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We have genetically encoded a dithiolane containing amino acid (dtF) in Escherichia coli (E. coli) using a polyspecific aminoacyl-tRNA synthetase (aaRS)/amber suppressor tRNA pair. To demonstrate the utility of dtF for bioapplications, we synthesized gold nanoparticle (AuNP) constructs with a mutant superfolder green fluorescent protein (sfGFP) [sfGFP-AuNP] as a model for the protein-metal conjugation. The resulting sfGFP-AuNP constructs show directional homogeneity and enhanced chemical durability compared to their cysteine analogues toward excess environmental 1,4-dithiothreitol (DTT).

First examples with the unknown tricyclic 4,8b-dihydro-3aH-indeno[1,2-d][1,3]dithiole ring system have been prepared. Also, imidazoles linked in ring position 5 to a ketene dithioacetal and 1,3-dithiane derivatives with an exocyclic cyano- and imidazole-substituted C–C double bond are completely new. All these compounds are either conformationally locked, C-linked or six-ring analogues of the antifungal agent luliconazole. Synthesis and fungicidal activity of these sterol biosynthesis inhibitors are reported.

A various carbazole derivativeswere synthesized for the synthesis 2,3-Dihydro-1H-carbazol-4(9H)-one O-acetyl oxime (3), ethyl 2-(2,3,4,9-tetrahydrospiro[carbazole-1,2'-[1,3]dithiolane]-2-yl)acetate (5), 2- hydroxyethyl {2,3,4,9-tetrahydrospiro[1H-carbazole-1,2'[1,3]dithiolane-4-one]-2-yl}-acetamide (7). These products (3, 5, and 7) were characterized by the spectroscopic techniques (IR, H-1 NMR, C-13 NMR and elemental analysis). Then, the observed FT-IR and NMR peaks of the studied compounds were compared with the calculated values. The FMO analyses disclosed that the (5) would prefer intermolecular interactions more than intramolecular interactions because of its higher energy gap. NBO analyses displayed that the n ->Pi* and Pi ->Pi* interactionswere responsible for the lowering of the stabilization energy. Themolecular docking studies showed that (5) exhibited highest binding affinitywith the human glutathione reductase at binding site (-7.21 kcal/mol). Also, the antioxidant activities were investigated using the CUPRAC method, and TEAC coefficient implied that compound (3) have an antioxidant property. In addition, docking calculations of the compound (3), (5), and(7) were performed on bacterial tyrosinase enzyme and human glutathione reductase protein. (C) 2021 Elsevier B.V. All rights reserved.

Novel imidazole-based ketene dithioacetals show impressive in planta activity against the economically important plant pathogens Alternaria solani, Botryotinia fuckeliana, Erysiphe necator and Zymoseptoria tritici. Especially derivatives of the topical antifungal lanoconazole, which bear an alkynyloxy or a heteroaryl group in the para-position of the phenyl ring, exhibit excellent control of the mentioned phytopathogens. These compounds inhibit 14α -demethylase in the sterol biosynthesis pathway of the fungi. Synthesis routes starting from either benzaldehydes or acetophenones as well as structure-activity relationships are discussed in detail.

A concise total synthesis of tetranorsesquiterpenoids applanatumol Z5 (3), possessing unique 6/5/5 ring system was disclosed with 7-step in 5-pot from commercially available starting materials. The key elements of the synthesis included an unexpected intramolecular dithiolane with alcohol oxidative coupling/deprotection sequence to create the unsaturated lactone as dienophile and a regioselective Diels-Alder reaction to assemble the 6/5/5 tricyclic scaffold including two vicinal quaternary carbon stereocenters. Late stage the diastereo- and regioselective carbonyl reduction led to achieve the total synthesis of (±) applanatumol Z5 (3).

A reproducible electro-assisted method is proposed for the fast and well-controlled formation of mixed binary 1,2-dithiolane-based SAMs on gold electrode from micromolar adsorbate solution concentrations. This has been made possible through the combined use of 1,2-dithiolane derivatives having comparable surface binding affinities, and the application of a moderate cathodic potential to the electrode until an equilibrium binary SAM coverage is reached. Dithiolane derivatives containing distinct redox-active ferrocenyl groups were synthesized and used for simultaneous and quantitative electrochemical monitoring the formation of binary SAMs. The corresponding separate electrochemical responses of each component in the mixed layer allowed for the determination of the adsorbate ratio, affording the overall as well as the individual chemisorption kinetics. Regardless of the different adsorption kinetics, the resulting adsorbate ratios at equilibrium in the SAM were found to be the same as in solution. When reporting the equilibrium surface concentration of the adsorbate as a function of its mole fraction in solution, a clear-cut linear relationship was obtained, making this method particularly useful for controlling and predicting the chemical composition of functional binary SAMs on gold surfaces

The parent compound 1,3-dithiolane L1 reacts with CuI providing the 2D coordination polymer (CP) [{Cu(μ2-I)2Cu}(μ2-L1)2] n (CP1). The Cu⋯Cu distance within the Cu(μ2-I)2Cu rhomboid is temperature-dependent and shrinks from 2.9081(7) (294 K) to 2.8743(5) (100 K). The 1D polymeric compound [{Cu(μ2-Br)}(μ2-L1)] n (CP2) was isolated upon treatment of CuBr with L1 in MeCN solution. Likewise, treatment of L1 with CuCl in a 1:1 ratio results in formation of the unusual 1D CP [{Cu(μ2-Cl)}(μ2-L1)] n (CP3). In contrast to CP1 incorporating dinuclear Cu(μ2-I)2Cu units as connection nodes, the isolated Cu atoms of CP2 and CP3 are bridged by a single μ2-Br or μ2-Cl ligand giving rise to infinite [Cu(μ2-X)Cu] n ribbons. Reaction of ferrocenecarbaldehyde with 1,2-ethanedithiol affords the crystallographically characterized ferrocenyl-dithiolane Fc-C(H)S2C2H4 (L2). L2 was used as organometallic dithioether ligand to assemble, upon treatment with CuI, the original luminescent 1D CP [{Cu2(μ4-I)(μ2-I)}(μ2-L2)] n (CP4), in which both S atoms of one L2 molecule span two copper centers of a meander-shaped infinite (CuI) n ribbon. Upon reaction of L2 with CuBr in a 1:2 ratio, the discrete tetranuclear cluster [{Cu4(μ2-Br)2(μ3-Br)2}(μ2-L2)2(MeCN)2] (CL1) is formed.

A stereoselective synthesis of a C1–C11 building block for the polyol-polyene antibiotic rimocidin has been developed. Its functional groups originate from a disubstituted indane, which underwent Birch reduction, and oxidative cleavage. This provided a dihydropyranone with a β-keto ester side-chain. The latter was subjected to a Noyori hydrogenation (ds > 97:3). An oxy-Michael addition gave a mixture of two spiroketals. Luche reduction then led to three spiroketals in an 80:10:10 ratio. The major spiroketal became isolable by separating one of the by-products chromatographically and the other by a diastereomer-selective thioketalization. The remaining spiroketal was ring-opened to give a dithiolane. Its CO2Me group was converted into the 1,3-dithiane unit of the target compound (i.e., 47) using an odor-reducing work-up procedure, which should prove to be generally useful.

Some N-phenyl lipoamide and 8-mercapto-N-phenyloctanamide derivatives were synthesized and their in vitro antiproliferative activity was evaluated. The experimental results indicated that 8-mercapto-N-phenyloctanamides might be good histone deacetylase inhibitors rather than N-phenyl lipoamides, who had thiol moiety at C6 position. To verify the antiproliferation data on structural basis, in silico docking studies of the representative compounds into the crystal structure of histone deacetylase-like protein using AutoDock 4.0 program were performed. Furthermore, sulfur acetylated 8-mercapto-N-phenyloctanamide improved its in vitro antiproliferative activity, probably due to the increasing of its cell membrane permeability. While the identification of enzymatic target of N-phenyl lipoamides with dithiolane is still ongoing.

Ethylene trithiocarbonate reacted with dimethyl acetylenedicarboxylate to furnish tetramethyl thiopyran-4-spiro-2′-(1,3-dithiolane)-2,3,5,6-tetracarboxylate, a new thiopyran-4-spiro-2′-(1,3-dithiolane) heterocyclic compound, as the minor product together with the major product dimethyl 2-thioxo-1,3-dithiole-4,5-dicarboxylate. The new heterocycle was probably formed through a [2 + 2] cycloaddition between ethylene trithiocarbonate and dimethyl acetylenedicarboxylate followed by a 1,3-dipolar cycloaddition or [4 + 2] cycloaddition. Crystal structure of the new compound revealed that the thiopyran ring and 1,3-dithiolane moiety were perpendicular to each other.

A simple route was developed for the synthesis of optically enriched β-amino-α-keto amides. The highly diastereoselective addition of alkyl dithiolanecarboxylates to optically enriched sulfinimines affords the corresponding β-amino-α-keto esters in which the ketone carbonyl group is protected as a dithiolane. Amidation of the ester functionality with a primary amine proceeds readily at room temperature. Treatment with HCl cleaves the N–S bond of the sulfinyl group to provide a free amine functionality, which can then be incorporated into a peptide. Removal of the dithiolane protecting group under oxidative conditions proceeds without epimerization as exemplified by a model dipeptide.

Newly synthesized naphthalene diimide 1 having two dithiolane moieties at its substituted termini bound to double stranded DNA by threading intercalation and the resulting complex was immobilized on the gold surface through a dithiolane-gold linkage as revealed by quartz crystal microbalance (QCM) experiments. DNA with 20-meric double stranded and 24-meric single stranded regions was indirectly immobilized on the gold electrode using this characteristic of 1. Hybridization efficiency was 92%, a value higher than 50% for a thiolated oligonucleotide under identical conditions. When this electrode was subjected to hybridization with a 124-meric target DNA in the presence of ferrocenylnaphthalene diimide (FND) as an electrochemical hybridization indicator, a large current increase was observed deriving from FND bound in the double stranded region newly formed between the probe and target DNA.

Well-defined and homogeneous, contamination-free self-assembled monolayers (SAMs) were fabricated by the chemisorption of lip-NH-p-C{sub 6}H{sub 4}-N {double_bond} N-p-C{sub 6}H{sub 4}-COOH (lip = {alpha}-lipoyl) onto gold. This adsorbate species is composed of a 1,2-dithiolane-based headgroup, an azobenzene-based (and hence photochromic) spacer unit and a carboxylic acid functional group. The SAM constituents are covalently attached to the substrate by the bidentate thiolate anchor groups and exhibit a strongly tilted binding configuration.

Novel 1,2-dithiolane/chroman hybrids bearing heterocyclic rings such as 1,2,4- and 1,3,4-oxadiazole, 1,2,3-triazole and tetrazole were designed and synthesized. The neuroprotective activity of the new analogues was tested against oxidative stress-induced cell death of glutamate-challenged HT22 hippocampal neurons. Our results show that bioisosteric replacement of amide group in 2-position of the chroman moiety, by 1,3,4-oxadiazole did not affect activity. However, analogue 5 bearing the 1,2,4-oxadiazole moiety showed improved neuroprotective activity. The presence of nitrogen heterocycles strongly influences the neuroprotective activity of 5-substituted chroman derivatives, depending on the nature of heterocycle. Replacement of the amide group of the first generation analogues by 1,2,4-oxadiazole or 1,2,3-triazole resulted in significant improvement of the activity against glutamate induced oxidative stress.

A sulfide with a bicyclic squalene hydrocarbon skeleton present in sediments from various depositional settings and of different geological age has been identified by synthesis of a reference compound. In contrast to previous expectations [cf. Schouten, S., Sinninghe Damste, J.S., de Leeuw, J.W., 1995. A novel triterpenoid carbon skeleton in immature sulphur-rich sediments. Geochimica et Cosmochimica Acta 59, 953–958; Gug, S., Schaeffer, P., Adam, P., Klein, S., Motsch, E., Albrecht, P., 2009. Identification of a sulfide derivative with a bicyclic hydrocarbon skeleton related to squalene. Part I: Synthesis of a dithiane triterpenoid. Organic Geochemistry 40, 876–884.], this sulfide bears two “S-spiro type“ thiolane moities, but not the two thiochromane moieties originally envisaged. The synthesis resulted in the formation of a complex isomeric mixture of compounds, all co-eluting in gas chromatography (GC) in the form of one broad peak, as is the case with the geochemical compound. The spiro-type sulfide was formed by intramolecular sulfurization of a polyunsaturated bicyclic squalene derivative of unknown biological origin. The presence of this sulfide in a number of Triassic to Miocene marine sediments from various and contrasting depositional settings (upwelling environments, shallow continental platforms, lagoonal sub-basins, hypersaline environments), all characterized by strongly anoxic conditions, but with or without photic zone anoxia, indicates that the microorganisms biosynthesizing the precursor bicyclic squalene occupy diverse ecological niches.

In this study, a new synthetic route for the total synthesis of (±)-uleine is described. The important step in the synthesis of this alkaloid consists of an intramolecular cyclization of the D ring of the azocino[4,3- b ]indole skeleton. Reduction of ( N -methyl){3-β-ethyl-4-oxo-2,3,4,9-tetrahydrospiro[1 H -carbazole-1,2′(1,3)dithiolane]-2-yl}-2-acetamide with borane yielded the corresponding ( N -methyl){3-β-ethyl-4-hydroxy-2,3,4,9-tetrahydrospiro[1 H -carbazole-1,2′(1,3)dithiolane]-2-yl}-2-acetamide, which underwent acid-catalyzed ring closure to produce azocino[4,3- b ]indole core. Finally, the synthesis of (±)-uleine was completed through several steps from the azocino[4,3- b ]indole core.

The pyruvate dehydrogenase multienzyme assembly (PDH) generates acetyl coenzyme A and reducing equivalents from pyruvate in a multiple-step process that is a nexus of central metabolism. We report crystal structures of the Geobacillus stearothermophilus PDH E1p subunit with ligands that mimic the prereaction complex and the postdecarboxylation product. The structures implicate residues that help to orient substrates, nurture intermediates, and organize surface loops so that they can engage a mobile lipoyl domain that receives the acetyl group and shuttles it to the next active site. The structural and enzymatic data suggest that H128beta performs a dual role: first, as electrostatic catalyst of the reaction of pyruvate with the thiamine cofactor; and second, as a proton donor in the second reaction of acetyl group with the lipoate. We also identify I206alpha as a key residue in mediating the conformation of active-site loops. We propose that a simple conformational flip of the H271alpha side chain assists transfer of the acetyl group from thiamine cofactor to lipoyl domain in synchrony with reduction of the dithiolane ring.

The C-1'-dithiolane Delta(8)-tetrahydrocannabinol (Delta(8)-THC) amphiphilic analogue (-)-2-(6a,7,10,10a-tetrahydro-6,6,9-trimethylhydroxy-6H-dibenzo[b,d]pyranyl)-2-hexyl-1,3-dithiolane (AMG3) is considered as one of the most potent synthetic analgesic cannabinoid (CB) ligands. Its structure is characterized by rigid tricyclic and flexible alkyl chain segments. Its conformational properties have not been fully explored. Structure-activity relationship (SAR) studies on classical CBs showed that the alkyl side chain is the most critical structural part for the receptor activation. However, reported low energy conformers of classical CB analogues vary mainly in the conformation of their alkyl side chain segment. Therefore, comparative molecular dynamics (MD) simulations of low energy conformers of AMG3 were performed in order to investigate its structural and dynamical properties in two different systems. System-I includes ligand and amphoteric solvent DMSO, simulating the biological environment and system-II includes ligand at active site of the homology models of CB1 and CB2 receptors in the solvent. The trajectory analysis results are compared for the systems I and II. In system-I, the dihedral angle defined between aromatic ring and dithiolane ring of AMG3 shows more resistance to be transformed into another torsional angle and the dihedral angle adjacent to dithiolane ring belonging in the alkyl chain has flexibility to adopt gauche+/- and trans dihedral angles. The rest of the dihedral angles within the alkyl chain are all trans. These results point out that wrapped conformations are dynamically less favored in solution than linear conformations. Two possible plane angles defined between the rigid and flexible segments are found to be the most favored and adopting values of approximately 90 degrees and approximately 140 degrees. In system-II, these values are approximately 90 degrees and approximately 120 degrees. Conformers of AMG3 at the CB1 receptor favor to establish a cis conformation defined between aromatic and dithiolane ring and a trans conformation in the CB2 receptor. These different orientations of ligand inside the binding pocket of CB1 and CB2 receptors may explain its different binding affinity in the two receptors. The results of this study can be applied to other synthetic classical CB ligands to produce low energy conformations and can be of general use for the molecules possessing flexible alkyl chain(s). In addition, this study can be useful when restraint of the alkyl chain is sought for optimizing drug design.

Treatment of substituted 1,3-dithiolanes and 1,3-oxathiolanes with methyl diazoacetate in the presence of Rh 2 (OAc) 4 effects ring expansion to the corresponding substituted 1,4-dithiane-2-carboxylates and 1,4-oxathiane-3-carboxylates. The sulfur ylides initially generated in these reactions undergo Stevens rearrangement in competition with both [2,3]-C–C-sigmatropic rearrangement and intramolecular fragmentation. In the case of 2-styryl-substituted 1,3-oxathiolane and 1,3-dithiolane, ring expansion on one-, three- and four-carbons subsequently takes place.

4-Methyl-3,4-dihydro-2H-1,4-benzoxazin-3-one 1 reacted with CS 2 and halo compounds to give thieno-1,4-benzoxazines 2a , b and 2-(1,3-dithiol-2-yliden)-1,4-benzoxazines 3a , b , respectively. Reaction of compound 1 with cyanoketene S,S diacetal afforded pyrano-1,4-benzoxazine derivatives 4 , 5 . Treatment of compound 1 with bromine in 1:2 molar ratio afforded 2,2-dibromo derivative 6 . Compound 6 reacted with bidentates, or with CS 2 and reactive methylenes to give the corresponding spiro compounds 7a–f and 8a–d , respectively. 2-(2-Bromo-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-3-yliden)malononitrile 10 was allowed to react with ethyl thioglycolate, aniline or benzylamine to yield thiopyrano-1,4-benzoxazine 11 or pyrrolo-1,4-benzoxazines 12a , b , respectively. 2-(1-Ethoxy-methyliden)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-3-one 13 reacted with CS 2 and reactive methylenes or malononitrile to give spiro dithiolane 14a–c and 2-(4-methyl-3-oxo–3,4-dihydro-2H-1,4-benzoxazin-2-ylidenmethyl)malononitri...

We report the ready asymmetric synthesis of nucleoside analogues containing a 1,3-dithiolane ring that mimics the sugar moiety of natural nucleosides. The synthesis is accomplished in three main steps from benzoyloxyethanal 1,3-dithiolane, the key step being its conversion into a chiral monosulfoxide by a modified Sharpless sulfo-oxygenation reaction. The nucleoside analogues were obtained in good overall yields and with excellent enantiomeric excesses. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

Lipoic acid (LA) has gained attention in the late 1940’s as a growth factor for micro-organisms. In 1951 Reed and co-workers [1] isolated 30 mg of this factor form 100 kg of liver and later on the molecular structure of LA (chemical name: 1,2-dithiolane-3-pentanoic acid) was elucidated. The compound has a chiral center at the C3 carbon atom (Fig. 1). Naturally occurring LA has the R configuration. LA is present in most pro– and eukaryotic cells. In our diet it can be found in several products such as meat, liver and heart. LA is considered not to be a vitamin because of possible biosynthesis in man. The physiological function of LA as a component in the pyruvate dehydrogenase complex is now textbook knowledge. In the enzyme complexes LA is linked by an amide bound to the γ-amino group of a lysine residue of the protein, giving the so-called lipoyl group. In this way the dithiolane ring is attached to the enzyme by a relatively long and flexible chain, which makes it possible for this group to react with the catalytic center of other enzymes in the enzyme complexes.

Molecules containing a dithiolane moiety are widely investigated due to their antioxidant properties. The archetypal representative of this class of compounds is lipoic acid and indeed the lipoic acid–dihydrolipoic acid couple is part of the antioxidant defence system of the cell. In the course of a program aiming to find improved antioxidants effective in vivo, we designed, synthesised and pharmacologically investigated new lipoic acid analogs. The salient feature of these structures is the connection, via a thioamide or a thiocarbamate, of a 1,2-dithiolane moiety bearing a carbon chain and a N -alkyl-substituted morpholine ring. It was expected that the antioxidant and chelating properties of these functional groups combined with the basicity of the morpholine ring will impact on the antioxidant as well as on the partition and solubility characteristics of the compounds. Indeed in vitro and in vivo pharmacological investigation showed that these new molecules and especially those containing a thiocarbamate linker possess superior antioxidant properties compared with α-lipoic acid and to the amide or carbamate linker analogs. In particular, some of these compounds efficiently cross the blood brain barrier (BBB) thus providing efficient protection from lethality in a situation of induced oxidative stress. Moreover the absence of the 1,2-dithiolane moiety does not completely abolish antioxidant effects thus demonstrating that these compounds are distinct new chemical entities and not merely lipoic acid prodrugs. The chemical and pharmacological features of these new antioxidants are presented and discussed in the following paper.

Tribenzofenestranes possessing the strained cis,cis,cis.trans[5.5.5.6]-fenestrane skeleton have been synthesized from cis-2.6-diphenylspiro[cyclohexane-1.2 ' -indane]-1 ' .3 ' -diols by twofold cyclodehydration, in striking analogy to the strategy used previously to construct the stereoisomeric all-cis-tribenzo[5.5.5.6]fenestranes from the corresponding trans-diphenylspirodiols. In this manner, both of the parent hydrocarbons, all-cis-tribenzo[5.5.5.6]fenestrane 3 and cis.cis.cis.trans-tribenzo[5.5.5.6]fenestrane 4, have been made accessible from the spirodiketones 5 and 6, respectively. The C6-functionalized derivatives of 4-cis.cis.cis.trans-fenestranol 9 and cis.cis.cis.trans-fenestranone 12-were prepared through cis-diphenylspirotriol 8 and cis-diphenyldispiroacetaldiol 11. by using the same strategy. The cis,cis, cis.trans-[5.5.5.6]fenestrane framework readily epimerizes to the more stable all-cis isomers under basic conditions, but is stable under neutral or acidic conditions. For example, cis,cis.cis.trans-fenestranone 12 yielded all-cis fenestrane 3 under Wolff-Kishner conditions, but cis,cis,cis,trans-isomer 4 under Clemmensen conditions. Epimerization was also circumvented by radical-induced desulfurization of fenestrane dithiolane 15 with nBu(3)SnH/AIBN. producing 4 in excellent yields. A single-crystal X-ray structure analysis of 4 revealed that, in accordance with force field and semi-empirical MO calculations. the extra strain of the benzoannelated cis,cis,cis,trans-[5.5.5.6]fenestratriene framework [E-strain(4)- E-strain(3) = 46 kJ mol(-1)] is due both to the almost perfect boat conformation of the six-membered ring and to considerable bond angle widening at the central non-bridged C4b-Cl5d-C11b unit (121). H/D exchange experiments with the cis cis,cis,trans hydrocarbon 4 under basic conditions demonstrated that the strain-induced epimerization to 3 occurs through direct deprotonation of the "epimeric" benzylic bridgehead C7a-H bond, which was found to be more acidic than the two C-H bonds at the benzhydrylic bridgeheads.

A synthetic study of the dioxolane derivatives of methylenedithio(ethylenedithio)-tetrathiafulvalene (MET), bis(methylenedithio)tetrathiafulvalene (MT), and methylene-dithiotetrathiafulvalene, their dithiolane analogues, and the oxathiolane derivative of MET has been undertaken to explore new organic metals. A practically useful preparation of the biheterocycle-fused 1,3-dithiol-2-ones as building blocks for these dichalcogenolane-linked tetrathiafulvalene (TTF) donors has been realized via the newly developed BF 3 -promoted reactions. The effect of the additional linked dichalcogenolane ring on the electron-donating ability is investigated by cyclic voltammetry. An X-ray crystallographic analysis of the oxathiolane-linked MET reveals that its molecular structure is isostructural with that of its dithiolane analogue but not bulkier than that of its dioxolane analogue. Several of the present TTF donors have produced metallic charge-transfer materials, two of which are characterized by X-ray crystallography. In the crystal structure of the 7,7,8,8-tetracyanoquinodimethane complex of the dioxolane-linked MT that exhibits metallic-like behavior around room temperature, the donor molecules are stacked head-to-tail to form the dimers, which are connected by C-H…O hydrogen bonds. On the other hand, in the metallic AsF 6 salt of the dioxolane-linked MET stable down to 2.0 K, the donor molecules are stacked head-to-head to form two-dimensional sheets despite the dioxolane ring being perpendicularly attached to the MET molecule.

A versatile preparation of an enantiopure aldehyde useful for the asymmetric total synthesis of filipin III was developed using a chiral oxazaborolidinone-promoted asymmetric aldol reaction with a dithiolane silyl nucleophile. The sign and magnitude of the specific rotation of the aldehyde, (4 R ,5 R )-2,2-dimethyl-5-formyl-4-pentyl-1,3-dioxane, were reconfirmed.

The first total synthesis of a potent inflammatory mediator 5-oxo-6(E),8(Z),11(Z),14(Z)-eicosatetraenoic acid (5-oxo-ETE) 2 and its biotransformation product 6,7-dihydro-5-oxo-ETE 5 is reported. A convergent synthesis for the unstable title compounds is accomplished via two synthons, dithiolane aldehyde 13 and bisdienyl phosphonium bromide 19. The synthetic 5-oxo-ETE 2 and its 8,9-trans isomer 3 were used to unequivocally confirm the structure of the biologically derived mediators. In addition, using synthetic 6,7-dihydro-5-oxo-ETE 5 we have been able to identify in neutrophils the formation of 6,7-dihydro-5-oxo-ETE 5.

A pharmacophore derived from the structure of the dithiolane derivative of haloperidol bound in the active site of the HIV-1 protease (HIV-1 PR) has been used to search a three-dimensional database for new inhibitory frameworks. This search identified an FMOC-protected N-tosyl arginine as a lead candidate. A derivative in which the arginine carboxyl has been converted to an amide has been crystallized with HIV-1 PR and the structure has been determined to a resolution of 2.5 A with a final R-factor of 18.5%. The inhibitor binds in an extended conformation that results in occupancy of the S2, S1', and S3' subsites of the active site. Initial structure-activity studies indicate that: (1) the FMOC fluorenyl moiety interacts closely with active site residues and is important for binding; (2) the N(G)-tosyl group is necessary to suppress protonation of the arginine guanidinyl terminus; and (3) the arginine carboxamide function is involved in interactions with the water coordinated to the catalytic aspartyl groups. FMOC-protected arginine derivatives, which appear to be relatively specific and nontoxic, offer promise for the development of useful HIV-1 protease inhibitors.

The chiral oxazaborolidinone-catalysed aldol reaction of a silyl ketene acetal involving a dithiolane moiety with β-silyloxy aldehyde resulted in the production of syn - and anti -1,3-diols with complete stereoselection by the choice of the stereochemistry of the catalyst. This reaction is an elegant example of enantioselective acyclic stereoselection under catalyst control.

Lipoic acid (1,2-dithiolane-3-pentanoic acid) is a pharmacophore with unique antioxidant and cytoprotective properties. We synthesized a library based upon the condensation of natural and unnatural amino acids with the carboxylic acid moiety of lipoic acid. SAR studies were conducted using a cardiac ischemia-reperfusion animal model. Cytoprotective efficacy was associated with the R-enantiomer of the dithiolane. Potency of library compounds was dictated by the acidic strength of the adduct. α- N -[(R)-1,2-dithiolane-3-pentanoyl]- l -glutamyl- l -alanine, designated CMX-2043, was chosen for further pharmacologic evaluation.

The antimicrobial activity of thirteen newly synthesized 4-thiazolidinones (TZONs) and four dithiolane derivatives was assessed against susceptible and resistant bacteria, including MRSA, as well as Candida albicans. The structure-activity relationships revealed that 4-Thiazolidinone derivatives harboring p-chlorophenyl and dicarboxyethyl at the 2-ethenyl and 5-arylidine positions of the thiazolidinone ring display considerable antibacterial properties. No antifungal activity was recorded by all tested compounds against Candida albicans. The possible potentiative (synergistic) effect of the most active compounds to a few commercial antibiotics was also investigated.

Summary Ten semicarbazone and nine thiosemicarbazone 1,3-dithiolanes (α, β and γ) were prepared and tested as radioprotector agents. Dithiolane is well known for its radioprotective properties; this compound protects 78% of mice if 500 mg/kg is administered 15 min before a 850 cGy irradiation dose [1]. For the first time, the combination of a semicarbazone or thiosemicarbazone group with a dithiolane moiety has been achieved within a single molecule. We also studied the potential anticonvulsant activities of these compounds, since benzodiazepines have been observed to greatly decrease radioinduced convulsions. Among the tested compounds, the correlation between the anticonvulsant activity and the radioprotective effect was not systematic.

Glycine decarboxylase consists of four protein components. Its structural and mechanistic heart is provided by the lipoic acid-containing H-protein which undergoes a cycle of reductive methylamination, methylamine transfer and electron transfer. Lipoic acid attached to a specific lysine side chain is assumed to act as a 'swinging arm' conveying the reactive dithiolane ring from one catalytic centre to another. The X-ray crystal structures of two forms of the H-protein have been determined. The lipoate cofactor is located in the loop of a hairpin configuration but following methylamine transfer it is pivoted to bind into a cleft at the surface of the H-protein. The lipoamide-methylamine arm is, therefore, not free to move in aqueous solvent.

Kottamide E, a novel alkaloid containing dibrominated indole enamide, oxalic acid diamide and 4-amino-1,2-dithiolane-4-carboxamide moieties, has been isolated from the New Zealand ascidian Pycnoclavella kottae. Characterisation was achieved by interpretation of spectroscopic data.

We report the synthetic and mechanistic studies on a new cyclic disulfide mitomycin dimer, 7- N ,7′- N ′-(1″,2″-dithiolanyl-3″,5″-dimethylenyl)bismitomycin C ( 8 ), and a diol mitomycin dimer, 7- N ,7′- N ′-(2″,4″-dihydroxy-1″,5″-pentanediyl)bismitomycin C ( 9 ). Mitomycin 8 is a dimer connected by a 1,2-dithiolane (a five-membered cyclic disulfide) linker, and was specifically designed to undergo nucleophilic activation and double DNA alkylations leading to efficient production of DNA interstrand cross-link (DNA ISC) adducts. Disulfide cleavage in 8 would generate two thiol groups that could serve as probes to activate two mitomycin rings. At first, the target mitomycin 8 was synthesized using mitomycin A ( 1 ) and the key intermediate, cyclic disulfide ( 10 ), which was prepared through a seven-step synthetic sequence. Diol mitomycin 9 was also synthesized from 1 and diamine salt 13 . Next, kinetic studies using solvolysis reaction revealed that the activation rates of 8 were much higher than those of 9 and mitomycin C ( 2 ) under nucleophilic conditions provided by Et 3 P presumably due to the presence of a cyclic disulfide unit in 8 . These findings led us to propose a nucleophilic activation pathway for 8 . Then, DNA ISC experiments further revealed that the levels of DNA ISC caused by 8 in the presence of Et 3 P were much higher (97%) than those by 9 (5%) and 2 (4%). More importantly, mitomycin 8 underwent much faster activation and produced slightly higher levels of DNA ISC than the previously reported mitomycins 5 – 7 . Overall, we concluded that 8 was highly efficient for both nucleophilic activation and corresponding DNA ISC formation, and that this differentiation came from the crucial function of the cyclic disulfide unit in 8 .

Two classes of ACK1 inhibitors, 4,5,6-trisubstituted furo[2,3-d]pyrimidin4-amines and 4,5,6-trisubstituted 7H-pyrrolo[2,3-d]pyrimidin-4-amines, were discovered and evaluated as ACK1 inhibitors. Further structural refinement led to the identification of potent and selective dithiolane inhibitor 37.

Rings A and B of the title compounds, C 18 H 15 NO 3 S (1) and C 14 H 15 NS 2 (2), are planar while the hydrogenated C rings are not. The rings in the tetrahydrocarbazole skeleton are twisted with respect to each other

Seventeen β- or γ-oximinoether-1,3-dithiolanes were prepared and tested as radioprotector agents. Dithiolanes are well known for their radioprotective properties, and, for the first time, the combination of an oximinoether group and dithiolane moiety has been achieved within a single molecule. Five molecules 2a, 2d, 3a, 3b and 3j have immediate and sustained radioprotective activity.

The preparation of the following compounds is reported: Cu2(dtt)Cl2, Cu(dtt)X (XCl, Br, I; dtt= 1,3-dithiolane-2-thione). The compounds are diamagnetic and stable to aerial oxidation at room temperature. IR spectroscopic results suggest that the thione-sulfur is involved in the coordination, and that a higher donation of this atom occur in Cu2(dtt)Cl2. Crystals of [Cu2(dtt)Cl2]n are monoclinic, space group P21/c with a=10.970(6), b=13.274(6), c=5.952(5) A, β=92.71(2)°, Z=4. The structure consists of two distinct polymeric chains ···CuClCuCl··· held together by bridging thionic sulfur atoms of the ligand. The Cu atoms in the two chains are different, having a distorted tetrahedral and trigonal coordination, respectively.

By linking the mercapto groups with isopropyl and introducing L-amino acid into the 5-carboxyl of DMSA a class of novel 5-(1-carbonyl-L-amino-acid)-2,2- dimethyl-[1,3]dithiolane-4-carboxylic acids were prepared. Their in vivo activities were evaluated on lead loaded mice at the dose of 0.4 mmol/kg. The results showed that the lead levels of the livers, kidneys, femurs and brains in particular could be efficiently decreased by 0.4 mmol/kg of 5-(1-carbonyl-L-amino-acid)-2,2-dimethyl-[1,3]dithiolane-4-carboxylic acids. The benefit of 5-(1-carbonyl-L-amino-acid)-2,2-dimethyl-[1,3]dithiolane-4-carboxylic acids to the detoxification of the brain lead was attributed to their transmembrane ability. Compared with the lead detoxification efficacy, they did not affect the essential metals such as Fe, Cu, Zn, and Ca of the treated mice. Silico molecular modeling predicted that 5-(1-carbonyl-L-amino-acid)-2,2-dimethyl-[1,3]dithiolane-4-carboxylic acids had no hepatotoxicity.

The syntheses of 3,3-dimethylenedithioaldehydes carring a CO2R, OTHP or OAc group at the ω-position in lineal five-carbon chains are reported. The dithiolane group makes these compounds substitutes of the corresponding unstable β-ketoaldehydes as synthetic five-carbon building blocks.

We report the results of ab initio Hartree-Fock calculations on the geometric and electronic structure and first-order (α) and second-order (β) molecular polarizabilities of a series of push-pull polyene molecules. The acceptor is in all cases an aldehyde group while the donor is either a benzodithia, a dithiolene, or a dithiolane group. The benzodithia polyenal compounds have recently been shown to present among the largest μ-β values ever measured. Theoretical results are found to be in excellent agreement with experimental data

The reactions of metalated trans-1,3-dithiolane 1,3-dioxide (10) with aldehydes have been studied through variations in the metal counterion, reaction temperature, and aldehyde. High yields of addu...

A concise and diastereoselective formal total synthesis of triptolide, a natural product with a wide range of biological properties, is described. The key reaction is an unprecedented 6-endo-Trig cationic cyclization of a 2-alkenyl-1,3-dithiolane precursor induced by TMSOTf as Lewis acid.