Synthesis of carbon-11-labeled 5-HT6R antagonists as new candidate PET radioligands for imaging of Alzheimer’s disease

Carbon-11-labeled serotonin (5-hydroxytryptamine) 6 receptor (5-HT₆R) antagonists, 1-[(2-bromophenyl)sulfonyl]-5-[¹¹C]methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole (O-[¹¹C]2a) and 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-[¹¹C]methyl-1-piperazinyl)methyl]-1H-indole (N-[¹¹C]2a), 5-[¹¹C]methoxy-3-((4-methylpiperazin-1-yl)methyl)-1-(phenylsulfonyl)-1H-indole (O-[¹¹C]2b) and 5-methoxy-3-((4-[¹¹C]methylpiperazin-1-yl)methyl)-1-(phenylsulfonyl)-1H-indole (N-[¹¹C]2b), 1-((4-isopropylphenyl)sulfonyl)-5-[¹¹C]methoxy-3-((4-methylpiperazin-1-yl)methyl)-1H-indole (O-[¹¹C]2c) and 1-((4-isopropylphenyl)sulfonyl)-5-methoxy-3-((4-[¹¹C]methylpiperazin-1-yl)methyl)-1H-indole (N-[¹¹C]2c), 1-((4-fluorophenyl)sulfonyl)-5-[¹¹C]methoxy-3-((4-methylpiperazin-1-yl)methyl)-1H-indole (O-[¹¹C]2d) and 1-((4-fluorophenyl)sulfonyl)-5-methoxy-3-((4-[¹¹C]methylpiperazin-1-yl)methyl)-1H-indole (N-[¹¹C]2d), were prepared from their O- or N-desmethylated precursors with [¹¹C]CH₃OTf through O- or N-[¹¹C]methylation and isolated by HPLC combined with SPE in 40–50% radiochemical yield, based on [¹¹C]CO₂ and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the molar activity (MA) at EOB was 370–740?GBq/μmol with a total synthesis time of ～40-min from EOB.     

Facile radiosynthesis of new carbon-11-labeled propanamide derivatives as selective androgen receptor modulator (SARM) radioligands for prostate cancer imaging

The androgen receptor (AR) is an attractive target for the treatment and molecular imaging of prostate cancer. New carbon-11-labeled propanamide derivatives were first designed and synthesized as selective androgen receptor modulator (SARM) radioligands for prostate cancer imaging using the biomedical imaging technique positron emission tomography (PET). The target tracers, (S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-3-(2-[¹¹C]methoxyphenoxy)-2-methylpropanamide ([¹¹C]8a), (S)-2-hydroxy-3-(2-[¹¹C]methoxyphenoxy)-2-methyl-N-(4-nitro-3-(trifluoromethyl)phenyl)propanamide ([¹¹C]8e), (S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-3-(4-[¹¹C]methoxyphenoxy)-2-methylpropanamide ([¹¹C]8c) and (S)-2-hydroxy-3-(4-[¹¹C]methoxyphenoxy)-2-methyl-N-(4-nitro-3-(trifluoromethyl)phenyl)propanamide ([¹¹C]8g), were prepared by O-[¹¹C]methylation of their corresponding precursors, (S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-3-(2-hydroxyphenoxy)-2-methylpropanamide (9a), (S)-2-hydroxy-3-(2-hydroxyphenoxy)-2-methyl-N-(4-nitro-3-(trifluoromethyl)phenyl)propanamide (9b), (S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-3-(4-hydroxyphenoxy)-2-methylpropanamide (9c) and (S)-2-hydroxy-3-(4-hydroxyphenoxy)-2-methyl-N-(4-nitro-3-(trifluoromethyl)phenyl)propanamide (9d), with [¹¹C]CH₃OTf under basic conditions and isolated by a simplified C-18 solid-phase extraction (SPE) method in 55 ± 5% (n = 5) radiochemical yields based on [¹¹C]CO₂ and decay corrected to end of bombardment (EOB). The overall synthesis time from EOB was 23 min, the radiochemical purity was >99%, and the specific activity at end of synthesis (EOS) was 277.5 ± 92.5 GBq/μmol (n = 5).     

Cytokinin activity of N-phenyl-N′-(4-pyridyl)urea derivatives

We have synthesized 35 N-phenyl-N′-(4-pyridyl)urea derivatives and tested their cytokinin activity in the tobacco callus bioassay. Among them, N-phenyl-N′- (2-chloro-4-pyridyl)urea is highly active, the optimum concentration of which is lower than 4 × 10^?9 M (0.001 ppm), 3 compounds, i.e. N-(2-methylphenyl)-N′-(2-chloro-4-pyridyl)urea, N-(3-methylphenyl)-N′-(2-chloro-4-pyridyl)urea and N-(3-chlorophenyl)-N′-(2-chloro-4-pyridyl) urea are as active as N⁶-benzyladenine (concentration for optimum yield: 4.4 × 10^?8 M or 0.01 ppm), and N-phenyl-N′-(2-methyl-4-pyridyl)urea and N-(2-chlorophenyl)-N′-(2-chloro-4-pyridyl)urea are as active as N-phenyl-N′-(4-pyridyl)urea (concentration for optimum yield: 4.7 × 10^?7 M or 0.1 ppm), while the activity of the other 29 compounds are not so remarkable and 11 of them are almost or completely inactive.     

Novel semicarbazones based 2,5-disubstituted-1,3,4-oxadiazoles: One more step towards establishing four binding site pharmacophoric model hypothesis for anticonvulsant activity

A series of novel N¹-{5-[(naphthalene-2-yloxy)methyl]-1,3,4-oxadiazol-2-yl}-N⁴-(4-substitutedbenzaldehyde)-semicarbazone, N¹-{5-[(naphthalene-2-yloxy)methyl]-1,3,4-oxadiazol-2-yl}-N⁴-[1-(4-substitutedphenyl)ethanone]-semicarbazone and N¹-{5-[(naphthalene-2-yloxy)methyl]-1,3,4-oxadiazol-2-yl}-N⁴-[1-(4-substitutedphenyl) (phenyl) methanone]-semicarbazone were designed and synthesized on the basis of semicarbazone based pharmacophoric model to meet the structural requirements necessary for anticonvulsant activity. The anticonvulsant activities of the compounds were investigated using maximal electroshock seizure (MES), subcutaneous pentylenetrtrazole (scPTZ) and subcutaneous strychnine (scSTY) models. Some of the selected active compounds were subjected to GABA assay to confirm their mode of action. The efforts were also made to establish structure activity relationships among synthesized compounds. The results of the present studying validated that the pharmacophoric model with four binding sites is essential for anticonvulsant activity.     

Chiral spin crossover iron(II) complex, fac-Λ-[Fe(HL)3](ClO4)2·EtOH (HL = 2-methylimidazol-4-yl-methylideneamino-R-(+)-1-methylphenyl)

A chiral spin crossover iron(II) complex, fac-Λ-[Fe^II(HL^R)₃](ClO₄)₂·EtOH was synthesized and its crystal structures in both the high-spin (HS) and low-spin (LS) states were determined, where HL^R denotes 2-methylimidazol-4-yl-methylideneamino-R-(+)-1-methylphenyl. The complex assumes octahedral coordination geometry of N₆ donor atoms by three bidentate ligands HL^R. The complex exists as the facial-Λ-isomer of fac-Λ-[Fe^II(HL^R)₃]²⁺ of the possible geometrical fac- and mer-isomers and the Δ- and Λ-enantiomorphs. The X-ray structural analyses revealed that the R-form of the ligand (HL^R) induces the fac-Λ-isomer of fac-Λ-[Fe^II(HL^R)₃]²⁺ and the S-form of the ligand (HL^S) induces the fac-Δ-isomer of fac-Δ-[Fe(HL^S)₃]²⁺. The complex fac-Λ-[Fe^II(HL^R)₃](ClO₄)₂·EtOH shows a complete steep spin crossover between the HS and the LS states at T_1/2 = 195 K.     

Nickel(II) and copper(II) complexes of Schiff base ligands containing N4O2 and N4S2 donors with pyrrole terminal binding groups: Synthesis, characterization, X-ray structures, DFT and electrochemical studies

A series of hexadentate ligands, H₂L^m (m = 1−4), [1H-pyrrol-2-ylmethylene]{2-[2-(2-{[1H-pyrrol-2-ylmethylene]amino}phenoxy)ethoxy]phenyl}amine (H₂L¹), [1H-pyrrol-2-ylmethylene]{2-[4-(2-{[1H-pyrrol-2-ylmethylene]amino}phenoxy)butoxy]phenyl}amine (H₂L²), [1H-pyrrol-2-ylmethylene][2-({2-[(2-{[1H-pyrrol-2-ylmethylene]amino}phenyl)thio]ethyl}thio)phenyl]amine (H₂L³) and [1H-pyrrol-2-ylmethylene][2-({4-[(2-{[1H-pyrrol-2-lmethylene]amino}phenyl)thio]butyl}thio) phenyl]amine (H₂L⁴) were prepared by condensation reaction of pyrrol-2-carboxaldehyde with {2-[2-(2-aminophenoxy)ethoxy]phenyl}amine, {2-[4-(2-aminophenoxy)butoxy]phenyl}amine, [2-({2-[(2-aminophenyl)thio]ethyl}thio)phenyl]amine and [2-({4-[(2-aminophenyl)thio]butyl}thio)phenyl]amine respectively. Reaction of these ligands with nickel(II) and copper(II) acetate gave complexes of the form ML^m (m = 1−4), and the synthesized ligands and their complexes have been characterized by a variety of physico-chemical techniques. The solid and solution states investigations show that the complexes are neutral. The molecular structures of NiL³ and CuL², which have been determined by single crystal X-ray diffraction, indicate that the NiL³ complex has a distorted octahedral coordination environment around the metal while the CuL² complex has a seesaw coordination geometry. DFT calculations were used to analyse the electronic structure and simulation of the electronic absorption spectrum of the CuL² complex using TDDFT gives results that are consistent with the measured spectroscopic behavior of the complex. Cyclic voltammetry indicates that all copper complexes are electrochemically inactive but the nickel complexes with softer thioethers are more easily oxidized than their oxygen analogs.     

Production of anti-self-H-2 antibodies by C3D2F1 mice hyperimmune to L cell/L1210 hybrids and L1210 leukemia cells

During the course of immunization of (C3H × DBA/2)F₁ mice (genotype H-2^k/b) with L cell (H-2^k/k)/L1210 leukemia cell (H-2^d/d) hybrids and L1210 leukemia cells, some of them produced a good titer of anti-self-H-2 (H-2^d) antibodies. Antigens recognized by this anti-self-H-2 antiserum were shown to be controlled by the H-2K-IA-IB-IJ-IE subregions of the H-2^d but not H-2^k nor H-2^b haplotypes of parental as well as F₁ origins and to have a tissue distribution identical to that of class 1 H-2 (H-2K/D) antigens.     

Interaction of the Laburnum anagyroides lectin with fucoantigens

We studied interaction of the lectin from the bark of Golden Rain shrub (Laburnum anagyroides, LABA) with a number of basic fucose-containing carbohydrate antigens by changes in its tryptophan fluorescence. The strongest LABA binding was observed for the trisaccharide H of type 6 [α-L-Fucp-(1-2)-β-D-Galp-(1-4)-D-Glc, K _a = 4.2 × 10³ M^?1]. The following antigens were bound with a weaker affinity: H-disaccharide α-L-Fucp-(1-2)-D-Gal, a glucoanalogue of tetrasaccharide Le^y α-L-Fucp-(1-2)-β-D-Galp-(1-4)-[α-L-Fucp-(1-3)]-D-Glc, and 6-fucosyl-N-acetylglucosamine, a fragment of core of the N-glycans family (K _a 1.1?1.7 × 10³ M^?1). The lowest binding was observed for L-fucose (K _a = 2.7 × 10² M^?1) and trisaccharide Le^a, (β-Galp-(1-3)-[α-L-Fucp-(1-4)]-GlcNAc (K _a = 6.4 × 10² M^?1). The Le^d, Le^a, and Le^x pentasaccharides and Le^b hexasaccharide were not bound to LABA.     

Synthesis,antimicrobial activity and QSAR studies of new 2,3-disubstituted-3,3a,4,5,6,7-hexahydro-2H-indazoles

Antimicrobial activity of synthesized 2,3-disubstituted-3,3a,4,5,6,7-hexahydro-2H-indazole derivatives indicated that 3-(4-chlorophenyl)-2-(4-nitrophenylsulfonyl)-3,3a,4,5,6,7-hexahydro-2H-indazole (6) and 3-(4-fluorophenyl)-2-(4-nitrophenylsulfonyl)-3,3a,4,5,6,7-hexahydro-2H-indazole (20) were the most active compounds. Further, the results of QSAR studies indicated the importance of topological parameters ²χ and ²χ^v in defining the antimicrobial activity of hexahydroindazoles.     

Isolation and Estimation of Cytokinins and Cytokinin-Containing Transfer RNAs from Cucumis sativus L. var. Guntur Seedlings

N⁶-(Δ²-Isopentenyl) adenosine antibodies were used for the isolation of free cytokinins and cytokinin-containing tRNAs from parts of Cucumis sativus L. var. Guntur seedlings and for the estimation of cytokinins in them. Immobilized N⁶-(Δ²-isopentenyl) adenosine antibodies retained tRNAs containing N⁶-(Δ²-isopentenyl) adenosine and N⁶-(4-hydroxy-3-methylbut-2-enyl) adenosine with equal efficiencies. There were at least five cytokinins in the free form in cucumber seedlings. N⁶-(4-Hydroxy-3-methylbut-2-enyl) adenosine, N⁶-(Δ²-isopentenyl) adenosine, and N⁶-(Δ²-isopentenyl) adenine were present at least to the extent of 80, 23, and 9 nanograms, respectively, in the cotyledons and 40, 6, and 3 nanograms, respectively, in the decotyledonated seedlings per gram of tissue. Only two cytokinins were found in the tRNAs of cucumber cotyledons, namely N⁶-(Δ²-isopentenyl) adenosine and N⁶-(4-hydroxy-3-methylbut-2-enyl) adenosine in amounts of 12 and 318 nanograms, respectively, per gram of tissue. Immunoaffinity chromatographic analysis of radiolabeled aminoacyl tRNAs from cucumber cotyledons showed that tRNA^Phe and tRNA^Tyr contained cytokinins whereas tRNA^Ala did not.     

Synthesis and preliminary biological evaluation of a novel P2X7R radioligand [18F]IUR-1601

The reference standard IUR-1601 ((S)-N-(2-chloro-3-(trifluoromethyl)benzyl)-1-(2-fluoroethyl)-5-oxopyrrolidine-2-carboxamide) was synthesized from tert-butyl (S)-5-oxopyrrolidine-2-carboxylate, fluoroethylbromide, and 2-chloro-3-(trifluoromethyl)benzylamine with overall chemical yield 12% in three steps. The target tracer [¹⁸F]IUR-1601 ((S)-N-(2-chloro-3-(trifluoromethyl)benzyl)-1-(2-[¹⁸F]fluoroethyl)-5-oxopyrrolidine-2-carboxamide) was synthesized from desmethyl-GSK1482160 with 2-[¹⁸F]fluoroethyl tosylate, prepared from 1,2-ethylene glycol-bis-tosylate and K[¹⁸F]F/Kryptofix2.2.2, in two steps and isolated by HPLC combined with SPE in 1–3% decay corrected radiochemical yield. The radiochemical purity was >99%, and the molar activity at end of bombardment (EOB) was 74–370?GBq/μmol. The potency of IUR-1601 in comparison with GSK1482160 was determined by a radioligand competitive binding assay using [¹¹C]GSK1482160, and the binding affinity K_i values for IUR-1601 and GSK1482160 are 4.31 and 5.14?nM, respectively.     

Assessing the impact of inductive electronic effects on the metrical parameters and reactivity of a series of ferrous complexes

Reported are four iron(II) complexes with N-benzyl-N,N′-bis(2-pyridylmethyl)-1,2-ethanediamine (L^H) and three electronically modified derivatives: N-(4-methoxy)benzyl-N,N′-bis(2-pyridylmethyl)-1,2-ethanediamine (L^OMe), N-(4-chloro)benzyl-N,N′-bis(2-pyridylmethyl)-1,2-ethanediamine (L^Cl), and N-(4-nitro)benzyl-N,N′-bis(2-pyridylmethyl)-1,2-ethanediamine (L^NO₂). The four ligands react with FeCl₂ to form a series of mononuclear species with the general formula [Fe(L^R)Cl₂]. The cis-α conformation of the ligand places the amine N-donors trans to the Fe-Cl bonds. The identity of the 4-benzyl substituent has profound influences on the lengths of the iron-ligand bonds, the optical spectra, and the redox activities of the [Fe(L^R)Cl₂] compounds.     

Structure of the O-polysaccharide of the lipopolysaccharide of Pragia fontium 97U116

The O-polysaccharide of Pragia fontium 97U116 was obtained by mild acid degradation of the lipopolysaccharide and studied by sugar analysis along with 1D and 2D ¹H and ¹³C NMR spectroscopy. The following structure of the pentasaccharide-repeating unit was established: →2)-α-d-Galf-(1→3)-α-l-Rhap2Ac^I-(1→4)-α-d-GlcpNAc^I-(1→2)-α-l-Rhap^II-(1→3)-β-d-GlcpNAc^II-(1→     

Covalent anthocyanin–flavonol complexes from the violet-blue flowers of Allium ‘Blue Perfume’

Three covalent anthocyanin–flavonol complexes (pigments 1–3) were extracted from the violet-blue flower of Allium ‘Blue Perfume’ with 5% acetic acid-MeOH solution, in which pigment 1 was the dominant pigment. These three pigments are based on delphinidin 3-glucoside as their deacylanthocyanin and were acylated with malonyl kaempferol 3-sophoroside-7-glucosiduronic acid or malonyl-kaempferol 3-p-coumaroyl-tetraglycoside-7-glucosiduronic acid in addition to acylation with acetic acid.By spectroscopic and chemical methods, the structures of these three pigments 1–3 were determined to be: pigment 1, (6^I-O-(delphinidin 3-O-(3^I-O-(acetyl)-β-glucopyranoside^I)))(2^VI-O-(kaempferol 3-O-(2^II-O-(3^III-O-(β-glucopyranosyl^V)-β-glucopyranosyl^III)-4^II-O-(trans-p-coumaroyl)-6^II-O-(β-glucopyranosyl^IV)-β-glucopyranoside^II)-7-O-(β-glucosiduronic acid^VI))) malonate; pigment 2, (6^I-O-(delphinidin 3-O-(3^I-O-(acetyl)-β-glucopyranoside^I)))(2^VI-O-(kaempferol 3-O-(2^II-O-β-glucopyranosyl^III)-β-glucopyranoside^II)-7-O-(β-glucosiduronic acid^VI))); and pigment 3, (6^I-O-(delphinidin 3-O-(3^I-O-(acetyl)-β-glucopyranoside^I)))(2^VI-O-(kaempferol 3-O-(2^II-O-(3^III-O-(β-glucopyranosyl^V)-β-glucopyranosyl^III)-4^II-O-(cis-p-coumaroyl)-6^II-O-(β-glucopyranosyl^IV)-β-glucopyranoside^II)-7-O-(β-glucosiduronic acid^VI))) malonate.The structure of pigment 2 was analogous to that of a covalent anthocyanin–flavonol complex isolated from Allium schoenoprasum where delphinidin was observed in place of cyanidin. The three covalent anthocyanin–flavonol complexes (pigment 1–3) had a stable violet-blue color with three characteristic absorption maxima at 540, 547 and 618 nm in pH 5–6 buffer solution. From circular dichroism measurement of pigment 1 in the pH 6.0 buffer solution, cotton effects were observed at 533 (+), 604 (−) and 638 (−) nm. Based on these results, these covalent anthocyanin–flavonol complexes were presumed to maintain a stable intramolecular association between delphinidin and kaempferol units closely related to that observed between anthocyanin and hydroxycinnamic acid residues in polyacylated anthocyanins. Additionally, an acylated kaempferol glycoside (pigment 4) was isolated from the same flower extract, and its structure was determined to be kaempferol 3-O-sophoroside-7-O-(3-O-(malonyl)-β-glucopyranosiduronic acid).     

Synthesis, characterization and X-ray crystal structure of [Re(L4)(CO)3]Br · 2CH3OH (L4 = N,N-bis[(2-diphenylphosphino)ethyl]methoxyethylamine): A model compound for novel cationic Tc(I)-tricarbonyl radiotracers useful for heart imaging

This report describes synthesis and evaluation of cationic complexes, [^99mTc(CO)₃(L)]⁺ (L = N-methoxyethyl-N,N-bis[2-(bis(3-ethoxypropyl)phosphino)ethyl]amine (L1), N-[(15-crown-5)-2-yl]-N,N-bis[2-(bis(3-ethoxypropyl)phosphino)ethyl]amine (L2) and N-[(18-crown-6)-2-yl]-N,N-bis[2-(bis(3-ethoxypropyl)phosphino)ethyl]amine (L3)) as potential radiotracers for heart imaging. Preliminary results from biodistribution studies in female adult BALB-c mice indicated that the cationic ^99mTc(I)-tricarbonyl complex, [^99mTc(CO)₃(L2)]⁺, has a significant localization in the heart at 60 min post-injection. To understand the coordination chemistry of these bisphosphine ligands with the ^99mTc(I)-tricarbonyl core, we prepared [Re(CO)₃(L4)]Br (L4: N,N-bis[(2-diphenylphosphino)ethyl]methoxyethylamine) as a model compound. [Re(CO)₃(L4)]Br has been characterized by elemental analysis, IR, ESI-MS, NMR (¹H, ¹³C, ¹H-¹H COSY, and ¹H-¹³C HMQC) methods, and X-ray crystallography. In solid state, [Re(CO)₃(L4)]⁺ has a distorted octahedron coordination geometry with PNP occupying one facial plane. The chelator backbone adopts a “chair” conformation with phosphine-P atoms at equatorial positions and the amine-N at the apical site. In solution, [Re(CO)₃(L4)]⁺ is able to maintain its cationic nature with no dissociation of carbonyl ligands or any of the three PNP donors.     

Facile synthesis of carbon-11-labeled sEH/PDE4 dual inhibitors as new potential PET agents for imaging of sEH/PDE4 enzymes in neuroinflammation

To develop PET tracers for imaging of neuroinflammation, new carbon-11-labeled sEH/PDE4 dual inhibitors have been synthesized. The reference standard N-(4-methoxy-2-(trifluoromethyl)benzyl)benzamide (1) and its corresponding desmethylated precursor N-(4-hydroxy-2-(trifluoromethyl)benzyl)benzamide (2) were synthesized from (4-methoxy-2-(trifluoromethyl)phenyl)methanamine and benzoic acid in one and two steps with 84% and 49% overall chemical yield, respectively. The standard N-(4-methoxy-2-(trifluoromethyl)benzyl)-1-propionylpiperidine-4-carboxamide (MPPA, 4) and its precursor N-(4-hydroxy-2-(trifluoromethyl)benzyl)-1-propionylpiperidine-4-carboxamide (5) were synthesized from methyl 4-piperidinecarboxylate, propionyl chloride and (4-methoxy-2-(trifluoromethyl)phenyl)methanamine in two and three steps with 62% and 34% overall chemical yield, respectively. The target tracers N-(4-[¹¹C]methoxy-2-(trifluoromethyl)benzyl)benzamide ([¹¹C]1) and N-(4-[¹¹C]methoxy-2-(trifluoromethyl)benzyl)-1-propionylpiperidine-4-carboxamide ([¹¹C]MPPA, [¹¹C]4) were prepared from their corresponding precursors 2 and 5 with [¹¹C]CH₃OTf through O-[¹¹C]methylation and isolated by HPLC combined with SPE in 25–35% radiochemical yield, based on [¹¹C]CO₂ and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the molar activity (A_M) at EOB was 370–740 GBq/μmol with a total synthesis time of 35–40-minutes from EOB.     

Roles of translesion synthesis DNA polymerases in the potent mutagenicity of tobacco-specific nitrosamine-derived O2-alkylthymidines in human cells

The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent human carcinogen. Metabolic activation of NNK generates a number of DNA adducts including O²-methylthymidine (O²-Me-dT) and O²-[4-(3-pyridyl)-4-oxobut-1-yl]thymidine (O²-POB-dT). To investigate the biological effects of these O²-alkylthymidines in humans, we have replicated plasmids containing a site-specifically incorporated O²-Me-dT or O²-POB-dT in human embryonic kidney 293T (HEK293T) cells. The bulkier O²-POB-dT exhibited high genotoxicity and only 26% translesion synthesis (TLS) occurred, while O²-Me-dT was less genotoxic and allowed 55% TLS. However, O²-Me-dT was 20% more mutagenic (mutation frequency (MF) 64%) compared to O²-POB-dT (MF 53%) in HEK293T cells. The major type of mutations in each case was targeted T → A transversions (56% and 47%, respectively, for O²-Me-dT and O²-POB-dT). Both lesions induced a much lower frequency of T → G, the dominant mutation in bacteria. siRNA knockdown of the TLS polymerases (pols) indicated that pol η, pol ζ, and Rev1 are involved in the lesion bypass of O²-Me-dT and O²-POB-dT as the TLS efficiency decreased with knockdown of each pol. In contrast, MF of O²-Me-dT was decreased in pol ζ and Rev1 knockdown cells by 24% and 25%, respectively, while for O²-POB-dT, it was decreased by 44% in pol ζ knockdown cells, indicating that these TLS pols are critical for mutagenesis. Additional decrease in both TLS efficiency and MF was observed in cells deficient in pol ζ plus other Y-family pols. This study provided important mechanistic details on how these lesions are bypassed in human cells in both error-free and error-prone manner.     

Photoproducts from the photolysis of tris(bipyridine)ruthenium(II) chloride in dimethylformamide

Six photoproducts were observed in the photolysis of [Ru(bpy)₃]²⁺ in N,N-dimethylformamide (DMF) in the presence of chloride ions. The primary products were cis-[Ru(bpy)₂Cl₂] and cis-[Ru(bpy)₂-(DMF)Cl]⁺. The remaining ruthenium products, which were thermally unstable to varying degrees, were cis-[Ru(bpy)₂Cl₂]⁺, [Ru(bpy)₃]⁺, and a binuclear species we have tentatively identified as [Ru(bpy)₂Cl]₂ⁿ⁺ (n = 3 or 4).     

Synthesis, crystal structures, cytotoxicity and qualitative structure-activity relationship (QSAR) of cis-bis{5-[(E)-2-(aryl)-1-diazenyl]quinolinolato}di-n-butyltin(IV) complexes, (n)Bu2Sn(L)2

A series of cis-bis{5-[(E)-2-(aryl)-1-diazenyl]quinolinolato}di-n-butyltin(IV) complexes has been synthesized and characterized by ¹H-, ¹³C-, ¹¹⁹Sn NMR, ESI-MS (electrospray ionization mass spectrometry), IR and ^119mSn Mössbauer spectroscopic techniques in combination with elemental analyses. The structures of four di-n-butyltin(IV) complexes, viz., ⁿBu₂Sn(L³)₂ (3), ⁿBu₂Sn(L⁴)₂ (4), ⁿBu₂Sn(L⁵)₂ (5) and ⁿBu₂Sn(L⁷)₂ · 0.5C₆H₆ (7) (LH = 5-[(E)-2-(aryl)-1-diazenyl)quinolin-8-ol) were determined by single crystal X-ray diffraction. In general, the complexes were found to adopt a distorted cis-octahedral arrangement around the tin atom. These complexes retain their solid-state structure in non-coordinating solvent as evidenced by ¹¹⁹Sn and ¹³C NMR spectroscopic results. The in vitro cytotoxicity of di-n-butyltin(IV) complexes (3-8) is reported against seven well characterized human tumour cell lines. The basicity of the two quinolinolato donor N and O atoms of the ligands are discussed in relation to the cytotoxicity data.     

Comb-shaped graft copolymers with cellulose side-chains prepared via click chemistry

Comb-shaped copolymers with cellobiose acetate or cellulose triacetate (CTA) side-chains, PPMA-g-(CTA2-C15) and PPMA-g-(CTA13-C15), were prepared by grafting N-(15-azidopentadecanoyl)-2,3,6-tri-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl)-β-d-glucopyranosylamine (CTA2-C15-N₃) and N-(15-azidopentadecanoyl)-tri-O-acetyl-β-cellulosylamine (CTA13-C15-N₃, number average degree of polymerization (DP_n) = 13) onto poly(2-propyn-1-yl methacrylate) (PPMA, weight average degree of polymerization (DP_w, X + Y = 5.59 × 10²)) via “click chemistry”. The copolymers were characterized by ¹H, ¹³C and two-dimensional NMR and size exclusion chromatography-multi-angle laser light scattering (SEC-MALS) measurements. The numbers of CTA side-chains (X) of PPMA-g-(CTA2-C15) and PPMA-g-(CTA13-C15) were calculated as 4.03 × 10² and 2.45 × 10², respectively. Copolymers with cellulosic side-chains, PPMA-g-(CELL2-C15) and PPMA-g-(CELL13-C15), were successfully obtained after deacetylation of PPMA-g-(CTA2-C15) and PPMA-g-(CTA13-C15), respectively. X-ray diffraction measurements revealed that PPMA-g-(CELL13-C15) showed crystalline pattern of cellulose II, which is believed to have anti-parallel orientation.