Sulfonyl Analogues Research Articles

An attempt to prepare sulfonyl analogues of fotemustine: unexpected rearrangement to sulfamate during nitrosation step

A flexible strategy to access to dialkyl (((N-(2-chloroethyl)-N-sulfamoyl) amino) arylmethyl) phosphonates, as sulfonamidophosphonates precursors of Fotemustine analogues was developed. The last nitrosation step proceeded as a rearrangement to the non expected sulfonate analogues.

Structure-Based design of Marine-derived Meridianin C derivatives as glycogen synthase kinase 3β inhibitors with improved oral bioavailability: From aminopyrimidyl-indoles to the sulfonyl analogues

Glycogen synthase kinase 3β (GSK-3β) has become an attractive target for the treatment of diabetes. Compound I is an indole-based GSK-3β inhibitor designed from the Meridianin C, a marine natural product (MNP) isolated from Aplidium meridianum. However, this compound has a moderate inhibitory activity toward GSK-3β (IC50 = 24.4 μM), moderate glucose uptake (38%), and especially, a low oral bioavailability (F = 11.4%). In the present study, applying the structure-based design strategy, a series of derivatives modified on the indole moiety were synthesized based on the lead compound I, followed by evaluating their cytotoxic activity, antihyperglycemic activity, and kinase inhibitory activity. Among this series, compound 6x with a sulfonyl group displayed the highest glucose uptake (83.5%) in muscle L6 cells, showing much higher inhibitory activity against GSK-3β (IC50 = 5.25 μM). Molecular docking indicated that compound 6x was properly inserted into the ATP-binding binding pocket of GSK-3β with a higher docking score (-8.145 kcal/mol) compared with that of compound I (-6.950 kcal/mol), interpreting the higher kinase inhibitory activity toward GSK-3β. Remarkably, compound 6x showed favorable drug-like properties, including significantly better oral bioavailability (F = 47.4%) and no two-week acute toxicity at a dose of 1 g/kg. Our findings suggest that these MNP-derived sulfonyl indole derivatives could be used as lead compounds for the development of anti-hyperglycemic drugs.

Synthesis and leishmanicidal evaluation of sulfanyl- and sulfonyl-tethered functionalized benzoate derivatives featuring a nitroimidazole moiety.

A series of new nitroimidazole-containing derivatives was synthesized by coupling of 2-[2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethylthio]ethanol with diversely substituted benzoic acids. Upon treatment with m-CPBA, 12 of these sulfanyl compounds were further oxidized to their sulfonyl analogs. All the 26 synthetic compounds were examined for in vitro activity against Leishmania (V.) braziliensis and Leishmania (L.) mexicana, and some of them displayed an efficient antileishmanial activity. Among the compounds tested, the catecholic derivative 2-{[2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl]sulfanyl}ethyl 3,4-dihydroxybenzoate (9a, LC50 = 13 and 11 µM) and the pyrogallolic derivative 2-{[2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl]sulfanyl}ethyl 3,4,5-trihydroxybenzoate (9b, LC50 = 4 and 1 µM) were the most active ones against the two Leishmania strains.

Examination of novel 4-aminoquinoline derivatives designed and synthesized by a hybrid pharmacophore approach to enhance their anticancer activities

In an attempt to develop effective and potentially safe anticancer agents, thirty-six 4-aminoquinoline derived sulfonyl analogs were designed and synthesized using a hybrid pharmacophore approach. The cytotoxicity of these compounds was determined using three breast tumor cell lines (MDA-MB231, MDA-MB468 and MCF7) and two matching non-cancer breast epithelial cell lines (184B5 and MCF10A). Although most of the compounds were quite effective on the breast cancer cells, the compound 7-chloro-4-(4-(2,4-dinitrophenylsulfonyl)piperazin-1-yl)quinoline (13; VR23) emerged as potentially the most desirable one in this series of compounds. Data from the NCI-60 cancer panel screening show that compound 13 is effective on a wide range of different cancers. Importantly, compound 13 is needed up to 17.6-fold less doses to achieve the same IC50 against cancer than non-cancer cells (MDA-MB468 vs MCF10A), suggesting that it can potentially be less toxic to normal cells. Cancer cells formed multiple centrosomes in the presence of compound 13, resulting in the cell cycle arrest at prometa-meta phase. This abnormality leads to eventual cell demise with sub-G1 DNA content typically shown with apoptotic cells. In addition, compound 13 also causes an increase in lysosomal volume in cancer but not in non-cancer cells, which may contribute at least in part to its preferential cancer cell-killing. The cancer cell-killing effect of compound 13 is highly potentiated when combined with either bortezomib or monastrol.

Ferromagnetically-coupled Ni(II) and Co(II) Tetranuclear Cubane Complexes with a Ligand of New Type - Sulfonyl Analogue of β-Diketonates

Ferromagnetically-coupled Ni(II) and Co(II) Tetranuclear Cubane Complexes with a Ligand of New Type - Sulfonyl Analogue of β-Diketonates

A Heck–Matsuda Process for the Synthesis of β‐Arylethenesulfonyl Fluorides: Selectively Addressable Bis‐electrophiles for SuFEx Click Chemistry

AbstractA Heck–Matsuda process for the synthesis of the otherwise difficult to access compounds, β‐arylethenesulfonyl fluorides, is described. Ethenesulfonyl fluoride (i.e., vinylsulfonyl fluoride, or ESF) undergoes β‐arylation with stable and readily prepared arenediazonium tetrafluoroborates in the presence of the catalyst palladium(II) acetate to afford the E‐isomer sulfonyl analogues of cinnamoyl fluoride in 43–97 % yield. The β‐arylethenesulfonyl fluorides are found to be selectively addressable bis‐electrophiles for sulfur(VI) fluoride exchange (SuFEx) click chemistry, in which either the alkenyl moiety or the sulfonyl fluoride group can be the exclusive site of nucleophilic attack under defined conditions, making these rather simple cores attractive for covalent drug discovery.

A Heck-Matsuda Process for the Synthesis of β-Arylethenesulfonyl Fluorides: Selectively Addressable Bis-electrophiles for SuFEx Click Chemistry.

A Heck-Matsuda process for the synthesis of the otherwise difficult to access compounds, β-arylethenesulfonyl fluorides, is described. Ethenesulfonyl fluoride (i.e., vinylsulfonyl fluoride, or ESF) undergoes β-arylation with stable and readily prepared arenediazonium tetrafluoroborates in the presence of the catalyst palladium(II) acetate to afford the E-isomer sulfonyl analogues of cinnamoyl fluoride in 43-97 % yield. The β-arylethenesulfonyl fluorides are found to be selectively addressable bis-electrophiles for sulfur(VI) fluoride exchange (SuFEx) click chemistry, in which either the alkenyl moiety or the sulfonyl fluoride group can be the exclusive site of nucleophilic attack under defined conditions, making these rather simple cores attractive for covalent drug discovery.

Abstract 822: Role of c-Myc in prostate cancer stem-like cell inhibition by sulforaphane

Abstract Chemopreventive efficacy of D,L-sulforaphane (SFN) against prostate cancer has been shown in a transgenic mouse model but the underlying mechanism is not fully understood. The present study demonstrates that c-Myc, which is an oncogenic transcription factor frequently upregulated in human prostate cancer, is a molecular target of SFN. Exposure of human prostate cancer cells (LNCaP, C4-2, and PC-3) and a cell line derived from prostate adenocarcinoma of a transgenic mouse (Myc-CaP) to SFN resulted in a marked decrease in c-Myc protein level. Naturally-occurring thio, sulfinyl, and sulfonyl analogues of SFN were also effective in causing suppression of c-Myc protein level. The c-Myc is a known regulator of cellular metabolism but basal glycolysis was not altered by SFN treatment in empty vector transfected or in c-Myc overexpressing PC-3 cells. The effect of SFN treatment on prostate cancer stem-like cells (pCSC) was also determined as c-Myc is implicated in their maintenance. Analysis of aldehyde dehydrogenase 1 activity, CD49f+ fraction, and sphere forming efficiency revealed dose-dependent inhibition of pCSC in SFN-treated cells. The pCSC inhibition by SFN was partially but significantly attenuated by overexpression of c-Myc. Expression profiling revealed upregulation of a set of stemness genes by c-Myc overexpression but their downregulation by SFN treatment. Finally, oral administration of SFN to Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) mice resulted in a marked decrease in c-Myc protein expression in the adenocarcinoma. In conclusion, this study indicates that c-Myc downregulation contributes to pCSC inhibition by SFN. This investigation was supported by grant CA115498 awarded by the National Cancer Institute. Citation Format: Su-Hyeong Kim, Avani R. Vyas, Shivendra V. Singh. Role of c-Myc in prostate cancer stem-like cell inhibition by sulforaphane. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 822.

Sulforaphane Inhibits c‐Myc‐Mediated Prostate Cancer Stem‐Like Traits

Preventive and therapeutic efficiencies of dietary sulforaphane (SFN) against human prostate cancer have been demonstrated in vivo, but the underlying mechanism(s) by which this occurs is poorly understood. Here, we show that the prostate cancer stem cell (pCSC)-like traits, such as accelerated activity of aldehyde dehydrogenase 1 (ALDH1), enrichment of CD49f+ fraction, and sphere forming efficiency, are attenuated by SFN treatment. Interestingly, the expression of c-Myc, an oncogenic transcription factor that is frequently deregulated in prostate cancer cells, was markedly suppressed by SFN both in vitro and in vivo. This is biologically relevant, because the lessening of pCSC-like phenotypes mediated by SFN was attenuated when c-Myc was overexpressed. Naturally occurring thio, sulfinyl, and sulfonyl analogs of SFN were also effective in causing suppression of c-Myc protein level. However, basal glycolysis, a basic metabolic pathway that can also be promoted by c-Myc overexpression, was not largely suppressed by SFN, implying that, in addition to c-Myc, there might be another SFN-sensitive cellular factor, which is not directly involved in basal glycolysis, but cooperates with c-Myc to sustain pCSC-like phenotypes. Our study suggests that oncogenic c-Myc is a target of SFN to prevent and eliminate the onset of human prostate cancer. J. Cell. Biochem. 117: 2482-2495, 2016. © 2016 Wiley Periodicals, Inc.

Synthesis and biological activity of new metronidazole derivatives

The development of new antimicrobial and antiparasitic agents offers the possibility of generating structures of increased potency. To this end, three sulphonate ester derivatives of metronidazole were synthesized. Treatment of the tosylate analogue with NaSPh and NaN3 gave the thiophenolate and azide derivatives, respectively. Oxidation of phenylthio derivative with mCPBA afforded the sulfonyl analogue. Similarly, cycloaddition of azido-metronidazole with various symmetric acetylene compounds furnished the 1,2,3-triazole analogues. Treatment of dimethyl dicarboxylate metronidazole derivative with guanidine hydrochloride in the presence of base resulted in the formation of the ring-expanded (fat) derivative, triazolo-diazepam derivative of metronidazole. Treatment of chlorometronidazole with silylated quinolones gave the quinolone analogues of metronidazole. The antigardiasis and antifungal activities of the synthesized compounds were investigated. In addition, all synthesized compounds were evaluated for their in vitro anti-HIV activity in MT-4 cells as non-nucleoside reverse transcriptase inhibitors.

ChemInform Abstract: Highly Functionalized Cyclohexa‐1,3‐dienes by Sulfonyl Nazarov Reagents.

AbstractDiphenylsilylprolinol is demonstrated to be an efficient catalyst for sulfonyl analogue Nazarov reagents (I) to afford chiral cyclohexa‐1,3‐dienes in a Diels—Alder reaction manner.

Diphen-yl[(phenyl-sulfan-yl)meth-yl]-λ(5)-phosphane-thione.

The title compound, C19H17PS2, results from the direct deprotonation of di­phenyl­methyl­phosphine sulfide and subsequent reaction with diphenyl di­sulfide. The C—P and C—S bond lengths of 1.8242 (18) and 1.8009 (18) Å, respectively, of the central P—C—S linkage are comparable to those found in the sulfonyl analogue, but are considerably longer than those reported for the dimetallated sulfonyl compound. The dihedral angle between the benzene rings of the di­phenyl­methyl moiety is 69.46 (7)°. No distinct inter­molecular inter­actions are present in the crystal structure.

Anti-Inflammatory Activity of Sulfur-Containing Compounds from Garlic

We identified four anti-inflammatory sulfur-containing compounds from garlic, and their chemical structures were identified as Z- and E-ajoene and oxidized sulfonyl derivatives of ajoene. The sulfur compounds inhibited the production of nitric oxide (NO) and prostaglandin E(2) (PGE(2)) and the expression of the pro-inflammatory cytokines tumor necrosis factor-α, interleukin-1β, and interleukin-6 in lipopolysaccharide (LPS)-activated macrophages. Western blotting and reverse transcription-polymerase chain reaction analysis demonstrated that these sulfur compounds attenuated the LPS-induced expression of the inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) proteins and mRNA. Moreover, these sulfur-containing compounds suppressed the nuclear factor-κB (NF-κB) transcriptional activity and the degradation of inhibitory-κBα in LPS-activated macrophages. Furthermore, we observed that they markedly inhibited the LPS-induced phosphorylations of p38 mitogen-activated protein kinases and extracellular signal-regulated kinases (ERK) at 20 μM. These data demonstrate that the sulfur compounds from garlic, (Z, E)-ajoene and their sulfonyl analogs, can suppress the LPS-induced production of NO/PGE(2) and the expression of iNOS/COX-2 genes by inhibiting the NF-κB activation and the phosphorylations of p38 and ERK. Taken together, these data show that Z- and E-ajoene and their sulfonyl analogs from garlic might have anti-inflammatory therapeutic potential.

ChemInform Abstract: Highly Stereoselective Double Michael Cyclization of 1-Phenylsulfinyl and Sulfonyl Analogues of the Nazarov Reagent.

The base-catalyzed double Michael addition of the β-keto sulfoxide 5 with 2-carbomethoxy-2-cyclohexenone (1) proceeds, after elimination of the sulfoxide moiety during chromatography on silica, to give the dehydrodecalin adduct 6 with high stereoselectivity.

Catalytic Asymmetric Synthesis of β‐Sultams as Precursors for Taurine Derivatives

Beta-sultams, biologically interesting sulfonyl analogues of beta-lactams, have been prepared by an organocatalytic asymmetric formal [2+2]-cycloaddition approach of non-nucleophilic imines with alkyl sulfonyl chlorides. In the case of very electron poor N-tosyl imines derived from chloral or ethylglyoxylate, this reaction type was catalyzed by cinchona alkaloids providing the heterocycles in high yield, with good diastereoselectivity and up to 94% ee. Mechanistic investigations suggested that the product formation proceeded via a zwitterionic imine-catalyst adduct. The scope was significantly extended by 2-pyridylsulfonyl imines derived from non-activated aromatic aldehydes employing Yb(OTf)3 as Lewis acid cocatalyst. The synthetic value of the strained enantioenriched beta-sultams was demonstrated by smooth nucleophilic ring opening reactions with O-, N- and C-nucleophiles yielding a variety of acyclic beta-aminosulfonyl (taurine) derivatives (sulfonates, sulfonamides, sulfones) without racemization or epimerization.

D,l-Sulforaphane causes transcriptional repression of androgen receptor in human prostate cancer cells

D,L-Sulforaphane (SFN), a synthetic analogue of cruciferous vegetable-derived L-isomer, inhibits the growth of human prostate cancer cells in culture and in vivo and retards cancer development in a transgenic mouse model of prostate cancer. We now show that SFN treatment causes transcriptional repression of androgen receptor (AR) in LNCaP and C4-2 human prostate cancer cells at pharmacologic concentrations. Exposure of LNCaP and C4-2 cells to SFN resulted in a concentration-dependent and time-dependent decrease in protein levels of total AR as well as Ser(210/213)-phosphorylated AR. The SFN-mediated decline in AR protein level was accompanied by a decrease in intracellular as well as secreted levels of prostate-specific antigen, an AR-regulated gene product. The decrease in AR protein level resulting from SFN exposure was not reversed in the presence of the protein synthesis inhibitor cycloheximide. Reverse transcription-PCR analysis revealed a dose-dependent decrease in AR mRNA levels, indicating transcriptional repression of this ligand-activated transcription factor. The SFN treatment inhibited AR promoter activity as revealed by luciferase reporter assay. Synthetic androgen (R1881)-stimulated nuclear translocation of AR was markedly suppressed in the presence of SFN in both cell lines. The SFN treatment also inhibited R1881-stimulated proliferation of LNCaP cells. Naturally occurring thio analogues (iberverin, erucin, and berteroin), but not the sulfonyl analogues (cheirolin, erysolin, and alyssin sulfone), of SFN were also effective in reducing protein levels of AR in LNCaP cells. In conclusion, the present study shows for the first time that SFN treatment causes transcriptional repression of AR and inhibition of its nuclear localization in human prostate cancer cells.

Catalytic Asymmetric Formation of β-Sultams

beta-Sultams, highly strained sulfonyl analogues of beta-lactams, were prepared enantio- and diastereoselectively by tertiary amine catalyzed [2 + 2] cycloaddition reactions. The title compounds are practical precursors of highly enantioenriched biologically interesting beta-aminosulfonyl derivatives.

Analysis of Mammalian Carboxylesterase Inhibition by Trifluoromethylketone-Containing Compounds

Carboxylesterases (CE) are ubiquitous enzymes that hydrolyze numerous ester-containing xenobiotics, including complex molecules, such as the anticancer drugs irinotecan (CPT-11) and capecitabine and the pyrethroid insecticides. Because of the role of CEs in the metabolism of many exogenous and endogenous ester-containing compounds, a number of studies have examined the inhibition of this class of enzymes. Trifluoromethylketone-containing (TFK) compounds have been identified as potent CE inhibitors. In this article, we present inhibition constants for 21 compounds, including a series of sulfanyl, sulfinyl, and sulfonyl TFKs with three mammalian CEs, as well as human acetyl- and butyrylcholinesterase. To examine the nature of the slow tight-binding inhibitor/enzyme interaction, assays were performed using either a 5-min or a 24-h preincubation period. Results showed that the length of the preincubation interval significantly affects the inhibition constants on a structurally dependent basis. The TFK-containing compounds were generally potent inhibitors of mammalian CEs, with Ki values as low as 0.3 nM observed. In most cases, thioether-containing compounds were more potent inhibitors then their sulfinyl or sulfonyl analogs. QSAR analyses demonstrated excellent observed versus predicted values correlations (r2 ranging from 0.908-0.948), with cross-correlation coefficients (q2) of approximately 0.9. In addition, pseudoreceptor models for the TKF analogs were very similar to structures and models previously obtained using benzil- or sulfonamide-based CE inhibitors. These studies indicate that more potent, selective CE inhibitors, containing long alkyl or aromatic groups attached to the thioether chemotype in TFKs, can be developed for use in in vivo enzyme inhibition.

Conformational and stereoelectronic investigation of chloromethyl methyl sulfide and its sulfinyl and sulfonyl analogs

The rotational equilibria of some sulfur-containing model compounds were theoretically determined, and a rationalization of the effects responsible for the results obtained is given. Experimental approaches, namely NMR and infrared, were also used to show the gauche (Cl C S CH 3 fragment) prevalence for these compounds and allowed us to elucidate the orbital interactions involved in such systems. The gauche rotamer of the sulfide is about 3.2 kcal mol −1 more stable than anti in the gas phase. For the sulfinyl derivative the relative energies for the most stable rotamers are 0.0, 1.0 and 1.7 kcal mol −1, corresponding to gauche-1 (C Cl antiperiplanar to S O), gauche-2 (C Cl antiperiplanar to lone pair) and anti. The calculated energy difference ( anti-gauche) between the sulfonyl rotamers is 2.6 kcal mol −1. Natural bond orbital analysis indicated that the anomeric effect ( n S → σ C Cl ∗ ) plays the main role in stabilization of gauche in the sulfide compound, and that other important hyperconjugative interactions also occur for the remaining compounds.

Different Transition-State Structures for the Reactions of β-Lactams and Analogous β-Sultams with Serine β-Lactamases

Beta-sultams are the sulfonyl analogues of beta-lactams, and N-acyl beta-sultams are novel inactivators of the class C beta-lactamase of Enterobacter cloacae P99. They sulfonylate the active site serine residue to form a sulfonate ester which subsequently undergoes C-O bond fission and formation of a dehydroalanine residue by elimination of the sulfonate anion as shown by electrospray ionization mass spectroscopy. The analogous N-acyl beta-lactams are substrates for beta-lactamase and undergo enzyme-catalyzed hydrolysis presumably by the normal acylation-deacylation process. The rates of acylation of the enzyme by the beta-lactams, measured by the second-order rate constant for hydrolysis, kcat/K(m), and those of sulfonylation by the beta-sultams, measured by the second-order rate constant for inactivation, k(i), both show a similar pH dependence to that exhibited by the beta-lactamase-catalyzed hydrolysis of beta-lactam antibiotics. Electron-withdrawing groups in the aryl residue of the leaving group of N-aroyl beta-lactams increase the rate of alkaline hydrolysis and give a Bronsted beta(lg) of -0.55, indicative of a late transition state for rate-limiting formation of the tetrahedral intermediate. Interestingly, the corresponding Bronsted beta(lg) for the beta-lactamase-catalyzed hydrolysis of the same substrates is -0.06, indicative of an earlier transition state for the enzyme-catalyzed reaction. By contrast, although the Bronsted beta(lg) for the alkaline hydrolysis of N-aroyl beta-sultams is -0.73, similar to that for the beta-lactams, that for the sulfonylation of beta-lactamase by these compounds is -1.46, compatible with significant amide anion expulsion/S-N fission in the transition state. In this case, the enzyme reaction displays a later transition state compared with hydroxide-ion-catalyzed hydrolysis of the beta-sultam.