Sulfur-containing Nucleophiles Research Articles

Mechanistic Studies on Bromocyclization of Unsaturated Thioester by Density Functional Theory and Experiment.

Using sulfur-containing nucleophiles in halocyclization has been underexplored notwithstanding their potential to generate novel S-heterocycles and despite the extensive exploration of oxygen, nitrogen, and carbon nucleophiles. In this study, we focused on the bromocyclization of alkenoic thioesters with N-bromoacetamide, which leads to the formation of cyclic bromosulfides. Investigation into the mechanistic pathways of these reactions revealed that the sulfur atom behaves as a nucleophile, leading to S-acetylsulfonium intermediates. HBr and Br2 played significant roles in these transformations.

In defense of platinum: Amino acidic polydentate ligands as a shield against sulphur-donor nucleophilic attacks

The interactions of sulfur-containing peptides and proteins with platinum-based anticancer agents are of significant interest in the field of bioinorganic chemistry. We previously modified the lead compound potassium {trichlorido[η2-(but-3-en-1-yl)-2-acetoxybenzoate]platinate(II)} (Pt-butene-ASA) by exchanging two chlorido ligands for an amino acid chelating ligand to improve its stability in aqueous solutions. In the current study, we demonstrate how this amino acid ligand strengthens the inertness of this class of complexes against sulfur-containing compounds. We incubated four complexes, each bearing an amino acid chelating ligand, with various sulfur-containing compounds of biological interest, such as DMSO, methionine, glutathione, and substance P. The reactions were monitored using NMR spectroscopy and mass spectrometry, allowing the identification by combination with IR ion spectroscopy of exotic pentacoordinate platinum(II) complexes as reaction intermediates. The results indicated that the reactivity of complexes 1–4 ((ethene,N-trans)(l-alaninato-N,O)chlorido(η2-ethene)platinate(II), (ethene,O-trans)(β-alaninato-N,O)chlorido(η2-ethene)platinate(II), (l-histidinato-N,N)chlorido(η2-ethene)platinate(II), and (olefin,N-trans)(l-alaninato-N,O)chlorido(η2-(but-3-en-1-yl)-2-acetoxy benzoate)platinate(II), respectively) is determined by the inner coordination sphere, and the addition of an amino acid ligand significantly reduces the rate of nucleophilic substitutions by sulfur-containing nucleophiles. In particular, the N,ethylene-trans isomers reacted only to a low extent with the free thiol in glutathione, while the O,ethylene-trans isomer was completely consumed within 2 h. Complex 4, the new lead compound, showed low reactivity towards S-nucleophiles in general, which confirms the concept of using amino acids as biocompatible bidentate ligands to adjust the reactivity and stability of this kind of metallodrugs.

Halogen-Induced Controllable Cyclizations as Diverse Heterocycle Synthetic Strategy.

In organic synthesis, due to their high electrophilicity and leaving group properties, halogens play pivotal roles in the activation and structural derivations of organic compounds. Recently, cyclizations induced by halogen groups that allow the production of diverse targets and the structural reorganization of organic molecules have attracted significant attention from synthetic chemists. Electrophilic halogen atoms activate unsaturated and saturated hydrocarbon moieties by generating halonium intermediates, followed by the attack of carbon-containing, nitrogen-containing, oxygen-containing, and sulfur-containing nucleophiles to give highly functionalized carbocycles and heterocycles. New transformations of halogenated organic molecules that can control the formation and stereoselectivity of the products, according to the difference in the size and number of halogen atoms, have recently been discovered. These unique cyclizations may possibly be used as efficient synthetic strategies with future advances. In this review, innovative reactions controlled by halogen groups are discussed as a new concept in the field of organic synthesis.

Dinuclear ruthenium(II) polypyridyl complexes: Mechanistic study with biomolecules, DNA/BSA interactions and cytotoxic activity

The substitution reactions of dinuclear Ru(II) polypyridyl complexes, i.e. [{RuCl(bpy)2}2(μ-pzn)][PF6]2 (1) and [{RuCl(phen)2}2(μ-pzn)][PF6]2 (2) (bpy = 2,2′-bipyridine, phen = 1,10-phenanthroline, μ-pzn = pyrazine), with mononucleotide guanosine-5′-monophosphate (5′-GMP) and sulfur-containing nucleophiles, such as l-methionine (l-Met) and glutathione (GSH) were studied by UV–Vis spectroscopy. The structures of dinuclear Ru(II) complexes 1 and 2 were preserved during the substitution processes and the calculated enthalpies and entropies of activation (ΔH≠ > 0, ΔS≠ < 0) supported an associative mechanism of substitution. The DNA binding affinity of complexes 1 and 2 was evaluated by UV–Vis, fluorescence emission spectroscopy and by viscosity measurements in aqueous phosphate buffer solution (PBS) at pH 7.40. Additionally, competitive binding reactions with an intercalative agent ethidium bromide (EB) and the known minor groove binder Hoechst 33258 were studied as well. The obtained results indicate that complexes 1 and 2 can interact with DNA through the intercalation and/or minor groove binding, where the latest was preferred. This observation is in a good agreement with the results obtained by molecular docking. Furthermore, both complexes strongly quenched the fluorescence of tryptophan residues in serum albumin (BSA) through both static and dynamic quenching (Ksv = 104–105 M−1). In addition, complexes 1 and 2 showed moderate cytotoxic activity against human breast cancer cells (MDA-MB-231), while both were inactive against human colorectal cancer cells (HCT-116).

Nucleophilic ring-opening of epoxides: trends in β-substituted alcohols synthesis

The present review deals with the ring-opening of epoxides by various carbon, nitrogen, oxygen, halogen, and sulfur-containing nucleophiles, which most of the resulting products are versatile intermediates in the synthesis of various biologically active compounds. The regioselectivity and environmentally benign nature of procedures for the synthesis of similar products have been also discussed in detail.

Synthesis and antiadrenergic properties of β-substituted alcohols based on 6-hydroxymethylpyridoxine

An approach to the synthesis of epoxides based on 6-hydroxymethylpyridoxine acetals was developed. The epoxides obtained were involved in the ring opening reactions by nitrogen-, oxygen-, and sulfur-containing nucleophiles. Cytotoxicity and antiadrenergic properties of some synthesized compounds were studied on the models in situ and in vivo.

Colorimetric and fluorimetric detection of cysteine: Unexpected Michael addition–elimination reaction

The synthesis of three isomers based on Michael addition mechanism for the detection of sulfur-containing species in aqueous solution is described. These compounds are constructed by conjugating an enone to a coumarin fluorophore. A substituted-phenyl (o, m, or p-) was appended at the carbonyl carbon to adjust the reactivity. The experimental results showed that (E)-7-(diethylamino)-3-(3-(3-hydroxyphenyl)-3-oxoprop-1-en-1-yl)-2H-chromen-2-one (m-QPS) and (E)-7-(diethylamino)-3-(3-(4-hydroxyphenyl)-3-oxoprop-1-en-1-yl)-2H-chromen-2-one (p-QPS) barely react with sulfur-containing nucleophiles, while (E)-7-(diethylamino)-3-(3-(2-hydroxyphenyl)-3-oxoprop-1-en-1-yl)-2H-chromen-2-one (o-QPS) exhibited a fast response toward sulfite, sulfide and thiols in DMSO/phosphate buffer (2:1). The above results are probably due to the intramolecular H-bonding activated Michael addition. More interestingly, cysteine triggered unusual photophysical responses of o-QPS: the original absorption (488 nm) and emission peaks (573 nm) underwent significant blue shifts initially and then recovered, which might be caused by the Michael addition and elimination reaction, respectively.

Synthesis of crown ethers with the incorporated cobalt bis(dicarbollide) fragment

A series of podands (acyclic analogues of crown ethers) related to 18-crown-6 was obtained by ring-opening reactions of the 1,4-dioxane derivative of nido-carborane [10-O(CH2CH2)2O-7,8-C2B9H11] with 1,2-S,S′- and O,O′-dinucleophiles (1,2-dimercaptoethane, 1,2-dimercaptobenzene, 1,2-dimercapto-ortho-carborane, 1,2-dihydroxy-ortho-carborane). By stepwise ring-opening reactions of the dioxane derivative with sulfur-containing nucleophiles the podand related to 15-crown-5 was prepared as well. The reactions of the obtained podands with CoCl2 result in the macrocyclic ring closure giving the corresponding crown ethers with the incorporated cobalt bis(dicarbollide) fragment K[8,8′-μ-S(OCH2CH2OCH2CH2)2-3,3′-Co(1,2-C2B9H9)2] and K[8,8′-μ-o-C6H4(OCH2CH2OCH2CH2S)2-3,3′-Co(1,2-C2B9H9)2]. The structure of Na[8,8′-μ-o-C6H4(OCH2CH2OCH2CH2S)2-3,3′-Co(1,2-C2B9H9)2] was determined by single crystal X-ray diffraction.

Bismuth A3-Corroles: Useful Precursors for the Development of meso-Substituted Free-Base Corroles

Systematic studies on regioselective functionalization reactions employing oxygen-, nitrogen-, and sulfur-containing nucleophiles with bismuth A₃-corroles under the influence of a strong non-nucleophilic base are reported. In the case of the thiols and dithiols a high-yielding reaction procedure was established to obtain mono-, di-, and tri-functionalized corroles at room temperature within short reaction times. The described method offers a possibility to attach bifunctional linker molecules to the <i>para</i>-position of the <i>meso-</i>pentafluorophenyl groups at positions 5, 10, and 15 of the corrole macrocycle. The described reaction strategy may serve as a versatile protocol for the covalent binding of corroles to proteins or antibodies and may be utilized to attach corroles on, for example, gold or titanium surfaces to study surface-supported reactions.

Abstract 3427: The dinuclear platinum agent, BBR3610-DACH, exhibits a significant anti-proliferative effect: Regulation of G1/S and G2/M cell cycle arrest and apoptosis induction.

Abstract BBR3610-DACH, a long-chain, bifunctional dinuclear PTII complex with a similar DNA binding mode to the Phase II clinical drug, BBR3464 and its potent analogue, BBR3610, was shown previously to be resistant to metabolic decomposition by sulfur-containing nucleophiles. Initial observations utilizing the alkaline comet assay indicate that BBR3610-DACH forms interstrand crosslinks. Cell cycle analysis using flow cytometry showed that BBR3610-DACH inhibited cell proliferation and caused G1/S and G2/M cell cycle arrest in HCT116 colorectal cells in a time dependent manner accompanied with significant s phase depletion. Similar experiments with synchronized cells showed a distinct G1 phase arrest elicited by the drug following release from arrest. Immunoblotting revealed a stabilization of p53 between 6-24hr after treatment with 20μM (IC90) BBR3610-DACH, with a concomitant increased levels of the cyclin dependent kinase inhibitors, p21 and p27. Cell proliferation assay using MTT and subsequent cell cycle studies with HCT116 p53-/- and HCT116 p21-/- indicated that the cytotoxicity profile of BBR3610-DACH was p21 dependent and partially dependent on the p53 status. However, no change was observed in the protein levels of cyclin E, CDK2, and CDC25A which are G1 phase regulators. Decrease in the levels of cyclin A and cyclin B1 at 24hrs suggested a G2/M block indicative of a possible mitotic catastrophe. Next, we examined whether the DNA damage sensor protein kinases, ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and RAD3 related (ATR) had a role in the cell cycle regulation after drug treatment. Studies using the ATM inhibitor, KU-60019 and caffeine (inhibits both ATM and ATR) revealed no apparent role of ATM but a possible dependence on ATR. Following the cell cycle effects, BBR3610-DACH induced cell death as seen from cleaved poly (ADP-ribose) polymerase-1 (PARP-1) levels as early as 6hrs after drug treatment. Interestingly, no cleaved caspase 3 was seen suggesting a caspase-independent PARP cleavage. Together these findings suggest that BBR3610-DACH is a major cell cycle inhibitory DNA binding platinum agent that could be further developed as a major chemotherapeutic. Citation Format: Vijay Menon, Erica Peterson, Sumitra Deb, Lawrence Povirk, Nicholas Farrell. The dinuclear platinum agent, BBR3610-DACH, exhibits a significant anti-proliferative effect: Regulation of G1/S and G2/M cell cycle arrest and apoptosis induction. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3427. doi:10.1158/1538-7445.AM2013-3427

Simple and Efficient Synthesis of N-Nitroethylenediamine Derivatives

A simple and efficient synthesis of N-nitroethylenediamine derivatives was carried out by reaction of 1-nitroimidazolidin-2-one with various nitrogen-, oxygen-, and sulfur-containing nucleophiles. The reactivity of primary and secondary amines, amino alcohols, hydrazines, amino acids, alcohols, and thiophenol was tested.

ChemInform Abstract: Imidazole-2-thiones: Synthesis, Structure, Properties

Abstract The literature data concerning the methods for preparing imidazole-2-thiones and their benzo analogs have been systematized, and the structure, physico-chemical properties and chemical conversions of these compounds have been considered. The methods for the synthesis of imidazole-2-thiones are classified according to reaction types including cyclization, reactions of halo- and oxoimidazole derivatives with sulfur-containing nucleophiles, and direct insertion of sulfur into position 2 of the imidazole ring. The structure of imidazole-2-thiones is discussed in terms of quantum-chemical calculations, X-ray diffraction data, dipole moments, UV, and IR as well as 1H and 15N NMR spectroscopy. Much attention has been given to nucleophilic addition of imidazole-2-thiones to acetylene and its derivatives as well as to alkenes with an activated double bond. The reactions of imidazole-2-thiones as nucleophilic agents, including alkylation, acylation, and interaction with carbonyl halides are discussed. Some...

ChemInform Abstract: Synthesis and Reactivity of Arenes Coordinated to Cyclopentadienyliron Cations

Abstract Over the past few decades, there has been tremendous interest in the chemistry of arenes coordinated to transition metal moieties due to their applications in the fields of organic and polymer synthesis. The electrophilicity of coordinated arenes allows for reactions with a number of carbon-, oxygen-, nitrogen- and sulfur-containing nucleophiles. This review describes the synthesis and reactivity of both mono- and polyiron arene complexes. Spectroscopic and electrochemical methods for the characterization of these coordination compounds are presented. The important synthetic applications of arene cyclopentadienyliron complexes are also described.

Oxonium derivatives of closo-decaborate in reactions with sulfur-containing nucleophiles

The reaction of the [B10H9O2C4H8]−, [B10H9OC4H8]−, and [B10H9OC5H10]− anions with negatively charged S-nucleophiles, such as SH−, SCN−, and S2O32−, resulted in the ring opening of the cyclic substituent and the formation of derivatives with the terminal thiol, thiocyanate, and thiosulfate groups. The structures of the products were confirmed by the IR, mass, and 1H, 11B, and 13C NMR spectra.

Conformation and recognition of DNA modified by a new antitumor dinuclear PtII complex resistant to decomposition by sulfur nucleophiles

Reported herein is a detailed biochemical and molecular biophysics study of the molecular mechanism of action of antitumor dinuclear PtII complex [{PtCl(DACH)}2-μ-Y]4+ [DACH=1,2-diaminocyclohexane, Y=H2N(CH2)6NH2(CH2)2NH2(CH2)6NH2] (complex 1). This new, long-chain bifunctional dinuclear PtII complex is resistant to metabolic decomposition by sulfur-containing nucleophiles. The results show that DNA adducts of 1 can largely escape repair and yet inhibit very effectively transcription so that they should persist longer than those of conventional cisplatin. Hence, they could trigger a number of downstream cellular effects different from those triggered in cancer cells by DNA adducts of cisplatin. This might lead to the therapeutic effects that could radically improve chemotherapy by platinum complexes. In addition, the findings of the present work make new insights into mechanisms associated with antitumor effects of dinuclear/trinuclear PtII complexes possible.

Trans labilization of am(m)ine ligands from platinum(II) complexes by cancer cell extracts

Cisplatin, cis-[Pt(NH(3))(2)Cl(2)], is an effective anticancer agent in wide clinical use whose efficacy is affected by cellular interactions with sulfur-containing nucleophiles. These interactions can potentially enhance the efficacy of the drug by mediating its delivery to nuclear DNA or inactivate the drug by binding to it irreversibly or by labilizing the NH(3) ligands. Despite the potential importance of trans-labilization reactions in the mechanism of action of the drug, few detailed studies on trans labilization of the ammines have been conducted. We used 2D NMR to show that some trans labilization occurs in proliferating cells and that aqueous extracts of cancer cells labilized 20% of the amine ligands of cis-[PtCl(2)((13)CH(3)NH(2))(2)] after a 12-h incubation. Both low molecular mass nucleophiles (less than 3 kDa) and high molecular mass nucleophiles (more than 3 kDa) labilize the amines with similar efficiency. Studies with model compounds show that thiols and thioethers bind to platinum(II) at similar rates, but thioethers are significantly more efficient at labilizing the am(m)ine at lower pH. N-Acetylcysteine is a more efficient trans-labilizer than glutathione, suggesting that the displacement of the amine proceeds through an associative mechanism. The lag time, the time that elapses from the formation of the Pt-S bond till the release of the amine trans to the sulfur, depends on the pH (for thiols), increasing at lower pH. Quantification of the platinum adducts obtained from incubation of cisplatin with cell extracts indicates that two thirds of the platinum is bound to cellular components with molecular mass greater than 3 kDa.

Kinetics of Cisplatin and Its Monohydrated Complex with Sulfur-Containing Compounds Designed for Local Otoprotective Administration

The anticancer drug cisplatin can cause permanent inner ear damage. We have determined the second-order degradation rate constant, k(Nu), of cisplatin and its more toxic monohydrated complex (MHC) in the presence of each of the sulfur-containing nucleophiles N-acetyl-l-cysteine, l-cysteine methyl ester, 1,3-dimethyl-2-thiourea, d-methionine, and thiosulfate, compounds that are under evaluation for local administration to prevent cisplatin-induced ototoxicity. MHC was isolated from a hydrolysis solution of cisplatin using liquid chromatography (LC). The degradations were evaluated by measuring the disappearance of MHC and cisplatin at 37 degrees C and pH 7.4 in the presence of each of the nucleophiles using LC and photometric detection. The k(Nu) of MHC and of cisplatin was 0.044 M(-1)sec(-1) and 0.012 M(-1)sec(-1) with N-acetyl-l-cysteine, 0.24 M(-1)sec(-1) and 0.067 M(-1)sec(-1) with l-cysteine methyl ester, 0.16 M(-1)sec(-1) and 0.074 M(-1)sec(-1) with 1,3-dimethyl-2-thiourea, 0.070 M(-1)sec(-1) and 0.069 M(-1)sec(-1) with d-methionine, and 3.9 M(-1)sec(-1) and 0.091 M(-1)sec(-1) with thiosulfate, respectively. Our results suggest that thiosulfate, as being the strongest nucleophile, is a promising candidate for local application in order to reduce the inner ear content of MHC and cisplatin. However, otoprotection is a multifactorial event, and it remains to be established how important nucleophilicity is for the effectiveness of the protecting agent.

Differential nephrotoxicity of cisplatin and a novel series of traditional Chinese medicine–platinum anticancer agents correlates with their chemical reactivity towards sulfur-containing nucleophiles

A series of novel traditional Chinese medicine-platinum compounds has been found to be active against a number of murine and human cancers both in vitro and in vivo. Their high potency and the lack of cisplatin cross-resistance are believed to be due to the inclusion of the protein phosphatase 2A-inhibiting demethylcantharidin in the novel structures. A simple reversed-phase high-performance liquid chromatographic method was developed and validated as a stability-indicating assay for the platinum compounds. Using cisplatin and carboplatin as reference compounds, the stability study agrees well with the literature-reported findings. The novel traditional Chinese medicine-platinum compounds were more stable than cisplatin in water and dextrose, but became unstable in normal saline, a characteristic similar to that of carboplatin. The developed assay was further applied to study the chemical reactivity of the novel platinum compounds towards physiologically important nucleophiles such as glutathione and cysteine. The novel compounds were considerably less reactive to the sulfur-containing nucleophiles than cisplatin. In-vitro cytotoxicity assay was performed in a porcine kidney LLC-PK1 cell line model to investigate the nephrotoxicity potential of the platinum compounds. The lower rate of hydrolysis and the decreased reactivity of the novel traditional Chinese medicine-platinum compounds towards sulfur-containing bionucleophiles appear to have reduced their toxicity when compared with cisplatin, yet the antitumor activities of the novel compounds have not been compromised.

N‐(2‐Bromotetrafluoroethyl) Derivatives of Five‐Membered Nitrogen‐Containing Heterocycles.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Reactions of α‐Phosphoryl‐α‐haloacetaldehydes with Difunctional Nucleophiles.

AbstractFor Abstract see ChemInform Abstract in Full Text.