinolone moiety acts as an electron donor. In addition, in non-polar n-hexane the furyl group may act as an acceptor, while in polar acetonitrile it may act as an electron donor. The energies of the upper and lower states of the normal form fluorescence have been decreased by the introduction of ortho-methyl group in FHQ. In all states, MFHQ exhibits large distortions of the dihedral angle between the chromone moiety and the furan group in para position. The ESIPT reaction is irreversible for the three derivatives in all cases studied in this work. Since experimental data with n-hexane are not available, results concerning this solvent are only predictions.     

Domain II + III of bovine serum albumin: Isolation and its characterization

Some properties of a fragment of bovine serum albumin containing residues 184–582 of the protein sequence, produced by cyanogen bromide cleavage, have been reported. Urea-induced difference spectra of the fragment showed considerable exposure of aromatic chromophores by 8 M urea. Reversible unfolding of the fragment by urea, as followed by difference spectral measurements at 30°C, pH 7.0, occurred in two distinct steps involving at least 3 major conformational states, namely the native (N), intermediate (X) and completely denatured (D) states. The co-operativity values for the two transitions, N⇌X and X⇌Dwere found to be 4.0 and 16.4, respectively. Analysis of the data on bilirubin binding to bovine serum albumin and its fragment suggested that the fragment retains significant amount of its native structure. However, hydrodynamic parameters such as Stokes radius (3.f14 nm), diffusion coefficient (6.98 × 10⁻⁷cm²/s) and frictional ratio (1.32) obtained by analytical gel chromatography as well as intrinsic viscosity (4.31 ml/g) indicates some asymmetry in the fragment molecule.     

Distinctive properties of the catalase B of Aspergillus nidulans

Aspergillus nidulans catalase B (CatB) was purified to homogeneity and characterized as a hydroperoxidase which resembles typical catalases in some physicochemical characteristics: (1) it has an apparent molecular weight of 360000 and is composed of four glycosylated subunits, (2) it has hydrophobic properties as revealed by extractability in ethanol/chloroform and binding to phenyl-Superose, and (3) it has an acidic isoelectric point at pH 3. 5. Also CatB exhibits some distinctive properties, e.g. it is not inhibited by the presence of 2% sodium dodecyl sulfate, 9 M urea or reducing agents. Furthermore, even though CatB does not exhibit any residual peroxidase activity, it is able to retain up to 38% of its initial catalase activity after incubation with the typical catalase inhibitor 3-amino-1,2,4-triazole.     

Correlations of conformational parameters and equilibrium conformational states in a variety of beta-D-arabinonucleosides and their analogues.

H nuclear magnetic resonance spectroscopy has been applied to a study of the conformations of a variety of purine and pyrimidine beta-D-arabinofuranosyl nucleosides. The experimental results, together with data collected from the literature, demonstrated the existence of reasonably good correlations between the coupling constants made it possible to define more accurately, than hitherto possible, the conformational states between which equilibria exist in solution. The equilibrium for the arabinonucleosides differs from that previously established for ribonucleosides; in particular, structural modifications and solvent effects may appreciably modify the conformational states between which equilibria exist. Preliminary measurements on some arabinosides in the syn conformation about the glycosidic bond indicated that these do not conform to the foregoing correlations, and will require separate study. A correlation has also been established between the conformation of the arabinose ring and that of the exocyclic 5'-CH2OH group. For both purine and pyrimidine arabinonucleosides, the conformational state 3E of the arabinose ring coexists to some extent with a gauche-gauche conformation of the exocyclic 5'-CH2OH, as in the case of pyrimidine (but not purine) ribonucleosides. Application of the foregoing to some biological problems is described.     

Chirality of aromatic bis-imides from their circular dichroism spectra

It is demonstrated that chirality of molecules composed of 1,2,4, 5-benzenetetracarboxydiimide (pyromellitic diimide) or 1,4,5, 8-naphthalenetetracarboxydiimide units is reflected by their exciton Cotton effects. The analysis is based on the calculated (ZINDO/S) excited states of the model diimide chromophores 1a and 2a. Rotation of the diimide chromophores around the C-N bond in diimides 3-5 is evaluated from the dynamic (1)H NMR data. A comparison of chiroptical properties of bis-diimides 3-5 with the CD spectra of bis-imides 6-8 is also presented. Copyright 2000 Wiley-Liss, Inc.     

Decay products of the S(3) state of the oxygen-evolving complex of photosystem II at cryogenic temperatures. Pathways to the formation of the S = 7/2 S(2) state configuration

The water-oxidizing complex of photosystem II cycles through five oxidation states, denoted S(i)() (i = 0-4), during water oxidation to molecular oxygen, which appears at the (transient) S(4) state. The recent detection of bimodal EPR signals from the S(3) state [Matsukawa, T., Mino, H., Yoneda, D., Kawamori, A. (1999) Biochemistry 38, 4072-4077] has drawn significant attention to this critical state. An interesting property of the S(3) state is the sensitivity to near-IR (NIR) light excitation. Excitation of the S(3) state by near-IR light at cryogenic temperatures induces among other signals a derivative-shaped EPR signal at g= 5 [Ioannidis, N., and Petrouleas, V. (2000) Biochemistry 39, 5246-5254]. The signal bears unexpected similarities to a signal observed earlier in samples that had undergone multiple turnovers and subsequently had been stored at 77 K for a week or longer [Nugent, J. H. A., Turconi, S., and Evans, M. C. W. (1997) Biochemistry 36, 7086-7096]. Recently, both signals were assigned to an S = 7/2 configuration of the Mn cluster [Sanakis, Y., Ioannidis, N., Sioros, G., and Petrouleas, V. (2001) J. Am. Chem. Soc. 123, 10766-10767]. In the present study, we employ bimodal EPR spectroscopy to investigate the pathways of formation of this unusual state. The following observations are made: (i) The g = 5 signal evolves in apparent correlation with the diminution of the S(3) state signals during the slow (tens of hours to several days range) charge recombination of S(3) with Q(A)(-) at 77 K. The tyrosyl radical D* competes with S(3) for recombination with Q(A)(-), the functional redox couple at cryogenic temperatures inferred to be D*/D(-). Transfer to -50 degrees C and above results in the relaxation of the g = 5 to the multiline and g = 4.1 signals of the normal S(2) state. (ii) The transition of S(3) to the state responsible for the g = 5 signal can be reversed by visible light illumination directly at -30 degrees C or by illumination at 4.2 K followed by brief (2 min) transfer to -50 degrees C in the dark. The latter step is required in order to overcome an apparent thermal activation barrier (charge recombination appears to be faster than forward electron transfer at 4.2 K). (iii) The "g = 5" state can be reached in a few tens of minutes at 4.2 K by near-IR light excitation of the S(3) state. This effect is attributed to the transfer of the positive hole from the Mn cluster to a radical (probably tyr Z), which recombines much faster than the Mn cluster with Q(A)(-). (iv) The above properties strongly support the assignment of the configuration responsible for the g = 5 signal to a modified S(2) state, denoted S(2)'. Evidence supporting the assignment of the S(2)' to a proton-deficient S(2) configuration is provided by the observation that the spectrum of S(2) at pH 8.1 (obtained by illumination of the S(1) state at -30 degrees C) contains a g = 5 contribution.     

Synthesis and Pharmacology of the enantiomers of the potential atypical antipsychotic agents 5-OMe-BPAT and 5-OMe-(2,6-di-OMe)-BPAT.

The optically pure enantiomers of the potential atypical antipsychotic agents 5-methoxy-2-[N-(2-benzamidoethyl)-N-n-propylamino]tetralin (5-OMe-BPAT, 5) and 5-methoxy-2-{N-[2-(2,6-dimethoxy)benzamidoethyl]-N-n-propylamino}t etralin [5-OMe-(2,6-di-OMe)-BPAT, 6] were synthesized and evaluated for their in vitro binding affinities at alpha1-, alpha2-, and beta-adrenergic, muscarinic, dopamine D1, D2A, and D3, and serotonin 5-HT1A and 5-HT2 receptors. In addition, their intrinsic efficacies at serotonin 5-HT1A receptors were established in vitro. (S)- and (R)-5 had high affinities for dopamine D2A, D3, and serotonin 5-HT1A receptors, moderate affinities for alpha1-adrenergic and serotonin 5-HT2 receptors, and no affinity (Ki > 1000 nM) for the other receptor subtypes. (S)- and (R)-6 had lower affinities for the dopamine D2A and the serotonin 5-HT1A receptor, compared to (S)- and (R)-5, and hence showed some selectivity for the dopamine D3 receptor. The interactions with the receptors were stereospecific, since the serotonin 5-HT1A receptor preferred the (S)-enantiomers, while the dopamine D2A and D3 receptors preferred the (R)-enantiomers of 5 and 6. The intrinsic efficacies at the serotonin 5-HT1A receptor were established by measuring their ability to inhibit VIP-induced cAMP production in GH4ZD10 cells expressing serotonin 5-HT1A receptors. Both enantiomers of 5 behaved as full serotonin 5-HT1A receptor agonists in this assay, while both enantiomers of 6 behaved as weak partial agonists. The potential antipsychotic properties of (S)- and (R)-5 were evaluated by establishing their ability to inhibit d-amphetamine-induced locomotor activity in rats, while their propensity to induce extrapyramidal side-effects (EPS) in man was evaluated by determining their ability to induce catalepsy in rats. Whereas (R)-5 was capable of blocking d-amphetamine-induced locomotor activity, indicative of dopamine D2 receptor antagonism, (S)-5 even enhanced the effect of d-amphetamine, suggesting that this compound has dopamine D2 receptor-stimulating properties. Since both enantiomers also were devoid of cataleptogenic activity, they are interesting candidates for further exploring the dopamine D2/serotonin 5-HT1A hypothesis of atypical antipsychotic drug action.     

Arsenate and phosphate as nucleophiles at the transition states of human purine nucleoside phosphorylase

Purine nucleoside phosphorylase (PNP) catalyzes the reversible phosphorolysis of 6-oxypurine (2'-deoxy)ribonucleosides, generating (2-deoxy)ribose 1-phosphate and the purine base. Transition-state models for inosine cleavage have been proposed with bovine, human, and malarial PNPs using arsenate as the nucleophile, since kinetic isotope effects (KIEs) are obscured on phosphorolysis due to high commitment factors. The Phe200Gly mutant of human PNP has low forward and reverse commitment factors in the phosphorolytic reaction, permitting the measurement of competitive intrinsic KIEs on both arsenolysis and phosphorolysis of inosine. The intrinsic 1'-(14)C, 1'-(3)H, 2'-(2)H, 9-(15)N, and 5'-(3)H(2) KIEs for inosine were measured for arsenolysis and phosphorolysis. Except for the remote 5'-(3)H(2), and some slight difference between the 2'-(2)H KIEs, all isotope effects originating in the reaction coordinate are the same within experimental error. Hence, arsenolysis and phosphorolysis proceed through closely related transition states. Although electrostatically similar, the volume of arsenate is greater than phosphate and supports a steric influence to explain the differences in the 5'-(3)H(2) KIEs. Density functional theory calculations provide quantitative models of the transition states for Phe200Gly human PNP-catalyzed arsenolysis and phosphorolysis, selected upon matching calculated and experimental KIEs. The models confirm the striking resemblance between the transition states for the two reactions.     

Structural, electronic, and elastic properties of K-As compounds: a first principles study

First-principle calculations are performed to investigate the structural, elastic and electronic properties of K-As compounds (KAs in NaP, LiAs and AuCu-type structures, KAs(2) in MgCu(2)-type structure, K(3)As in Na(3)As, Cu(3)P and Li(3)Bi-type structures, and K(5)As(4) in A(5)B(4)-type structure). The lattice parameters, cohesive energy, formation energy, bulk modulus, and the first derivative of bulk modulus (to fit to the Murnaghan's equation of state) of the considered structures are calculated and reasonable agreement is obtained, and the phase transition pressure is also predicted. The repeated calculations on the electronic band structures and the related partial density of states are also given. The calculated second-order elastic constants based on the stress-strain method and the other related quantities such as Young's modulus, shear modulus, Poisson's ratio, sound velocities, Debye temperature, and shear anisotropy factors for considered structures are presented, and trends are discussed.     

Photo-oxygenation sensitized by dyes

This paper discusses the mechanism of photooxygenation reactions sensitized by dyes, such as: rose bengal, methylene blue, tetraphenylporphin and chlorophyll a. First it is shown more particularly that: the quantum yields of singlet oxygen O2(1 delta g) production gamma delta, and of intersystem crossing singlet S1-triplet T1, gamma is, are not always equal and that the possibilities gamma delta greater than or less than gamma is may occur or are observed; the processes S1 + O2(3 sigma)----T1 + O2(3 sigma) and T1 + O2(3 sigma)----S0 + O2(1 delta g) are mainly if not fully responsible for the quenching of the singlet and triplet excited states of the sensitizer by oxygen. Thereafter, clear indication is given of the considerable complication of the photooxygenation which may arise from particular properties of the investigated substrate A (or of other compounds present in the reaction medium) and which may result in a decrease of the oxygenation quantum yield phi O2. It is shown that this lowering of phi O2 is due to that of gamma delta and/or of phi A, (the probability that O2(1 delta g) yields an oxygenation product AO2) since phi O2 = gamma delta phi A. The latter effect can be induced by the quenching of singlet oxygen by the dye, a process which is quite general and which must be always taken into account in kinetic studies.