Thiocyanate Derivatives Research Articles

Simple and efficient synthesis of allo- and threo-3,3′-dimethylcystine derivatives in enantiomerically pure form

A simple and efficient method for the synthesis of allo- and threo-3,3′-dimethylcystine derivatives is reported. Various tosyl and bromo derivatives of Cbz-, Boc-, and Fmoc- protected threonine methyl esters have been prepared and subjected to nucleophilic substitution with potassium thiocyanate in acetonitrile to yield the corresponding thiocyanate derivatives in moderate yield. The thiocyanates are readily converted to the corresponding allo- and threo-3,3′-dimethylcystine derivatives via reductive dimerization with benzyltriethylammonium tetrathiomolybdate.

Fluorine-containing aryloxyethyl thiocyanate derivatives are potent inhibitors of Trypanosoma cruzi and Toxoplasma gondii proliferation

As a part of our project aimed at developing new safe chemotherapeutic and chemoprophylactic agents against tropical diseases, fluorine-containing drugs structurally related to 4-phenoxyphenoxyethyl thiocyanate ( 1) 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. This thiocyanate derivative had previously proven to be an effective agent against T. cruzi proliferation. Fluorine-containing thiocyanate derivatives 2 and 3 were threefold more potent than our lead drug 1 against intracellular T. cruzi. The biological evaluation against T. gondii was also very promising. The IC 50 values corresponding to 2 and 3 were at the very low micromolar level against tachyzoites of T. gondii. Both of these drugs are interesting examples of effective antiparasitic agents that have outstanding potential not only as lead drugs but also to be used for further in vivo studies.

Enantioselective Addition of Diethylzinc to Aldehydes in the Presence of Chiral Aprotic Ligands.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Electrochemical thiocyanation of dodecahydro-7,8-dicarba-nido-undecaborate and 7,8-dimethyldecahydro-7,8-dicarba-nido-undecaborate monoanions

Electrochemical thiocyanation of the dodecahydro-7,8-dicarba-nido-undecaborate and 7,8-dimethyldecahydro-7,8-dicarba-nido-undecaborate monoanions afforded thiocyanate derivatives of these compounds, which were isolated as alkylammonium salts. The structures of the synthesized compounds were determined by the data from IR, 1H and 11B NMR, and 11B-11B NMR COSY spectroscopy.

Synthesis of 2-(aminocarbonylmethylthio)-1 H-imidazoles as novel Capravirine analogues

Different analogues of Capravirine (AG-1549) or S-1153 were prepared by synthesis of 2-(5-benzyl-4-isopropyl-1-methyl-2,3-dihydro-1 H-imidazol-2-ylthio)acetamide ( 3a– c), ethyl [5-benzyl-1-(ethoxymethyl)-4-ethyl-1 H-imidazol-2-ylthio]acetate ( 10), 2-[5-alkyl-4-substituted 1-(pyridin-4-ylmethyl)-1 H-imidazol-2-ylthio]acetamides ( 12a– f), and 2-[5-benzyl-1-(benzyloxymethyl)-4-isopropyl-1 H-imidazol-2-ylthio]acetamides ( 14a– l) from their corresponding amino acids through a sequence of reactions: Dakin–West reaction, hydrolysis, condensation with thiocyanate derivatives, alkylation with 2-iodoacetamide and ethyl chloroacetate, and coupling with 4-pyridylmethyl chloride, ethoxymethyl chloride and benzyloxymethyl chloride. All the synthesized compounds were screened for their activity against HIV-1 (wild type) and some of them (especially Capravirine like structures) were found active.

Enantioselective addition of diethylzinc to aldehydes in the presence of chiral aprotic ligands

Optically active amino thiocyanate derivatives of (−)-norephedrine were found to act as effective aprotic ligands for enantioselective addition of diethylzinc to aldehydes. This reaction provided optically active secondary alcohols with ee up to 96%.

Reactive sulfur species: aqueous chemistry of sulfenyl thiocyanates.

Sulfenyl thiocyanate (RSSCN) derivatives of penicillamine (PENSCN) and glutathione (GSSCN) have been synthesized in situ at pH = 0 from equilibrium mixtures that consists of hypothiocyanous acid (HOSCN), thiocyanogen ((SCN)2), and trithiocyanate ((SCN)3-). The electrophilic thiocyanating agent N-thiocyanatosuccinimide (NTS) also reacts with PEN and GSH to yield the corresponding RSSCN derivatives. PENSCN and GSSCN were characterized by NMR, ES-MS, and IR spectroscopy. While stable at pH = 0, at higher pH the RSSCN derivatives decompose to give products that are consistent with hydrolysis and formation of reactive sulfenic acids.

Anion complexation by glycocluster thioureamethyl cavitands: novel ESI-MS-based methods for the determination of Ka values.

A series of saccharide-thiourea functionalized cavitands was prepared in good yields (72-86 %) by reaction of a tetrakis(aminomethyl) cavitand with the thiocyanate derivatives of acetylated glucose, galactose, and cellobiose. The anion complexation behavior of the acetylated and deacetylated glycocluster thioureamethyl cavitands was studied with electrospray ionization mass spectrometry (ESI-MS) in acetonitrile and in a 1:1 acetonitrile/water mixture, respectively. All compounds show a preference for Cl(-). A linear relationship was found between the square root of the intensity and the concentration of the formed host-guest complex. Based on this relationship, novel methods have been developed to determine K(a) values, by means of direct titration and competition experiments.

Design, synthesis, and biological evaluation of aryloxyethyl thiocyanate derivatives against Trypanosoma cruzi.

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.

SYNTHESIS OF SULFUR-CONTAINING HETEROCYCLIC COMPOUNDS BASED ON ISOTHIOCYANATE DERIVATIVES OF PERFLUOROOLEFINS (REVIEW)*

The paper reviews data on the synthesis of heterocyclic compounds with perfluoroalkyl groups based on the reaction of thiocyanate and isothiocyanate derivatives of perfluoroolefins with mononucleophilic reagents (C-, O-, S-, P-, and N-nucleophiles). It was shown that such derivatives are prospective synthons for the production of 1,3-thiazoles and 1,3-thiazolines. The factors affecting the formation of the heterocyclic system are identified.

Synthesis and binding to plant lectins of sulfur-containing analogues of βGal1,3αGalNAc (T-antigen)

Analogues of the tumor-associated T-antigen (βGal1,3αGalNAc) containing 4,6-epidithio and 4,6-thietan modifications were synthesized from the α-allyl glycoside of βGalα1,3G1cNAc via suitable thiocyanate derivatives. Binding to three leguminous lectins as model systems was investigated in an enzyme-linked lectin assay (ELLA) and IC 50 values comparable to the corresponding natural disaccharides T-antigen, lactose and N-acetyllactosamine were found.

Design and synthesis of aryloxyethyl thiocyanate derivatives as potent inhibitors of Trypanosoma cruzi proliferation.

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.

Effects of 4,4′-diisothyocyanatostilbene-2,2′-disulfonic acid on Trypanosoma cruzi proliferation and Ca 2+ homeostasis

Cell viability requires the perfect functioning of the processes controlling ATP and Ca 2+ homeostasis. It is known that cell death caused by a variety of toxins or pathological conditions is associated with a disruption of ATP and Ca 2+ homeostasis. This study shows that 4,4′-diisothyocyanatostilbene-2,2′-disulfonic acid (DIDS) inhibits Trypanosoma cruzi epimastigote cell growth. This thiol-reagent thiocyanate derivative was able to inhibit two ecto-enzymes present in this parasite. The ecto-ATPase and ecto-phosphatase activities were inhibited in a dose-dependent manner ( K i=47.7 and 472.5 μM, respectively), but the 5′nucleotidase and 3′nucleotidase activities were not. DIDS uptake was approached by fluorescence microscopy. Pulse–chase experiments revealed the DIDS accumulation in compartments, presumably endocytic, in the posterior region of epimastigotes. In addition, we show that the T. cruzi mitochondria studied in permeabilized cells are able to accumulate and retain medium Ca 2+ in the absence of DIDS. However, in the presence of increasing concentrations of DIDS (50–200 μM), Ca 2+ transport was inhibited in a dose-dependent manner. DIDS also caused a disruption of the mitochondrial membrane potential, in the same concentration range, thus explaining its effect on Ca 2+ uptake. The presence of EGTA prevented the elimination of the mitochondrial membrane potential (ΔΨ), supporting previous data suggesting that the binding of Ca 2+ to the mitochondrial membrane exposes buried thiols to react with DIDS. This thiocyanate derivative was also able to inhibit Ca 2+ uptake by the endoplasmic reticulum in a dose-dependent manner. Taken together, the data presented here provide further insights into the mechanisms underlying the antiproliferative actions of DIDS in T. cruzi.

Structure-activity relationship of new growth inhibitors of Trypanosoma cruzi.

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.

Synthesis and properties of sym-triazene derivatives 12. Synthesis of 2,4-bis(trichloromethyl)-6-substituted sym-triazenes containing a sterically hindered phenol group

6-Substituted 2,4-bis(trichloromethyl)-sym-triazet:es containing the 2,6-di-tert-butylphenol group are synthesized by simultaneous cyclotrimerization of trichloroacetonitrile with the nitrile or thiocyanate derivative of the sterically hindered phenol in the presence of gaseous HCl. Significant amounts of 2,4,6-tris(trichloromethyl)-sym-triazene are formed as a byproduct.

Synthesis and structure of a series of lanthanide(III) thiocyanate derivatives with THF, [Ln(NCS) 3(THF) 4

The thiocyanate complexes Ln(NCS) 3 · (THF) 4 (Ln = Nd, Eu and Er) have been prepared and their structure was studied in the solid state by X-ray diffractometric methods. They crystallize in the monoclinic space group P2 1/ a with a ranging from 19.279(9) for Nd to 18.980(9) Å for Er; b, c and β have almost constant values: b = 8.11 ± 0.01 Å, c = 17.68 ± 0.05 Å and β = 111.0 ± 0.03°. A peculiar feature of these complexes is the octa-coordination, the dimeric nature and the fact that in the molecule the NCS groups are coordinated as mono (LnNCS) and bidentate (LnNCSLN) ligands. The structural units assume an almost undistorted square antiprismatic coordination geometry; they are linked through bridges of NCS groups. The Ln ⋯ S distances range from 3.10 (Nd) to 3.26 Å (Er); these values correspond to rather weak bond interactions, but are unambiguously recognized as coordinating values in geometrical terms.

Activated thiocyanates in the synthesis of heterocyclic hansa yellow analogues. Synthesis and colour measurements of 1-(5'-imino-4'-phenyl-4',5'-dihydro-1',3',4'-(hiadiazol-2'-yl)-3(pyrid-2'-yl)amiono-1,2,3-trioxopropane 2-arylhydrazone derivatives as dyes for synthetic-polymer fibres

In a sequence of reactions the activated thiocyanate derivative 2 was used to synthesize new Hansa Yellow dyestuffs embodying two heterocyclic moieties. The structure of the dyes was inferred from spectral and analytical data. Spectral behaviour of the dyes indicated that they existed essentially in the hydrazone form (5-C). Dyeings of the compounds on polyester were assessed with a view to evaluating the percentage reflectance of the dyed fibre at different wave-lengths in the visble region and the Kubelka-Munk equation was used to calculate the K S function of the dyed materials.

Reactions of phenothiazine thiocyanate derivatives with dialkyldithiophosphoric acids

The addition products of dialkyldithiophosphoric acids to the C≡N bond in 3-thiocyanatophenothiazine rearrange to give relatively more stable S-(3-phenothiazinyl)-N-dialkoxythiophosphoryldithiocarbamates. An analogous derivative, formed in the reaction of diethyldithiophosphoric acid with 3-thiocyanato-10-ethylphenothiazine, is unstable and decomposes to give 3-mercapto-10-ethylphenothiazine and diethylisothiocyanatothiophosphate. The main pathway in the reaction of dialkyldithiophosphoric acids with 10-(thiocyanatoacetyl)phenothiazine appears to be acid-catalyzed cyclization of the latter to give 4-(10-phenothiazinyl)-3-thiazolin-2-one. However, the formation of 3-dialkoxythiophosphoryl-4-thiazolidinone-2-thiones is also observed in these reactions; these products result from rearrangement of the addition products of dithio acids to C≡N bonds, followed by subsequent heterocyclization via elimination of phenothiazine. The molecular structure of 3-diisopropoxythiophosphoryl-4-thiazolidinone-2-thione was investigated by x-ray structural analysis; the heterocyclic fragment in this molecule exists in an envelope conformation with the nitrogen atom deviating from the plane of the other four atoms.

Assembly of functional rhodopsin requires a disulfide bond between cysteine residues 110 and 187.

Cysteine residues 110 and 187 are essential for the formation of the correct bovine rhodopsin structure (Karnik, S. S., Sakmar, T. P., Chen, H.-B., and Khorana, H. G. (1988) Proc. Natl. Acad. Sci. U. S. A. 85, 8459-8463). We now show that the sulfhydryl groups of these 2 cysteine residues interact to form a disulfide bond. Rhodopsin mutants containing cysteine----serine substitutions were prepared as follows. In one mutant, CysVII, all the 10 cysteine residues of rhodopsin were replaced by serines. A second mutant, CysVIII, contained only C110 and C185; a third mutant, CysIX, contained only C185 and C187 while the fourth mutant, CysX, contained only C110 and C187. Only mutant CysX formed functional rhodopsin. Mutants CysVIII and CysIX reacted with [3H]iodoacetic acid showing the presence of free sulfhydryl groups while mutant CysX was inert to this reagent. CysX reacted with cyanide ion to form a thiocyanate derivative showing the presence of a disulfide bond. The C110-C187 disulfide bond is buried in rhodopsin because reactions with disulfide reducing agents and cyanide ion require prior treatment with denaturants.

Preparation of 1,3-Functionalized Adamantanes by the Lewis Acid Catalyzed Electrophilic Cyclization of 7-Methylenebicyclo[3.3.1]nonan-3-one in the Presence of π- andN-Nucleophiles

Preparation of 1,3-difunctionalized adamantane derivatives from 7-methylenebicyclo[3.3.1] nonane-3-one (1) in the presence of nucleophiles under Lewis acid catalysis is described. Reaction of 1 with benzene using a variety of Lewis acid catalysts gave 1,3-diphenyladamantane (4) as the major product. Trimethylsilyl cyanide and azide efficiently reacted with 1 in the presence of zinc iodide as the catalyst to give good yields of the corresponding 3-trimethylsiloxyadamantyl isocyanide and azide, respectively. Trimethylsilyl isothiocyanate gave a 1:1 mixture of the thiocyanate and isothiocyanate derivatives. Silyl enol ethers, such as those of acetophenone and cyclopentanone, and allyltrimethylsilane also reacted with 1 to afford the corresponding 1,3-difunctionalized adamantanes.