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The discovery of the antioxidant activity of selenoenzyme glutathione peroxidase (GPx) has attracted growing attention in the biochemistry of selenium. Among molecules which mimic the structure of the active site of the enzyme, N-phenyl-1,2-benzisoselenazolin-3-one 1, Ebselen, exhibited useful anti-inflammatory properties. It has been extensively investigated and has undergone clinical trials as an anti-inflammatory agent. Unfortunately, Ebselen exhibits relatively poor catalytic activity, prompting attempts to design more efficacious GPx mimetics that would retain his low toxicity while manifesting improved catalytic properties. In this context, novel 1,2-benzoselenazine and 1,2-benzoselenazols, which are five and six membered homologues of Ebselen were synthesized and characterized. One structure has been proven by single crystal X-ray crystallography.

La deshydratation des acides hydroxymethyles sur les positions 2,3 ou 3,2 du benzo(b)selenophene conduit aux deux lactones isomeres. Dans le benzo(b)thiophene, seule la lactone dont le groupement carbonyle est en position 3 a pu etre obtenue par cette methode. La lactone isomere a cependant pu etre synthetisee a partir du nitrile alcool correspondant par l'intermediaire d'un iminoester interne. Dans le cas du benzofuranne, aucune des deux lactones n'a pu etre obtenue quelle que soit la methode employee. Nous discutons les raisons de cette difference de comportement.

Nous etudions la reactivite des methyl-2 et methyl-3 benzo(b)selenophenes vis-a-vis d'agents electrophiles (reactions de bromuration, de Friedel et Crafts). Nous decrivons egalement une serie de syntheses realisees sur les positions 2 et 3 de l'heterocycle de base.

Nous decrivons une nouvelle voie d'acces au cycle benzo(b)selenophene. Cette methode est basee sur la reaction d'acetals halogenes avec le selenium via les organo-metalliques. Nous examinons ensuite diverses voies de synthese qui ne donnent pas de resultats satisfaisants. Enfin, nous generalisons d'avantage la methode de quaternisation decrite precedemment.

Nous decrivons une nouvelle synthese de benzo(b)furannes, thiophenes et selenophenes substitues en position 2 par un groupement alcoyle ou aryle. Cette voie d'acces originale a de tels heterocycles est basee sur la cyclisation d'ethers (O, S, Se) portant en position ortho un groupement acetonyle ou phenacyle. Nous examinons egalement les possibilites de generalisation d'une telle reaction.

Nous avons synthetise un certain nombre d'acides cetoniques ainsi que certains de leurs derives (chlorures, esters normaux et cycliques). Grâce au comportement chimique de ces acides, nous degageons une structure probable pour ces substances tautomeres. Cette structure sera etablie avec certitude dans un travail ulterieur par des mesures physico-chimiques realisees sur tous les derives synthetises ci-dessous.

Dans le cadre de l'etude de l'action des reactifs nucleophiles sur les perchlorates de selenopyrylium, nous decrivons la synthese des perchlorates de 1-benzothieno (3,2-b) et (2,3-b) selenopyrylium. Ces composes relativement stables ont ete caracterises notamment par leurs spectres de RMN et UV. Leur reactivite sera decrite ulterieurement.

Nous nous sommes efforces sans succes de preparer les chlorures des acides o-acetyl et o-benzoyl-phenylacetiques, et nous montrons que cet echec est lie a la presence d'hydrogenes mobiles sur le groupement–CH2–. Nous preparons en consequence les acides o-acetyl et o-benzoyl-phenyl α, α dimethylacetiques ainsi que leur chlorure d'acide, afin d'en etudier la structure et les proprietes notamment par comparaison avec les chlorures d'acides homologues inferieurs. Nous montrons par spectrographie infra-rouge que toutes les substances derivant de ces chlorures d'acides possedent la forme cyclique et appartiennent a la classe des isochromannones-3.

The syntheses and spectral characterization of the metabolites of a new organo-selenium drug (ebselen) are described.

Synthesis of 1,3-benzoselenazine derivatives is attempted via cyclization of o-methylselenobenzoylformamidines, via ring-expansion of 1,2-benzisoselenazolin-3-ones and via N-ethoxy-carbonyl o-bromoselenobenzaldimine. This research succeeded in the synthesis of 2,3-dihydro-4H-1,3-benzoselenazine-2,4-dione and 2,3-dihydro-4H-1,3-benzoselenazine-4-one.

Nous avons etudie dans ce chapitre les proprietes des acides cetoniques aromatiques ortho substitues possedant un groupement intercale entre le cycle aromatique et le carbonyle. Ces acides revelent des proprietes presqu' integralement cycliques; il en est de meme a tortiori de leurs chlorures, ainsi que de tous les derives formes a partir de ceux-ci. Nous avons discute les raisons de cette evolution de structure.

The synthesis of 2,4-dichlorophenylselenoacetic acid (2,4-D-Se) may be completed in three steps starting from 2,4-dichloroaniline. The selenium is inserted in the molecule by reaction of a diazonium salt with potassium selenocyanate. 2,4-D-Se has been tested as an auxin in several bioassays including the regeneration of somatic embryos, adventitious root formation and the associated temporary increase of endogenous auxins at the induction phase, and callus formation, and compared with the natural auxin indoleacetic acid (IAA), the classical synthetic auxin(s) naphthaleneacetic acid (NAA) and/or 2,4-dichlorophenoxyacetic acid (2,4-D), and with the synthetic seleniated IAA, 3-(benzo[b]selenienyl) acetic acid, BSAA. These biological assays classified 2,4-D-Se together with BSAA among the most powerful synthetic auxins. The role of selenium is briefly discussed.

Irradiation (λ = 350 nm) of 1H-[2]benzothiopyran-1-one (2) in the solid state affords selectively and in good yield 6aα, 6bα, 12bα, 12cα -tetrahydrocyclobuta[1, 2-c:4, 3-c′]bis([2]benzothiopyran)-5, 8-dione (3), the head-to-head (HH) cis-cisoid-cis-cyclodimer of 2, X-Ray analysis of 2 confirms that this reaction proceeds according to the well-established topochemical principles. The same dimer 3 is obtained in low yields on irradiation of 10−1M solutions of 2 in either MeOH or MeCN, while no conversion at all is observed in benzene. On irradiation of 2 in MeCN in the presence of tetrachloroethene, the [2 + 2] photocycloadduct 4 is formed in good yield, the conversion 2 4 being efficiently quenched by naphthalene. In contrast, no reaction is observed -on irradiation of 2 in the presence of 2, 3-dimethylbut-2-ene, neither in polar nor in apolar solvents.

(S)-4-Chloro-2-fluorophenylalanine and (S)-(α-methy)-4-chloro-2-fluorophenylalanine were synthesized and labeled with no carrier added (n.c.a.) fluorine-18 through a radiochemical synthesis relying on the highly enantioselective reaction between 4-chloro-2-[18F]fluorobenzyl iodide and the lithium enolate of (2S)-1-(tert-butyloxycarbonyl)-2-(tert-butyl)-3-methyl-1,3-imidazolidine-4-one for (S)-4-chloro-2-[18F]fluorophenylalanine and (2S,5S)-1-(tert-butyloxycarbonyl)-2-(tert-butyl)-3,5-dimethyl-1,3-imidazolidine-4-one for (S)-(α-methyl) -4-chloro-2-[18F] fluorophenylalanine. Quantities of about 20–25 mCi were obtained at the end of sy nthesi s, ready for injection after hydrolysis and high performance liquid chromatography (HPLC) purification, with a radiochemical yield of 17%–20% corrected to the end of bombardment after a total synthesis time of 90–105 min from [18F] fluoride. The enantiomeric excesses were shown to be 97% or more for both molecules without chiral separation and the radiochemical and chemical purities were 98% or better.

With peptide analogues of their natural substrates (the glycopeptide units of nascent peptidoglycan), the DD-peptidases exhibit a strict preference for D-Ala-D-Xaa C-termini. Gly is tolerated as the C-terminal residue, but with a significantly decreased activity. These enzymes were also known to hydrolyse various ester and thiolester analogues of their natural substrates. Some thiolesters with a C-terminal leaving group that exhibited L stereochemistry were significantly hydrolysed by some of the enzymes, particularly the Actinomadura R39 DD-peptidase, but the strict specificity for a D residue in the penultimate position was fully retained. These esters and thiolesters also behave as substrates for beta-lactamases. In this case, thiolesters exhibiting L stereochemistry in the ultimate position could also be hydrolysed, mainly by the class-C and class-D enzymes. However, more surprisingly, the class-C Enterobacter cloacae P99 beta-lactamase also hydrolysed thiolesters containing an L residue in the penultimate position, sometimes with a higher efficiency than the D isomer.

With peptide substrates, the penicillin-sensitive dd-peptidases exhibit a strict specificity for d-Ala-d-Xaa C-termini. Only glycine is tolerated as the C-terminal residue, but with a significantly decreased activity. These enzymes also hydrolyse various ester and thiolester analogues of their natural substrates. Some of the thiolesters whose C-terminal leaving group exhibited an l stereochemistry were significantly hydrolysed by some of the studied enzymes, particularly by the Actinomadura R39 dd-peptidase. By contrast, the strict specificity for a d residue in the penultimate position was fully retained. The same esters and thiolesters also behaved as substrates for β-lactamases. In this case, thiolesters exhibiting l stereochemistry in the C-terminal position could also be hydrolysed, mainly by the class C and class D enzymes. But, more surprisingly, the class C Enterobacter cloacae P99 β-lactamase also hydrolysed thiolesters containing an l residue in the penultimate position, sometimes more efficiently than the d isomer.

In the course of a study of 1,2-benzoselenazin-4-one heterocyclic homologues of ebselen, a well known anti-oxidizing agent, the crystal structure determination of the title compound, C13H8N2O3Se, was carried out and revealed a monoclinic polymorph of the previously reported triclinic form. In both polymorphs, the centroids of the heterocyclic rings are nearly superimposed in projection along their normal. In the title compound, the molecular planes pack along two directions.

[5-131I]Iodotropapride is a benzamidic compound which displays high affinity and selectivity for dopaminergic receptors. It was prepared from the corresponding brominated compound by a nucleophilic substitution with [131I]iodine (t1/2 = 8.02 days, E gamma = 364 keV) based on the use of Cu(I) as catalyst and high specific activity of [131I]NaI. After i.v. injection in rats the tracer crosses the blood-brain barrier (0.42 +/- 0.06% of injected dose in the total brain) and demonstrates a high affinity binding to the striatum. The striatum-to-cerebellum ratio increases with time and reaches values of 9 and 22 at 30 and 120 min after injection, respectively. This specific uptake in the striatum is saturable and can be blocked by pretreatment with different D2 antagonists. When labeled with 123I (t1/2 = 13 h, E1 = 159 keV), the corresponding [123I]iodotropapride may be useful for the investigation of the D2 dopamine receptors in humans with single photon emission computer tomography (SPECT).

The synthesis of new, highly efficient DNA photoinactivating agents comprising an atom of sulfur or selenium in place of oxygen in the psoralen system is described.

Asymmetric nucleophilic synthesis of 6-[18F]fluoro- l -dopa was investigated in order to reach an enantiomeric excess of close to 100% of the l form of this amino acid. The radiochemical synthesis required [18F]fluoride as fluorinating agent and regioselective nucleophilic substitution of commercially available 6-nitroveratraldehyde. The [18F]fluorobenzaldehyde thus obtained was easily converted to the corresponding 2-[18F]fluoro-4,5-dimethoxybenzyl bromide. This alkylating agent was added to the lithium enolates of 1-(S)-(−)camphor imine of t-butyl glycinate (1) and (S)-(−)-1-Boc-2-t-butyl-3-methyl-4-imidazolidinone [(S)- Boc-BMI] (2) in order to compare the enantiomeric excess of the l form obtained in each case with these two chiral inductors. The l -isomer of fluorodopa was isolated after H1 hydrolysis and HPLC purification in 5–10% radiochemical yield (decay corrected). The overall synthesis time was of 110 min. Through this synthetic pathway, the l -isomer of fluorodopa was obtained in 83% e.e with 1 and 96% e.e with 2 respectively, as determined by chiral HPLC. A practical three step preparative scale synthesis of 6-[19F]fluoro- d,l -dopa is also presented.

The synthesis of the 7-nitro-2-phenyl-1,2-benzisoselenazol-3(2H)-one 3a leads to an abnormal behavior due to a dipole stabilisation between the nitro group and the selenium atom. The first ever synthesis of a 2,1-benzoxasetenol-3-one 5 is described. The unexpected insertion of a sulfur atom from thionyl chloride results in the formation of the 7-nitro-2,1-benzothiaselenol-3-one 6 .

Ortholithiation reactions are shown to be effective tools for the synthesis of Ebselen (N-phenyl-benzisoselenazolin-3-one) derivatives.

Starting from the known 6-methoxyanthranilic acid (5), we have synthesized in six steps the selenium analogue of psilocine (1c). The key intermediate is the 4- methoxyselenoindoxyl (8), which is condensed with the dimethylaminocarbamoylmethylenetriphenylphosphorane to give the aromatic amide (9a). Its reduction with lithium aluminiumhydride leads to the methoxyamine (9b) which is finally demethylated by sodium ethanethiolate to 1c

(S)-4-Chloro-2-fluorophenylalanine and (S)-(α-methy)-4-chloro-2-fluorophenylalanine were synthesized and labeled with no carrier added (n.c.a.) fluorine-18 through a radiochemical synthesis relying on the highly enantioselective reaction between 4-chloro-2-[18F]fluorobenzyl iodide and the lithium enolate of (2S)-1-(tert-butyloxycarbonyl)-2-(tert-butyl)-3-methyl-1,3-imidazolidine-4-one for (S)-4-chloro-2-[18F]fluorophenylalanine and (2S,5S)-1-(tert-butyloxycarbonyl)-2-(tert-butyl)-3,5-dimethyl-1,3-imidazolidine-4-one for (S)-(α-methyl) -4-chloro-2-[18F] fluorophenylalanine. Quantities of about 20–25 mCi were obtained at the end of sy nthesi s, ready for injection after hydrolysis and high performance liquid chromatography (HPLC) purification, with a radiochemical yield of 17%–20% corrected to the end of bombardment after a total synthesis time of 90–105 min from [18F] fluoride. The enantiomeric excesses were shown to be 97% or more for both molecules without chiral separation and the radiochemical and chemical purities were 98% or better.

Irradiation (λ = 350 nm) of 1H-[2]benzothiopyran-1-one (2) in the solid state affords selectively and in good yield 6aα, 6bα, 12bα, 12cα -tetrahydrocyclobuta[1, 2-c:4, 3-c′]bis([2]benzothiopyran)-5, 8-dione (3), the head-to-head (HH) cis-cisoid-cis-cyclodimer of 2, X-Ray analysis of 2 confirms that this reaction proceeds according to the well-established topochemical principles. The same dimer 3 is obtained in low yields on irradiation of 10−1M solutions of 2 in either MeOH or MeCN, while no conversion at all is observed in benzene. On irradiation of 2 in MeCN in the presence of tetrachloroethene, the [2 + 2] photocycloadduct 4 is formed in good yield, the conversion 2 4 being efficiently quenched by naphthalene. In contrast, no reaction is observed -on irradiation of 2 in the presence of 2, 3-dimethylbut-2-ene, neither in polar nor in apolar solvents.

Tropapride, (exo)-2,3-dimethoxy-N-[8-(phenylmethyl)-8- azabicyclo[3.2.1]oct-3-yl]benzamide hydrochloride, has been labeled with fluorine-18 at the 2- and 4-positions of its benzylic group. Two synthetic pathways were investigated: the first one required the alkylation of the norbenzyl precursor with 2- or 4-[18F]fluorobenzyl bromide (radiochemical yield of 5% EOB, 180 min); the second method consisted of a reductive amination of norbenzyl tropapride with 2- or 4-[18F]fluorobenzaldehyde (20% EOB, 110 min). In both cases, the specific activity was found to be greater than 1 Ci/mumol (EOS). Animal studies in rats showed the percentage of the injected dose localizing in the whole brain to be 0.6 +/- 0.09 and 0.2 +/- 0.03 at 2 h post injection for the para- and the ortho-[18F]fluoro analogs of tropapride respectively. Cerebral biodistribution studies showed at 4 h a striatum uptake of 5 +/- 0.7% of the injected dose per gram of striatum for the para derivative with a low fixation into the frontal cortex and the cerebellum (% ID/g FC0.4 and % ID/g Cb0.3). The selectivity of 4-[18F]fluorotropapride for D2 dopaminergic sites was demonstrated through blocking experiments with ketanserin, spiperone and halopemide. The saturability was confirmed by the use of variable specific activities. These preliminary results showed that 4-[18F]fluorotropapride can be considered as a potent radiopharmaceutical for the study of the dopaminergic system with PET.

The synthesis of 2H-3,4-dihydro-1,2-benzoselenazin-3-ones which are six-membered homologues of Ebselen is described in order to evaluate their glutathione peroxidase-like activity. Spectral data of these new heterocycles are given.

The synthesis of various [18F]fluoroaromatic aldehydes using activated nitro precursors and amino-polyether supported nucleophilic substitution with 18F− is reported. These radiolabelled fluorinated aldehydes (radiochemical yields: 50–75%) are powerful key intermediates leading after treatment with NaBH4 and SOBr2 (SOCL2) to further active intermediates for example substituted [18F]fluorobenzyl bromides (yields 30–50% EOB). These benzaldehydes and bromides are particularly useful for the preparation of new radiopharmaceuticals (e.g. fluorotroprapride, fluorodexetimide) either by reductive amination or by aromatic N-alkylation. The preparation of various amino acids in D, L (50:50) or enriched L form by asymmetric synthesis is also possible (e.g. L -6-[18F]fluorodopa, L -4-[18F]fluoro-m-tyrosine). It can be anticipated that the 18F-labelled fluoroaldehydes will find widespread application in radiopharmaceutical chemistry.

The synthesis of the 7-nitro-2-phenyl-1,2-benzisoselenazol-3(2H)-one 3a leads to an abnormal behavior due to a dipole stabilisation between the nitro group and the selenium atom. The first ever synthesis of a 2,1-benzoxasetenol-3-one 5 is described. The unexpected insertion of a sulfur atom from thionyl chloride results in the formation of the 7-nitro-2,1-benzothiaselenol-3-one 6 .

Ortholithiation reactions are shown to be effective tools for the synthesis of Ebselen (N-phenyl-benzisoselenazolin-3-one) derivatives.

The NCA asymmetric synthesis of l -6-[18F]fluorodopa starting from (1R,2R,5R)-[(+)-2-hydroxypinanyl- 3-idene]glycine t-butyl ester as chiral agent has been developed. After 18F-fluorination of the two commercially available aldehydes either 6-nitroveratraldehyde or 6-nitropiperonal, the required alkylating [18F]fluorobenzyl bromide derivative can be easily prepared by treatment with NaBH4 followed by SOBr2. Alkylation of the Schiff base was carried out with the lithium salt of 2,2,6,6-tetramethylpiperidine as base in anhydrous THF at −78°C. Following hydrolysis of the protecting groups with hydroxylamine and Hl, the l -amino acid was obtained in 75% l form (ee 50%) with a 10% decay corrected (120 min) radiochemical yield.

The synthesis of novel 1,2-benzoselenazin-4-ones which are six-membered homologues of ebselen, is described in order to evaluate their glutathione peroxidase-like activity.

Publisher Summary This chapter describes serine-type D-Ala-D-Ala peptidases and penicillin-binding proteins. Penicillin is a suicide substrate. Because of the endocyclic nature of the scissile β-lactam amide bond, the leaving group of the enzyme acylation step remains part of the acyl enzyme. The first part only of the transfer cycle is achieved, leading to a long-lived; serine ester-linked acyl(penicilloyl)-enzyme and the enzyme behaves as a penicillin-binding protein (PBP). All bacteria possess an assortment of low and high molecular weight membrane-bound PBPs. The low molecular weight PBPs are single catalytic entities. The bulk of the protein is on the outer face of the plasma membrane and bears a carboxy-terminal extension, the end of which serves as membrane anchor. The low molecular weight PBPs helps to control the extent of wall peptidoglycan cross-linking throughout the life cycle of the cells. The high molecular weight PBPs involved in wall peptidoglycan assembly and cell morphogenesis are multimodule proteins. The bulk of the protein is on the outer face of the membrane and consists of an N-terminal module, fused to a C-terminal, penicillin-binding module.

In the crystal structure of the title compound, C9H7NOSe, a potential anti-oxidizing agent, the whole mol­ecule lies in the (0,y,z) plane except for two methyl H atoms, whose positions are symmetry-related across that plane. A close Se⋯Se contact [3.359 (2) A] is observed. There are no hydrogen bonds.

Thioester substrates can be used to study the hydrolysis and transfer reactions catalysed by beta-lactamases and DD-peptidases. With the latter enzymes, accumulation of the acyl-enzyme can be detected directly. The efficiency of various amines as acceptor substrates was in excellent agreement with previous results obtained with peptide substrates of the DD-peptidases. The results indicated the presence of a specific binding site for the acceptor substrates. Although most of the results agreed well with a simple partition model, more elaborate hypotheses will be needed to account for all the data presented.

Reaction of selenolates anions with N-chloroamines affords selenenamides in moderate to good yields.