Formal Syntheses of (-)-Lepadiformines A, C, and (-)-Fasicularin.

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.

Alpha-glucosidase and amylase inhibitory effects of Eruca vesicaria subsp. longirostris essential oils: synthesis of new 1,2,4-triazole-thiol derivatives and 1,3,4-thiadiazole with potential inhibitory activity.

Context: The substantial increase in the number of diabetics has encouraged the search for new pharmacological strategies to face this problem. In this regard, triazole and its derivatives have attracted considerable attention for the past few decades due to their pharmacological significance. Objective: Evaluation of the inhibitory activity of α-glucosidase and α-amylase in essential oils extracted from plant Eruca vesicaria (L) Cav. subsp. longirostris (Brassicaceae) (EVL) and to verify whether the triazoles and thiadiazol bearing the lipophilic 4-methylthiobutyl group synthesized from the essential oil contribute to this activity. Materials and methods: The essential oils were extracted by hydrodistillation from leaf, stem, root, and fruit of EVL, and their chemical compositions were analyzed by gas chromatography and gas chromatography-mass spectrometry. We present here the synthesis of three new types of 1,2,4-triazole-thiol and 1,3,4-thiadiazol and the structures were confirmed by NMR, mass spectrometry. The α-glucosidase and α-amylase inhibitory activities were investigated in vitro. Results: The main compound in fruit, stem, and root was erucin (96.6, 85.3, and 83.7%, respectively). The three essential oils of the fruit, stem, and root have strong inhibitory activity on α-glucosidase and α-amylase; IC50 values of roots were 0.81 ± 0.02 µg/mL and 0.13 ± 0.01 µg/mL, respectively. Derivatives 1 b, 2 b, 3 b, and 2c showed remarkable inhibitory activity against α-glucosidase with potencies better than that of acarbose with IC50 values ranging between 0.49 and 1.43 µM. Conclusions: Current results indicate that ECL fruit essential oil can be used as a natural precursor for the synthesis of triazoles as potential hypoglycemic agents.

Cross-Metathesis Approach to the Tricyclic Marine Alkaloids (-)-Fasicularin and (-)-Lepadiformine A.

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.

Selenium-containing analogues of WC-9 are extremely potent inhibitors of Trypanosoma cruzi proliferation.

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 ED50 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.

Recent advances in the chemistry of organic thiocyanates.

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.

General and practical formation of thiocyanates from thiols.

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.

Thiocyanation of BODIPY dyes and their conversion to thioalkylated derivatives.

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.

Oxidative nucleophilic strategy for synthesis of thiocyanates and trifluoromethyl sulfides from thiols.

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.

Detailed kinetics and mechanism of the oxidation of thiocyanate ion (SCN-) by peroxomonosulfate ion (HSO5(-)). Formation and subsequent oxidation of hypothiocyanite ion (OSCN-).

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 unified route to the welwitindolinone alkaloids: total syntheses of (-)-N-methylwelwitindolinone C isothiocyanate, (-)-N-methylwelwitindolinone C isonitrile, and (-)-3-hydroxy-N-methylwelwitindolinone C isothiocyanate.

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.

Concise approach to benzisothiazol-3(2H)-one via copper-catalyzed tandem reaction of o-bromobenzamide and potassium thiocyanate in water.

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.

Synthesis, reactions and antimicrobial activities of 8-ethoxycoumarin derivatives.

Condensation of 3-acetyl-8-ethoxycoumarin (3) with thiosemicarbazide gave ethylidenehydrazinecarbothioamide 5, which was transformed into the thiazolidin-4-one derivatives 6,7. Interaction of 3 with DMF/POCl(3) gave b-chloroacroline derivative 8. Treatment of 3 with malononitrile gave benzo[c]chromone and 2-aminobenzonitrile derivatives 9 and 10, respectively with respect to the reaction conditions. Condensation of 3-(2-bromoacetyl)-8-ethoxycoumarin (4) with o-phenylenediamine gave 3-(quioxaline-2-yl)-8-ethoxycoumarin hydrobromide (11), while 4 reacted with 2-aminopyridine to give chromenopyridopyrimidine derivative 12. Condensation of 4 with potassium thio-cyanate/methanol gave an unexpected derivative, 2H-chromeno-3-carboxy(methyl-carbonimidic)thioanhydride 16, which upon treatment with (NH(2))(2)·H(2)O gave 3-ethoxy-2-hydroxybenzaldehyde azine 19. Interaction of 4 with thiourea derivatives gave thiazole derivatives 20a-c. The structures of the newly synthesized compounds were confirmed by their spectra data. The newly synthesized compounds were also screened for their antimicrobial activity.

Breakdown products of neoglucobrassicin inhibit activation of Nrf2 target genes mediated by myrosinase-derived glucoraphanin hydrolysis products.

Glucosinolates (GLSs) present in Brassica vegetables serve as precursors for biologically active metabolites, which are released by myrosinase and induce phase 2 enzymes via the activation of Nrf2. Thus, GLSs are generally considered beneficial. The pattern of GLSs in plants is various, and contents of individual GLSs change with growth phase and culture conditions. Whereas some GLSs, for example, glucoraphanin (GRA), the precursor of sulforaphane (SFN), are intensively studied, functions of others such as the indole GLS neoglucobrassicin (nGBS) are rather unknown as are functions of combinations thereof. We therefore investigated myrosinase-treated GRA, nGBS and synthetic SFN for their ability to induce NAD(P)H:quinone oxidoreductase 1 (NQO1) as typical phase 2 enzyme, and glutathione peroxidase 2 (GPx2) as novel Nrf2 target in HepG2 cells. Breakdown products of nGBS potently inhibit both GRA-mediated stimulation of NQO1 enzyme and Gpx2 promoter activity. Inhibition of promoter activity depends on the presence of an intact xenobiotic responsive element (XRE) and is also observed with benzo[a]pyrene, a typical ligand of the aryl hydrocarbon receptor (AhR), suggesting that suppressive effects of nGBS are mediated via AhR/XRE pathway. Thus, the AhR/XRE pathway can negatively interfere with the Nrf2/ARE pathway which has consequences for dietary recommendations and, therefore, needs further investigation.

Synthesis, characterization, and reaction pathways for the formation of a GMP adduct of a cytotoxic thiocyanato ruthenium arene complex.

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.

Enantiopure sulforaphane analogues with various substituents at the sulfinyl sulfur: asymmetric synthesis and biological activities.

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.

Design and synthesis of H2S-donor hybrids: A new treatment for Alzheimer's disease?

Hydrogen sulphide (H2S) is an endogenous gasotransmitter, largely known as a pleiotropic mediator endowed with antioxidant, anti-inflammatory, pro-autophagic, and neuroprotective properties. Moreover, a strong relationship between H2S and aging has been recently identified and consistently, a significant decline of H2S levels has been observed in patients affected by Alzheimer's disease (AD). On this basis, the use of H2S-donors could represent an exciting and intriguing strategy to be pursued for the treatment of neurodegenerative diseases (NDDs). In this work, we designed a small series of multitarget molecules combining the rivastigmine-scaffold, a well-established drug already approved for AD, with sulforaphane (SFN) and erucin (ERN), two natural products deriving from the enzymatic hydrolysis of glucosinolates contained in broccoli and rocket, respectively, endowed both with antioxidant and neuroprotective effects. Notably, all new synthetized hybrids exhibit a H2S-donor profile in vitro and elicit protective effects in a model of LPS-induced microglia inflammation. Moreover, a decrease in NO production has been observed in LPS-stimulated cells pre-treated with the compounds. Finally, the compounds showed neuroprotective and antioxidant activities in human neuronal cells. The most interesting compounds have been further investigated to elucidate the possible mechanism of action.

Identification, synthesis, and enzymology of non-natural glucosinolate chemopreventive candidates.

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.

Synthesis of S-glycosyl thiophosphates, thiophosphonates and thiophosphinates by the Michaelis-Arbuzov rearrangement of anomeric thiocyanates.

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.

Ionic thiocyanate (SCN(-)) production, fate, and phytotoxicity in soil amended with Brassicaceae seed meals.

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.

Ultrasound-assisted thiocyanation of aromatic and heteroaromatic compounds using ammonium thiocyanate and DDQ.

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.