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Marine tricyclic alkaloids lepadiformine and fasicularin, with a unique perhydropyrrolo[2,1- j]quinoline or perhydropyrido[2,1- j]quinoline framework, were synthesized starting from the B ring of the tricyclic system. This approach includes a highly stereocontrolled diallylation of a cyclic enaminoester and subsequent ring-closing metathesis to construct the A/B ring system, which was transformed into key lactams 32 and 33, and amino alcohol 37. Thus, we achieved formal syntheses of (-)-lepadiformines A, C, and (-)-fasicularin in a divergent manner.

The obligate intracellular parasite, Trypanosoma cruzi is the etiologic agent of Chagas disease or American trypanosomiasis, which is the most prevalent parasitic disease in the Americas. The present chemotherapy to control this illness is still deficient particularly in the chronic stage of the disease. The ergosterol biosynthesis pathway has received much attention as a molecular target for the development of new drugs for Chagas disease. Especially, inhibitors of the enzymatic activity of squalene synthase were shown to be effective compounds on T. cruzi proliferation in in vitro assays. In the present study we designed, synthesized and evaluated the effect of a number of isosteric analogues of WC-9 (4-phenoxyphenoxyethyl thiocyanate), a known squalene synthase inhibitor, on T. cruzi growth in tissue culture cells. The selenium-containing derivatives turned out to be extremely potent inhibitors of T. cruzi growth. Certainly, 3-phenoxyphenoxyethyl, 4-phenoxyphenoxyethyl, 4-(3-fluorophenoxy)phenoxyethyl, 3-(3-fluorophenoxy)phenoxyethyl selenocyanates and (±)-5-phenoxy-2-(selenocyanatomethyl)-2,3-dihydrobenzofuran arose as relevant members of this family of compounds, which exhibited effective ED 50 values of 0.084 µM, 0.11 µM, 0.083, µM, 0.085, and 0.075 µM, respectively. The results indicate that compounds bearing the selenocyanate moiety are at least two orders of magnitude more potent than the corresponding skeleton counterpart bearing the thiocyanate group. Surprisingly, these compounds exhibited excellent selectively index values ranging from 900 to 1800 making these molecules promising candidates as antiparasitic agents., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

A cross-metathesis protocol has been developed to provide facile access to highly hindered trisubstituted α-branched olefins, which when coupled with a cationic azaspirocyclization reaction, generates the marine alkaloids (-)-fasicularin 2 and a pro-forma synthesis of (-)-lepadiformine A 1.

Two rhodamine-active probes RBAI (Rhodamine B-di-Aminobenzene-phenyl Isothiocyanate) and RGAI (Rhodamine 6G-di-Aminobenzene-phenyl Isothiocyanate) were designed, synthesized and characterized. The probes were developed as fluorescent and colorimetric chemodosimeters in ethanol-water solution with a broad pH span (5-10) and high selectivity toward Hg 2+ but no significant response toward other common competitive cations. The Hg 2+ -promoted ring opening of spirolactam of the rhodamine moiety induced cyclic guanylation of the thiourea moiety, which resulted in the dual chromo- and fluorogenic observation (off-on). Cytotoxicity and bioimaging studies by L929 living cells and living mice indicated that the probes were negligible cytotoxicity, cell permeable and suitable for detecting Hg 2+ in biological environments. Moreover, the new probes not only displayed excellent abilities for the successful detection of Hg 2+ in L929 living cells and living mice but also able to detect Hg 2+ by adsorbing on solid surfaces and quantitative detection of Hg 2+ in real water samples with good recovery (more than 90%), indicating that they have promising prospect for application for Hg 2+ sensing in environmental and biological sciences., (Copyright © 2017. Published by Elsevier Inc.)

1-Butyl-3-methylimidazolium thiocyanate [BMIM]SCN has been presented on extractive desulfurization of liquid fuel. The FTIR, (1)H-NMR, and C-NMR have been discussed for the molecular confirmation of synthesized [BMIM]SCN. Further, thermal, conductivity, moisture content, viscosity, and solubility analyses of [BMIM]SCN were carried out. The effects of time, temperature, sulfur compounds, ultrasonication, and recycling of [BMIM]SCN on removal of dibenzothiophene from liquid fuel were also investigated. In extractive desulfurization, removal of dibenzothiophene in n-dodecane was 86.5 % for mass ratio of 1:1 in 30 min at 30 °C under the mild process conditions. [BMIM]SCN could be reused five times without a significant decrease in activity. Also, in the desulfurization of real fuels, multistage extraction was examined. The data and results provided in the present paper explore the significant insights of imidazolium-based ionic liquids as novel extractant for extractive desulfurization of liquid fuels.

Organic thiocyanates are important synthetic intermediates to access valuable sulfur-containing compounds. In this review the different methods for their preparation and their synthetic applications will be presented. The literature of the last 15 years will be covered, highlighting selected recent advances in the chemistry of this class of compounds. We hope to offer chemists the tools to have a good grasp of this singular functionality and open the door to further progress in this chemistry.

Reducing dilute aqueous HAuCl4 with sodium thiocyanate (NaSCN) under alkaline conditions produces 2 to 3 nm diameter nanoparticles. Stable grape-like oligomeric clusters of these yellow nanoparticles of narrow size distribution are synthesized under ambient conditions via two methods. The delay-time method controls the number of subunits in the oligoclusters by varying the time between the addition of HAuCl₄ to alkaline solution and the subsequent addition of reducing agent, NaSCN. The yellow oligoclusters produced range in size from ~3 to ~25 nm. This size range can be further extended by an add-on method utilizing hydroxylated gold chloride (Na(+)[Au(OH₄-x)Clx](-)) to auto-catalytically increase the number of subunits in the as-synthesized oligocluster nanoparticles, providing a total range of 3 nm to 70 nm. The crude oligocluster preparations display narrow size distributions and do not require further fractionation for most purposes. The oligoclusters formed can be concentrated >300 fold without aggregation and the crude reaction mixtures remain stable for weeks without further processing. Because these oligomeric clusters can be concentrated before derivatization they allow expensive derivatizing agents to be used economically. In addition, we present two models by which predictions of particle size can be made with great accuracy.

A high-yielding method for the direct thiocyanation of BODIPY dyes is described. In 1,3-dimethyl BODIPYs, the thiocyanato group adds at position 2, whereas the insertion occurs at position 5 in 3-amino BODIPYs. The transformation of the thiocyanato group enables the synthesis of thioalkylated BODIPYs. 2-Thioalkylated BODIPYs and 3-thiocyanato-5-piperidino BODIPYs exhibit interesting spectroscopical features. Hence, the described synthetic methodology can be used for the photophysical tuning of BODIPY dyes.

A novel transition-metal-free cross-coupling method for the one-step synthesis of thiocyanates via the C-S bond cleavage of readily available thioethers with aryl(cyano)-iodonium triflates as the cyanating agent is developed. This process features relatively broad substrate scopes, less-toxic hypervalent iodine reagents, mild operating conditions, excellent functional group compatibilities, and affords various thiocyanates in moderate to good yields.

A new method for the cyanation of thiols and disulfides using cyanobenziodoxol(on)e hypervalent iodine reagents is described. Both aliphatic and aromatic thiocyanates can be accessed in good yields in a few minutes at room temperature starting from a broad range of thiols with high chemioselectivity. The complete conversion of disulfides to thiocyanates was also possible. Preliminary computational studies indicated a low energy concerted transition state for the cyanation of the thiolate anion or radical. The developed thiocyanate synthesis has broad potential for various applications in synthetic chemistry, chemical biology and materials science., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Thiocyanates and trifluoromethyl sulfides are important compounds and have classically been synthesized via multistep procedures together with the formation of significant amounts of byproducts. Herein, we demonstrate an oxidative nucleophilic strategy for the synthesis of thiocyanates and trifluoromethyl sulfides from thiol starting materials using nucleophilic reagents such as TMSCN and TMSCF3 (TMS = trimethylsilyl). In the presence of a 2 × 2 manganese oxide-based octahedral molecular sieve (OMS-2) and potassium fluoride (KF), various structurally diverse thiocyanates and trifluoromethyl sulfides could be synthesized in almost quantitative yields (typically >90%). The presented cyanation and trifluoromethylation reactions proceed through the OMS-2-catalyzed oxidative homocoupling of thiols to give disulfides followed by nucleophilic bond cleavage to produce the desired compounds and thiolate species (herein S-trimethylsilylated thiols). OMS-2 can catalyze oxidative homocoupling of the thiolate species, thus resulting formally in the quantitative production of thiocyanates and trifluoromethyl sulfides from thiols.

Bacterial resistance to commonly used antibiotics has been recognized as a significant global health issue. In this study, we carried out the screening of a family of allylic thiocyanates for their action against a diversity of bacteria and fungi with a view to developing new antimicrobial agents. Allylic thiocyanates bearing halogenated aryl groups, which were readily obtained in two steps from the Morita-Baylis-Hillman adducts, showed moderate-to-high activity against selective pathogens, including a methicillin-resistant S. aureus (MRSA) strain. In particular cases, methyl (Z)-3-(2,4-dichlorophenyl)-2-(thiocyanomethyl)-2-propenoate exhibited antimicrobial activity comparable to the reference antibiotic Imipenem.

Planar (N-benzyl-N-furfuryldithiocarbamato-S,S')(thiocyanato-N)(triphenylphospine)nickel(II), [Ni(bfdtc)(NCS)(PPh3)], (1) was prepared from bis(N-benzyl-N-furfuryldithiocarbamato-S,S')nickel(II), [Ni(bfdtc)2], (2) and characterized by elemental analysis, cyclic voltammetry, electronic, IR and variable temperature (1)H and (13)C NMR spectra. For complex 1, the thioureide vCN value is shifted to higher wavenumber compared to 2 and N(13)CS2 carbon signal observed for 1 is additionally shielded compared to the parent complex 2, suggesting increased strength of the thioureide bond due to the presence of the π-accepting phosphine. In the room temperature (13)C NMR spectrum of 1, two pseudo doublets are observed in the aliphatic region. Variable temperature (13)C NMR spectral studies suggest that the fast thiocyanate exchange appears to be responsible for the appearance of pseudo doublets. Single crystal X-ray structural analysis of 1 and 2 confirm the presence of four coordinated nickel in a distorted square planar arrangement with the NiS2PN and NiS4 chromophores, respectively. The NiS bonds are symmetric in 2 (2.1914(14) and 2.2073(13)Å). But significant asymmetry in NiS bond distances was observed in 1 (2.2202(8)Å and 2.1841Å). This observation clearly supports the less effective trans effect of SCN(-) over PPh3. Cyclic voltammetric studies revealed easier reduction of nickel(II) to nickel(I) in complex 1 compared to 2., (Copyright © 2014 Elsevier B.V. All rights reserved.)

As a part of our project pointed at the search of new safe chemotherapeutic and chemoprophylactic agents against parasitic diseases, several compounds structurally related to 4-phenoxyphenoxyethyl thiocyanate (WC-9), which were modified at the terminal aromatic ring, were designed, synthesized and evaluated as antiproliferative agents against Trypanosoma cruzi, the parasite responsible of American trypanosomiasis (Chagas disease) and Toxoplasma gondii, the etiological agent of toxoplasmosis. Most of the synthetic analogs exhibited similar antiparasitic activity being slightly more potent than the reference compound WC-9. For example, the nitro derivative 13 showed an ED₅₀ value of 5.2 μM. Interestingly, the regioisomer of WC-9, compound 36 showed similar inhibitory action than WC-9 indicating that para-phenyl substitution pattern is not necessarily required for biological activity. The biological evaluation against T. gondii was also very promising. The ED₅₀ values corresponding for 13, 36 and 37 were at the very low micromolar level against tachyzoites of T. gondii., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Two new N3O donor ketoxime Schiff bases (HL(1) and HL(2)) have been synthesized by condensing N,N-dimethylethylenediamine with diacetylmonoxime and benzilmonoxime, respectively in a 1:1 ratio. Reaction of Cu(ClO4)2·6H2O with HL(1) resulted in a discrete oximato-bridged dinuclear Cu(II) complex [Cu2(L(1))2(H2O)2](ClO4)2 (1). The same reaction in presence of NaSCN affords the complex {[Cu(II)2(L(1))2][Cu(I)4(μ(1,3)-SCN)4(μ(1,1,3)-SCN)2]}n (2), where partial Cu(II)→Cu(I) reduction is observed. In 2, arrays of [Cu(II)2(L(1))2](2+) cationic units are inserted in between 2D {[Cu(I)4(SCN)6](2-)}n layers and connected via μ(1,1,3)-SCN(-) links, thus forming a 3D network. On the other hand, reaction of Cu(CH3COO)2 and HL(2) in the presence of NaSCN gave rise to a mixed-valence pentanuclear cluster {[Cu(II)2(L(2))2(NCS)]2[Cu(I)(SCN)(μ(1,1)-SCN)(μ(1,3)-SCN)]} (3) where Cu(II) is also partly reduced to Cu(I). In compound 3, two cationic [Cu(II)2(L(2))2(NCS)](+) units are bridged by the anionic [Cu(I)(SCN)3](2-) unit through long Cu-SCN linkages. The ligands and the complexes have been characterized by elemental analysis, UV/Vis and IR spectroscopy. The complexes are further characterized by single crystal X-ray diffraction and variable temperature magnetic (VTM) studies. Finally a complete magneto-structural correlation has been established between compounds 1-3 and all the characterized Cu dimers with a double NO bridge.

A series of sulforaphane derivatives were synthesized and evaluated in vitro for their cytotoxicity against five cancer cell lines (HepG2, A549, MCF-7, HCT-116 and SH-SY5Y). The pharmacological results showed that many of the derivatives displayed more potent cytotoxicity than sulforaphane (SFN). Furthermore, SFN and derivative 85 could induce cell cycle arrest at S or G2/M phase and cell apoptosis. SFN and 85 exhibited time- and dose-dependent activation on Nrf2 transcription factor, and 85 acted as a more potent Nrf2 inducer than SFN., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

The haloperoxidase-catalyzed in vivo oxidation of thiocyanate ion (SCN(-)) by H(2)O(2) is important for generation of the antimicrobial hypothiocyanite ion (OSCN(-)), which is also susceptible to oxidation by strong in vivo oxidizing agents (i.e., H(2)O(2), OCl(-), OBr(-)). We report a detailed mechanistic investigation on the multistep oxidation of excess SCN(-) with peroxomonosulfate ion (HSO(5)(-) in the form of Oxone) in the range from pH 6.5 to 13.5. OSCN(-) was detected to be the intermediate of this reaction under the above conditions, and a kinetic model is proposed. Furthermore, by kinetic separation of the consecutive reaction steps, the rate constant of the direct oxidation of OSCN(-) by HSO(5)(-) was determined: k(2) = (1.6 ± 0.1) × 10(2) M(-1) s(-1) at pH 13.5 and k(2)(H) = (3.3 ± 0.1) × 10(3) M(-1) s(-1) at pH 6.89. A critical evaluation of the estimated activation parameters of the elementary steps revealed that the oxidations of SCN(-) as well as the consecutive OSCN(-) by HSO(5)(-) are more likely to proceed via 2e(-)-transfer steps rather than 1e(-) transfer.

A number of adducts of copper(I) thiocyanate with bulky tertiary phosphine ligands, and some nitrogen-base solvates, were synthesized and structurally and spectroscopically characterised. CuSCN:PCy3 (1:2), as crystallized from pyridine, is shown by a single crystal X-ray study to be a one-dimensional polymer ...(Cy3P)2CuSCN(Cy3P)2CuSCN... (1) with the four-coordinate copper atoms linked end-on by S-SCN-N bridging thiocyanate groups. A second form (2), obtained from acetonitrile, was also identified and shown by IR and 31P CPMAS NMR spectroscopy to be mononuclear, with the magnitude of the dν(Cu) parameter measured from the 31P CPMAS and the ν(CN) value from the IR clearly establishing this compound as three-coordinate [(Cy3P)2CuNCS]. Two further CuSCN/PCy3 compounds CuSCN:PCy3 (1:1) (3), and CuSCN:PCy3:py (1:1:1) (4) were also characterized spectroscopically, with the dν(Cu) parameters indicating three- and four-coordinate copper sites, respectively. Attempts to obtain a 1:2 adduct with tri-t-butylphosphine have yielded, from pyridine, the 1:1 adduct as a dimer [(Bu(t)3P)((SCN)(NCS))Cu(PBu(t)3)] (5), while similar attempts with tri-o-tolylphosphine (from acetonitrile and pyridine (= L)) resulted in solvated 1:1:1 CuSCN:P(o-tol)3:L forms as dimeric [{(o-tol)3P}LCu((SCN)(NCS))CuL{P(o-tol)3}] (6 and 8). The solvent-free 1:1 CuSCN:P(o-tol)3 adduct (7), obtained by desolvation of 6, was characterized spectroscopically and dν(Cu) measurements from the 31P CPMAS NMR data are consistent with the decrease in coordination number of the copper atom from four (for 6) (P,N(MeCN)Cu,S,N) to three (for 7) (PCuS,N) upon loss of the acetonitrile of solvation. These results are compared with those previously reported for mononuclear and binuclear PPh3 adducts which demonstrate a clear tendency for the copper centre to remain four-coordinate. The IR spectroscopic measurements on these compounds show that bands in the far-IR spectra provide a much more definitive criterion for distinguishing between bridging and terminal bonding than does an often-used empirical rule based on ν(CN) in the mid-IR, which leads to the wrong conclusion in some cases.

A concise approach to various benzisothiazol-3(2H)-one derivatives has been developed by copper-catalyzed the reaction of o-bromobenzamide derivatives with potassium thiocyanate (KSCN) in water. The reaction proceeds via a tandem reaction with S-C bond and S-N bond formation., (© 2012 American Chemical Society)

As part of a comprehensive strategy to the welwitindolinone alkaloids possessing a bicyclo[4.3.1]decane core, we report herein concise asymmetric total syntheses of (-)-N-methylwelwitindolinone C isothiocyanate (2a), (-)-N-methylwelwitindolinone C isonitrile (2b), and (-)-3-hydroxy-N-methylwelwitindolinone C isothiocyanate (3a) from a common tetracyclic intermediate. The crucial vinyl chloride moiety was installed through electrophilic chlorination of a hydrazone, but only after adjustment of reactivity to circumvent a facile skeletal rearrangement. Selective desulfurization and oxidation of 2a provided access to 2b and 3a, respectively. Notably, this work provides corrected (1)H and (13)C NMR spectral data for 3a., (© 2011 American Chemical Society)

Single crystals of cadmium manganese thiocyanate, CdMn(SCN)4 (CMTC) have been successfully synthesized and grown by slow evaporation solution growth technique using water as solvent at room temperature. The crystal was characterized by different techniques for finding its suitability for device fabrications. From the single crystal XRD the crystal system was identified as tetragonal. The functional groups were identified from FTIR analysis. The optical studies have been carried out and found that the tendency of transmission observed from the specimen with respect to the wavelength of light is practically more suitable for the present trends in communication engineering. From the thermal analysis the decomposing temperature of the grown crystal is more significant when compared with the studies performed earlier., (Copyright © 2011 Elsevier B.V. All rights reserved.)

A new inorganic-organic hybrid compound [O2NBzQL]4[Cd(SCN)4(NCS)2] (O2NBzQL=1-(4'-NO2-benzyl)quinolinium cation) has been synthesized and characterized by IR, UV, elemental analysis and X-ray crystallography. Cd(II) atom has an distorted octahedral environment with an N4S2 donor set. In solid state there are three types of face-to-face π-π interactions between adjacent cations and multiform C-H⋯S and C-H⋯N hydrogen bonds between [O2NBzQL]+ cations and cadmium thiocyanate anions. The luminescent properties of the title compound were both investigated in H2O solution and in solid state at room temperature, respectively., (Copyright © 2010 Elsevier B.V. All rights reserved.)

A series of complexes of the type [M(L)(dppe)X2]; where M=Zn(II) or Cd(II); L=4-(2'-thiazolylazo)chlorobenzene (L1), 4-(2'-thiazolylazo)bromobenzene (L2) and 4-(2'-thiazolylazo) iodobenzene (L3); dppe=1,2-bis(diphenylphosphino)ethane; X=N3- or NCS- have been prepared and characterized on the basis of their microanalysis, molar conductance, thermal, IR, UV-vis and 1H NMR spectral studies. IR spectra show that the ligand L is coordinated to the metal atom in bidentate manner via azo nitrogen and thiazole nitrogen. An octahedral structure is proposed for all the complexes. The thermal behavior of the complexes revealed that the thiocyanato complexes are thermally more stable than the azido complexes. All the complexes exhibit blue-green emission with high quantum yield as the result of the fluorescence from the intraligand emission excited state., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Novel quinazolines 4-11, 15 and triazoloquinazolines 12-14 bearing biologically active sulfonamide moieties were synthesized. All the newly synthesized compounds were evaluated for their in vitro anticancer activity against liver cancer cell line (HEPG2). Some of the screened compounds exhibited interesting cytotoxic activity compared to doxorubicin as a reference drug. The most active compounds 13 and 15 were selected and evaluated for their ability to enhance the cell killing effect of gamma-radiation, compound 15 was superior to doxorubicin in radiation combination therapy.

The organoruthenium complex [(eta(6)-hmb)Ru(en)(Cl)][PF6] (hmb is hexamethylbenzene, en is ethylenediamine) undergoes facile aquation and then reacts with KSCN in unbuffered solution to give the S-coordinated thiocyanato product [(eta(6)-hmb)Ru(en)(S-SCN)]+ which slowly converts to the thermodynamically favored N-bound complex [(eta(6)-hmb)Ru(en)(N-NCS)]+ (1+). Complex 1 was synthesized and characterized by X-ray crystallography and mass spectrometry. Despite its lack of hydrolysis over 24 h, complex 1 exhibits moderate cytotoxicity (IC(50) 24 microM) towards the human ovarian cancer cell line A2780, comparable with that of the chlorido analogue which is thought to be activated (towards potential target DNA) via a rapid aquation (Wang et. al. in Proc Natl Acad Sci USA 102:18269-18274, 2005). Detailed kinetic studies suggest that complex 1 binds to guanosine 5'-monophosphate (GMP) through direct N7 substitution of the N-bound SCN ligand. In the presence of a high concentration of chloride (104 mM), however, complex 1 may bind partly to GMP via Cl substitution.

A convergent and high-yielding approach for the asymmetric synthesis of sulforaphane 2 and four analogues differently substituted at the sulfinyl sulfur has been developed. The key step of the synthesis is the diastereoselective synthesis of sulfinate ester 23-S(S), using the DAG (diacetone-D-glucofuranose)-methodology. The biological activity of these compounds as inductors of phase II detoxifying enzyme has been studied by determining their ability to activate the cytoprotective transcription factor Nrf2.

A new and short synthesis of nematocidal natural products, thiocyanatin A and 1,8,16-trihydroxyhexadecane, from readily available starting compounds 1,7-heptanediol and 1,9-nonanediol in six steps is described.

Brassicaceae seed meals produce ionic thiocyanate (SCN (-)), a bioherbicidal compound. This study determined the fate of SCN (-) in a field soil amended with seed meals of Sinapis alba, Brassica juncea, and Brassica napus and quantified crop phytotoxicity by monitoring carrot ( Daucus carota) emergence. Meals were applied at 1 or 2 t ha (-1), and soils were sampled to 35 cm for SCN (-). Maximum SCN (-) (211 micromol kg (-1) of soil) was measured at 5 days in 0-5 cm samples from plots amended with S. alba meal at 2 t ha (-1). Less than 30 micromol of SCN (-) kg (-1) of soil was measured at soil depths below 15 cm. At 44 days, SCN (-) was <15 micromol kg (-1) of soil in all treatments. Emergence inhibition of carrots seeded 15-36 days after meal amendment was found only in S. alba treatments. The rapid decrease of SCN (-) concentrations in Brassicaceae meal-amended soil indicates limited potential for off-site environmental impacts.

Thiocyanation of various aromatic and heteroaromatic compounds has been achieved in the presence of ammonium thiocyanate (NH(4)SCN) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in methanol solution under ultrasound irradiation. An ultrasonic probe of 24 kHz frequency has been used for this study. Whereas the use of ultrasound increases the rate of reactions compared with reactions at reflux conditions, the electron-donor ability of aromatic nucleus enhances also the rate of reaction.

Isothiocyanates (ITCs) are one of the many classes of breakdown products of glucosinolates found in crucifers such as broccoli and are thought to be partially responsible for the reduced risk of degenerative diseases associated with the consumption of vegetables. The production of ITCs such as L-sulforaphane is dependent on the hydrolytic bioactivities of myrosinase, localized both within vegetable tissues and within flora of the human GI tract, and is associated with important cancer chemopreventive activities. We hypothesized that novel isothiocyanates with enhanced chemopreventive properties relative to L-sulforaphane could be identified and that their glucosinolate precursors could be synthesized. From a library of 30 synthetic ITCs, we identified several with bioactivities equal or superior to those of L-sulforaphane. The corresponding non-natural glucosinolate precursors to these novel ITCs were constructed and found to be substrates for myrosinase. By utilizing a novel RP-HPLC assay to monitor myrosinase-dependent hydrolysis reactions, 2,2-diphenylethyl glucosinolate and (biphenyl-2-yl)methyl glucosinolate were shown to exhibit 26.5 and 2.8 %, respectively, of the relative activity of sinigrin and produced their corresponding ITCs in varying yields. These data support the notion that non-natural glucosinolates can act as prodrugs for novel ITCs, with a mechanism of action reliant on their hydrolytic cleavage by myrosinase. Such non-natural glucosinolates may serve as very economical chemopreventive agents for individuals at risk for cancers of and around the GI tract.

Reaction of anomeric thiocyanates with a series of O-alkyl or O-trimethylsilyl phosphite, phenylphosphonite and diphenylphosphinite derivatives afforded the corresponding S-glycosyl thiophosphates, thiophosphonates and thiophosphinates in good yields. These derivatives had been previously applied as glycosyl donors in the synthesis of benzyl glycosides and disaccharides with excellent stereoselectivity.

The nitrile stretching mode of the thiocyanate moiety is a nearly ideal probe for measuring the local electric field arising from the organized environment of the interior of a protein. Nitriles were introduced into three proteins: ribonuclease S (RNase S), human aldose reductase (hALR2), and the reaction center (RC) of Rhodobacter capsulatus, through a facile synthetic scheme for the transformation of cysteine residues into thiocyanatoalanine. Vibrational Stark effect spectroscopy and Fourier transform infrared spectroscopy on the modified proteins demonstrated that thiocyanate residues are a highly general tool for probing electrostatic fields in proteins.

The hypothiocyanate anion (OSCN)(-) is reported to be a major product of the lactoperoxidase/H(2)O(2)/(SCN)(-) system, and this anion is proposed to have significant antimicrobial properties. The collision induced (CID) negative ion mass spectrum of "(OSCN)(-)" has been reported: there is a pronounced parent anion at m/z 74, together with fragment anions at m/z 58 (SCN)(-) and 26 (CN)(-). These fragment anions are consistent with structure (OSCN)(-). However there is also a lesser peak at m/z 42 (OCN(-) or CNO(-)) in this spectrum which is either formed by rearrangement of (OSCN)(-) or from an isomer of this anion. The current theoretical investigation of (OSCN)(-) and related isomers, together with the study of possible rearrangements of these anions, indicates that ground-state singlet (OSCN)(-) is a stable species and that isomerization is unlikely. The three anions (OSCN)(-), (SCNO)(-), and (SNCO)(-) have been synthesized (in the ion source of a mass spectrometer) by unequivocal routes, and their structures have been confirmed by a consideration of their collision induced (negative ion) and charge reversal (positive ion) mass spectra. The CID mass spectrum of (SCNO)(-) shows formation of m/z 42 (CNO(-)), but the corresponding spectra of (OSCN)(-) or (SNCO)(-) lack peaks at m/z 42. Combined theoretical and experimental data support earlier evidence that the hypothiocyanite anion is a major oxidation product of the H(2)O(2)/(SCN)(-) system. However, the formation of m/z 42 in the reported CID spectrum of "(OSCN)(-)" does not originate from (OSCN)(-) but from another isomer, possibly (SCNO)(-).

A very short and efficient enantioselective total synthesis of the tricyclic marine alkaloids (-)-lepadiformine (3), (+)-cylindricine C (1c), and (-)-fasicularin (4) has been developed utilizing the formyloxy 1-azaspiro[4.5]decane 5 as a common intermediate. The key strategic element for the synthesis was the formic acid-induced intramolecular conjugate azaspirocyclization, which proved to be a highly efficient and stereoselective way to rapid construction of the 1-azaspirocyclic substructure of these natural products in a single operation. Thus, the common intermediate 5, synthesized in two steps with 70% overall yield starting from the known (S)-N-Boc-2-pyrrolidinone 7 via the conjugate spirocyclization using an acyclic ketoamide 6, was utilized for the concise and stereoselective total synthesis of (-)-lepadiformine (3), which was accomplished in seven steps with 45% overall yield from 5 (31% yield from 7). The developed strategy based on the conjugate spirocyclization was also applied to the stereoselective total synthesis of (+)-cylindricine C (1c), which was achieved in 10 steps from 5 in 18% overall yield (12% yield from 7). Further application of this approach using 5 led to the synthesis of (-)-fasicularin (4), wherein an extremely efficient method for the introduction of the thiocyanato group via an aziridinium intermediate at the last step was developed. Thus, the highly efficient first enantioselective total synthesis of (-)-fasicularin was accomplished in nine steps with an overall yield of 41% from 5 (28% yield from 7).

An asymmetric formal synthesis of fasicularin (1) is described. This natural product, isolated from the extracts of the marine invertebrate Nephteis fasicularis, has shown modest cytotoxicity towards Vero cells. Fasicularin is among only two members of the cylindricine family of natural products, along with lepadiformine (2), to possess a trans A-B ring junction. Key steps of this approach to 1 involve a siloxy-epoxide semipinacol rearrangement of 5 to 6, a B-alkyl Suzuki-Miyaura coupling reaction by using enol trifluoromethanesulfonate 19 and a substrate-directed hydrogenation reaction of 24. This formal synthesis also highlights the difficulty in the incorporation of the thiocyanate functionality present in 1.

A series of 5-thiocyanatomethyl- and 5-alkyl-3-aryl-1,2,4-oxadiazoles were synthesized and evaluated for their activity against kinetoplastid parasites. Formation of the oxadiazole ring was accomplished through the reaction of benzamidoximes with acyl chlorides, while the thiocyanate group was inserted by reacting the appropriate 5-halomethyl oxadiazole with ammonium thiocyanate. The thiocyanate-containing compounds possessed low micromolar activity against Leishmania donovani and Trypanosoma brucei, while the 5-alkyl oxadiazoles were less active against these parasites. 3-(4-Chlorophenyl)-5-(thiocyanatomethyl)-1,2,4-oxadiazole (compound 4b) displayed modest selectivity for L. donovani axenic amastigote-like parasites over J774 macrophages, PC3 prostate cancer cells, and Vero cells (6.4-fold, 3.8-fold, and 9.1-fold, respectively), while 3-(3,4-dichlorophenyl)-5-(thiocyanatomethyl)-1,2,4-oxadiazole (compound 4 h) showed 30-fold selectivity against Vero cells but was not selective against PC3 cells. In a murine model of visceral leishmaniasis, compound 4b decreased liver parasitemia caused by L. donovani by 48% when given in five daily i.v. doses at 5mg/kg and by 61% when administered orally for 5 days at 50 mg/kg. These results indicate that aromatic thiocyanates hold promise for the treatment of leishmanial infections if the selectivity of these compounds can be improved.

As a continuation of our project aimed at the search for new and safe chemotherapeutic and chemoprophylactic agents against American trypanosomiasis (Chagas' disease), several drugs structurally related to 4-phenoxyphenoxyethyl thiocyanate (4) were designed, synthesized, and evaluated as antiproliferative agents against the parasite responsible for this disease, the hemoflagellated protozoan Trypanosoma cruzi. This thiocyanate derivative was previously shown to be an effective and potent agent against T. cruzi proliferation. Several drugs possessing thiocyanate groups proved to be effective growth inhibitors of T. cruzi growth. Among the designed compounds, it is important to point out the extremely potent activity shown by 11, 23, 38, 53, 90, 99, and 117 against the epimastigote forms of the parasite. All of them exhibited IC(50) values in the low micromolar range, and these values were comparable with those presented by our lead drug 4 and ketokonazole, a well-known antiparasitic agent. The activity displayed by the nitrogen-containing derivative 90 was very promising with IC(50) values of 3.3 microM. Several other thiocyanate derivatives also proved to be very potent inhibitors of the multiplication of T. cruzi epimastigotes, such as compounds 28, 33, 43, 48, 56, 61, 66, 71, 76, and 124. Compound 43 resulted in being a promising drug because it was also very effective against amastigotes, the clinically more relevant form of the parasite. This compound was 3-fold more potent than 4, while 11 showed nearly the same activity as our lead drug against intracellular T. cruzi. It was very surprising that the experimental juvenoid 124, although fairly devoid of activity against epimastigotes, was very effective against intracellular amastigotes growing in myoblasts. The rest of the designed compounds showed a broad degree of inhibitory action, from moderately active drugs to drugs almost devoid of antiparasitic activity. Compound 43 is an interesting example of an effective antichagasic agent that presents excellent prospectives not only as a lead drug but also to be used for further in vivo studies.

The total synthesis of the cytotoxin fasicularin is described. The key steps include the following: (1) an intermolecular Diels-Alder cycloaddition of a 2-(triflamido)acrolein with the dioxolane ketal of trideca-1,3-dien-7-one to establish the trans-perhydroisoquinoline stereochemistry, (2) a stereoelectronically controlled hydride addition to a N(1)-C(2) iminium ion to introduce the equatorial hexyl substituent, and (3) elaboration of the pyrido ring by an internal aldol reaction.

Bioassay-directed fractionation of the EtOH extract of an Oceanapia sp. collected off the northern Rottnest Shelf, Australia, has yielded three novel dithiocyanates, thiocyanatins A (1), B (2a), and C (2b). The structures were determined by detailed spectroscopic analysis and confirmed by total synthesis. In addition to featuring an unprecedented dithiocyanate functionality, thiocyanatins possess an unusual 1,16-difunctionalized n-hexadecane carbon skeleton and are revealed as a hitherto unknown class of nematocidal agent.

This article reports the transformation of O-acetylisophotosantonin, obtained by photochemical rearrangement of santonin, into plagiochiline N, an ent-2,3-secoaromadendrane isolated from Plagiochila ovalifolia. The synthesis was carried out in a sequence involving as the key steps (a) the substitution of the lactone moiety by a gem-dimethylcyclopropane ring through a synthetic intermediate having a C(6)-C(7) double bond and (b) the ozonolysis of the C(2)-C(3) bond followed by cyclization to the dihydropyran ring characteristic of plagiochiline N. Spectroscopic data of the synthetic product fully coincided with the reported data for the natural product.

As a part of our project directed at the search of new chemotherapeutic agents against American trypanosomiasis (Chagas' disease), several drugs possessing the 4-phenoxyphenoxy skeleton and other closely related structures employing the thiocyanate moiety as polar end group were designed, synthesized, and evaluated as antiproliferative agents against Trypanosoma cruzi, the parasite responsible for this disease. These thiocyanate analogues were envisioned bearing in mind the potent activity shown by 4-phenoxyphenoxyethyl thiocyanate (compound 8) taken as lead drug. This compound had previously proved to be an extremely active growth inhibitor against T. cruzi with IC(50) values ranging from the very low micromolar level in epimastigotes to the low nanomolar level in the intracellular form of the parasite. Of the designed compounds, the ethyl thiocyanate drugs connected to nonpolar skeletons, namely, arylthio, 2,4-dichlorophenoxy, ortho-substituted aryloxy, and 2-methyl-4-phenoxyphenoxy (compounds 15, 34, 47, 52, 72, respectively), were shown to be very potent antireplicative agents against T. cruzi. On the other hand, conformationally restricted analogues as well as branched derivatives at the aliphatic side chain were shown to be moderately active against T. cruzi growth. The biological activity of drugs bearing the thiocyanate group correlated quite well with the activity exhibited by their normal precursors, the tetrahydropyranyl ether derivatives, when bonded to the same nonpolar skeleton. Compounds having the tetrahydropyranyl moeity as polar end were proportionally much less active than sulfur-containing derivatives in all cases. Drugs 47 and 72 also resulted to be very active against the amastigote form of the parasite growing in myoblasts; however, they were slightly less active than the lead drug 8. On the other hand, compounds 34 and 52 were almost devoid of activity against myoblasts. Surprisingly, the dithio derivative 15 was toxic for myoblasts.

A new semi-synthetic way to produce glucoraphanin (2), the bio-precursor of the potential anticarcinogen sulforaphane (3), has been developed. Starting from glucoerucin (1), isolated from ripe seeds of Eruca sativa, glucoraphanin was obtained through chemoselective oxidation. Controlled myrosinase-catalysed hydrolysis of this precursor quantitatively afforded sulforaphane.

Several drugs bearing the 4-phenoxyphenoxy skeleton and other closely related structures were designed, synthesized, and evaluated as antiproliferative agents against Trypanosoma cruzi, the etiologic agent of Chagas' disease. The new class of drugs was envisioned by modifying the nonpolar 4-phenoxyphenoxy moiety replacing selected aromatic protons by different groups via electrophilic aromatic substitution reactions as well as introducing a sulfur atom at the polar extreme. Of the designed compounds, sulfur-containing derivatives were shown to be potent antireplicative agents against T. cruzi. Among these drugs, 4-phenoxyphenoxyethyl thiocyanate (compound 56) proved to be an extremely active growth inhibitor of the epimastigote forms of T. cruzi and displayed an IC50 of 2.2 microM. Under the same assay conditions, this drug was much more active than Nifurtimox, one of the drugs currently in clinical use to control this disease. This thiocyanate derivative was also a very active inhibitor against the intracellular form of the parasite at the nanomolar level. Other sulfur derivatives prepared also exhibited very potent antiproliferative action against T. cruzi. The presence of a sulfur atom at the polar extreme for this family of compounds seems to be very important for biological action because this atom was always associated with high inhibition values. 4-Phenoxyphenoxyethyl thiocyanate presents very good prospective not only as a lead drug but also as a potential chemotherapeutic agent.

The present study was undertaken to prepare a novel 4-pyranone compound 5-benzylaxy-2-thiocyanatomethyl-4-pyranone as well as to investigate its effects on neoplastic cell growth. Three cell lines (murine leukemia L1210, human leukemia K562 and rat pituitary GH4C1 cells) were used in our experiments. The cell growth, DNA, RNA, protein synthesis, and cytoplasmatic protein phosphorylation after the treatment of GH4C1 cells with 5-benzyloxy-2-thiocyanatomethyl-4-pyranone were investigated. We found that the above new 4-pyranone derivative at 2.6 microM significantly (p < 0.05) inhibits neoplastic cell growth, and inhibits (p < 0.05) DNA synthesis.

Chemoprevention involves the use of natural or synthetic substances to reduce the risk of developing cancer. Two dietary components capable of mediating chemopreventive activity in animal models by modulation of drug-metabolizing enzymes are sulforaphane, an aliphatic isothiocyanate, and brassinin, an indole-based dithiocarbamate, both found in cruciferous vegetables. We currently report the synthesis and activity of a novel cancer chemopreventive agent, (+/-)-4-methylsulfinyl-1-(S-methyldithiocarbamyl)-butane (trivial name, sulforamate), an aliphatic analogue of brassinin with structural similarities to sulforaphane. This compound was shown to be a monofunctional inducer of NAD(P)H:quinone oxidoreductase [quinone reductase (QR)], a Phase II enzyme, in murine Hepa 1c1c7 cell culture and two mutants thereof. Induction potential was comparable to that observed with sulforaphane (concentration required to double the specific activity of QR, approximately 0.2 microM), but cytotoxicity was reduced by about 3-fold (IC50 approximately 30 microm). In addition, sulforaphane, as well as the analogue, increased glutathione levels about 2-fold in cultured Hepa 1c1c7 cells. Induction of QR was regulated at the transcriptional level. Using Northern blotting techniques, time- and dose-dependent induction of QR mRNA levels were demonstrated in Hepa 1c1c7 cell culture. To further investigate the mechanism of induction, HepG2 human hepatoma cells were transiently transfected with QR-chloramphenicol acetyltransferase plasmid constructs containing various portions of the 5'-region of the QR gene. Sulforaphane and the analogue significantly induced (P < 0.0001) CAT activity at a concentration of 12.5 microM by interaction with the antioxidant responsive element (5-14-fold induction) without interacting with the xenobiotic responsive element. Moreover, both compounds significantly induced mouse mammary QR and glutathione S-transferase activity (feeding of 3 mg/mouse intragastric for 4 days), whereas the elevation of hepatic enzyme activities was less pronounced. Both sulforaphane and the analogue were identified as potent inhibitors of preneoplastic lesion formation in carcinogen-treated mouse mammary glands in organ culture (84 and 78% inhibition at 1 microm, respectively). On the basis of these results, the sulforaphane analogue can be regarded as a readily available promising new cancer chemopreventive agent.

We report the synthesis and structural characterization of the novel Edman-type protein-sequencing reagent 4-(3-pyridinylmethylaminocarboxypropyl) phenyl isothiocyanate. A panel of thiohydantoins prepared from this reagent were found stable during liquid chromatography-electrospray mass spectrometry and were detectable at the low femtomole sensitivity level. Furthermore, the signal detected for these compounds in the mass spectrometer was linear from the low femtomole to the low picomole range. The derivatives showed uv absorbance spectra comparable to their phenylthiohydantoin counterparts. The extinction coefficient for the 4-(3-pyridinylmethylaminocarboxypropyl) phenyl thiohydantoin tyrosine was determined by adsorptive sequence analysis of a synthetic pentapeptide featuring an N-terminal 125I-labeled tyrosine. The sequence data suggest that the reagent will be useful for extended sequence analysis of proteins and peptides using commercially available gas-liquid-phase sequencers.

Three new site-directed irreversible (wash-resistant) ligands for the high-affinity phencyclidine (PCP) binding site associated with the N-methyl-D-aspartate (NMDA) receptor were synthesized and their binding characteristics were studied. (+)-3- And (+)-2-isothiocyanato-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cycl ohepten-5,10 - imine hydrochloride ((+)-8a,b.HCl) were prepared in four steps from the corresponding nitro derivatives (+)-4a,b, which were obtained by nitration of (+)-3 (MK-801). In the same way the optical antipode (-)-8a.HCl was synthesized from (-)-3. At a concentration of 100 nM, the 3-isothiocyanate derivative (+)-8a irreversibly labeled approximately 50% of the (+)-[3H]-3 binding sites, compared to 20 microM needed for its optical antipode (-)-8a and the 2-isothiocyanate (+)-8b. The apparent Ki values for reversible inhibition of (+)-[3H]-3 binding by (+)- and (-)-8a and (+)-8b were 37,838, and 843 nM, respectively. In contrast, metaphit (1b) and etoxadrol m-isothiocyanate (2b), two previously reported irreversible ligands for the PCP binding site, label about 50% of the (+)-[3H]-3 binding sites at 100 microM and 250 nM, respectively, with apparent Ki values for reversible inhibition of 535 and 94 nM. Compound (+)-8a is also a selective affinity ligand, displaying little or no irreversible in vitro affinity at 100 microM for opioid, benzodiazepine, muscarinic, and dopamine receptors. At a 25 microM concentration, (+)-8a caused an irreversible 52% reduction of binding to sigma 1-receptors. Compound (+)-8a is the most potent known electrophilic affinity label for the PCP binding site. Its potency and selectivity should enable it to be a valuable tool for the elucidation of the structure and function of the NMDA receptor-associated PCP binding site in the mammalian central nervous system.

Novel fluorogenic Edman reagents, 7-N,N-dimethylaminosulphonyl-4- (2,1,3-benzoxadiazolyl)isothiocyanate (DBD-NCS) and 7-aminosulphonyl-4-(2,1,3-benzoxadiazolyl)isothiocyanate (ABD-NCS) having no fluorescence themselves were synthesized. The derivatives of amino acids with DBD-NCS fluorescence at 505 nm with excitation at 385 nm. They were separated on a reversed-phase HPLC column and detected at the sub-picomol level. Ala-Phe derivatized with DBD-NCS was cleaved by acid to generate DBD-thiocarbamyl-Ala.

A new radioiodination reagent, 3-iodophenylisothiocyanate (3-IPI) has been developed for coupling to monoclonal antibodies. The starting material, 3-tri-n-butylstannylphenylisothiocyanate was prepared via a reaction of hexabutylditin with 3-bromoaniline, followed by treatment with thiophosgene with an overall yield of 72%. The radioiodination of this tin precursor with Na[125I]I/iodogen in chloroform gave 3-[125I]IPI in 23-55% radiochemical yield and 81-99.6% radiochemical purity. Purification of the impure product by high pressure liquid chromatography increased the radiochemical purity of the product up to 99%. These results suggest that 3-IPI may be a useful ligand for radioiodination and coupling to a variety of monoclonal antibodies.