Sulfoxide Analogs Research Articles

Bench‐Stable Electrophilic Reagents for the Direct Di‐ and Trifluoroethylthiolation of Indoles

AbstractTwo saccharine‐based electrophilic reagents were developed for the direct introduction of SCH2CF3 and SCH2CF2H motifs via a C−S bond forming reaction. Their large‐scale preparation and reactivity performance has been carefully examined, enabling access to a series of indoles through open‐flask reactions. Sulfone and sulfoxide analogs (S(O)nCH2RF, n=1,2) are also accessible by sequential oxidation reactions.

Mutation of Methionine to Asparagine but Not Leucine in Parathyroid Hormone Mimics the Loss of Biological Function upon Oxidation.

Human parathyroid hormone (PTH) is an 84-amino acid peptide that contains two methionine (Met) residues located at positions 8 and 18. It has long been recognized that Met residues in PTH are subject to oxidation to become Met sulfoxide, resulting in a decreased biological function of the peptide. However, the mechanism of the lost biological function of PTH oxidation remains elusive. To characterize whether the shift from the hydrophobic nature of the native Met residue to the hydrophilic nature of Met sulfoxide plays a role in the reduction of biological activity upon PTH oxidation, we conducted in silico and in vitro site-directed mutagenesis of Met-8 and Met-18 to the hydrophilic residue asparagine (Asn) or to the hydrophobic residue leucine (Leu) and compared the behavior of these mutated peptides with that of PTH oxidized at Met-8 and/or Met-18. Our results showed that the biological activity of the Asn-8 and Asn-8/Asn-18 mutants was significantly reduced, similar to Met-8 sulfoxide and Met-8/Met-18 sulfoxide analogues, while the functions of Asn-18, Leu-8, Leu-8/Leu-18 mutants, or Met-18 sulfoxide analogues were similar to wild-type PTH. This is rationalized from molecular modeling and immunoprecipitation assay, demonstrating disruption of hydrophobic interactions between Met-8 and Met-18 of PTH and type-1 PTH receptor (PTHR1) upon mutation or oxidation. Thus, these novel findings support the notion that the loss of biological function of PTH upon oxidation of Met-8 is due, at least in part, to the conversion from a hydrophobic to a hydrophilic residue that disrupts direct hydrophobic interaction between PTH and PTHR1.

Synthesis, biological evaluation and X-ray analysis of bicalutamide sulfoxide analogues for the potential treatment of prostate cancer

The androgen receptor (AR) is a pivotal target for the treatment of prostate cancer (PC) even when the disease progresses toward androgen-independent or castration-resistant forms. In this study, a series of sulfoxide derivatives were prepared and their antiproliferative activity evaluated in vitro against four different human prostate cancer cell lines (22Rv1, DU-145, LNCaP and VCap). Bicalutamide and enzalutamide were used as positive controls. Compound 28 displayed significant enhancement in anticancer activity across the four PC cell lines with IC50 = 9.09 – 31.11 µM compared to the positive controls: bicalutamide (IC50 = 45.20 –51.61 µM) and enzalutamide (IC50 = 11.47 – 53.04 µM). Sulfoxide derivatives of bicalutamide were prepared efficiently from the corresponding sulfides using only one equivalent of mCPBA, limiting the reaction time to 15–30 min and maintaining the temperature at 0 °C. Interestingly, three pairs of sulfoxide diastereomers were separated and NMR comparison of their diastereotopic methylene (CH2) group is presented. X-ray diffraction crystal structure analysis provided relative configuration assignment at the chiral sulfur and carbon centres. Molecular modelling study of the four diastereoisomers of compound 28 is described.

In vivo pharmacokinetic study and oral glucose tolerance test of sulfoxide analogs of GPR40 agonist TAK-875.

TAK-875 (compound 1) was the only GPR40 agonist with promising oral glucose-lowering effect, which entered phase III clinical trials. In previous studies, we successfully synthesized the TAK-875 sulfoxide analog 2, which was further separated to optically pure compounds 3 (S, S, 100.0% de) and 4 (R, S, 100.0% de). In vitro biological evaluation revealed that the sulfoxide analogs 3 and 4 possessed comparable GPR40 agonist activity to TAK-875. Herein, in order to further evaluate the druglikeness of TAK-875 sulfoxide analogs, the pharmacokinetic properties of compounds 2, 3, and 4 in rats were investigated and compared with that of TAK-875. The results showed that sulfoxide (2, 3, and 4) and sulfone (TAK-875) could be converted into each other in different degrees in vivo. Interestingly, compound 3 showed higher drug exposure calculated by the AUC sum of sulfoxide and sulfone in plasma than TAK-875, 2 and 4. In order to further investigate the in vivo glucose-lowering potency of sulfoxide analogs, asymmetric synthesis was carried out and led to two sulfoxides with moderate de values, 5 (S, S, 66.4% de) and 6 (R, S, 71.0% de). The following oral glucose tolerance test (OGTT) in rats showed that 5 (S, S, 66.4% de) had stronger glucose-lowering effect in vivo than 6 (R, S, 71.0% de) and TAK-875, which could be partly rationalized by the superior pharmacokinetic property of sulfoxide 3 (the main component of 5) relative to sulfoxide 4 (the main component of 6) and TAK-875.

Radiation induced oxidation of [18F]fluorothia fatty acids under cGMP manufacturing conditions

ObjectiveThe objectives of the present work were to optimize and validate the synthesis and stability of 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid ([18F]FTHA) and 16-[18F]fluoro-4-thia-palmitic acid ([18F]FTP) under cGMP conditions for clinical applications. MethodsBenzyl-14-(R,S)-tosyloxy-6-thiaheptadecanoate and methyl 16-bromo-4-thia-palmitate were used as precursors for the synthesis of [18F]FTHA and [18F]FTP, respectively. For comparison, a fatty acid analog lacking a thia-substitution, 16-[18F]fluoro-palmitic acid ([18F]FP), was synthesized from the precursor methyl 16-bromo-palmitate. A standard nucleophilic reaction using cryptand (Kryptofix/K222, 8.1 mg), potassium carbonate (K2CO3, 4.0 mg) and 18F-fluoride were employed for the 18F-labeling and potassium hydroxide (0.8 M) was used for the post-labeling ester hydrolysis. The final products were purified via reverse phase semi-preparative HPLC and concentrated via trap and release on a C-18 plus solid phase extraction cartridge. The radiochemical purities of the [18F]fluorothia fatty acids and [18F]FP were examined over a period of 4 h post-synthesis using an analytical HPLC. All the syntheses were optimized in an automated TRACERlab FX-N Pro synthesizer. Liquid chromatography mass spectrometry (LCMS) and high resolution mass spectrometry (HRMS) was employed to study the identity and nature of side products formed during radiosynthesis and as a consequence of post-synthesis radiation induced oxidation. ResultsRadiosyntheses of [18F]FTHA, [18F]FTP and [18F]FP were achieved in moderate (8–20% uncorrected) yields. However, it was observed that the HPLC-purified [18F]fluorothia fatty acids, [18F]FTHA and [18F]FTP at higher radioactivity concentrations (>1.11 GBq/mL, 30 mCi/mL) underwent formation of 18F-labeled side products over time but [18F]FP (lacking a sulfur heteroatom) remained stable up to 4 h post-synthesis. Various radiation protectors like ethanol and ascorbic acid were examined to minimize the formation of side products formed during [18F]FTHA and [18F]FTP synthesis but showed only limited to no effect. Analysis of the side products by LCMS showed formation of sulfoxides of both [18F]FTHA and [18F]FTP. The identity of the sulfoxide side product was further confirmed by synthesizing a non-radioactive reference standard of the sulfoxide analog of FTP and matching retention times on HPLC and molecular ion peaks on LC/HRMS. Radiation-induced oxidation of the sulfur heteroatom was mitigated by dilution of product with isotonic saline to reduce the radioactivity concentration to <0.518 GBq/mL (14 mCi/mL). ConclusionsSuccessful automated synthesis of [18F]fluorothia fatty acids were carried out in cGMP facility for their routine production and clinical applications. Instability of [18F]fluorothia fatty acids were observed at radioactivity concentrations exceeding 1.11 GBq/mL (30 mCi/mL) but mitigated through dilution of the product to <0.518 GBq/mL (14 mCi/mL). The identities of the side products formed were established as the sulfoxides of the respective thia fatty acids caused by radiation-induced oxidation of the sulfur heteroatom.

Pyridinium 1,4-zwitterionic thiolates as a useful class of sulfur-containing synthons: application to the synthesis of 2,5-dihydro-1,4,5-thiadiazepines.

A novel [4+3] cascade cyclization reaction of pyridinium 1,4-zwitterionic thiolates with azoalkenes derived from α-halo hydrazones in situ has been developed. This reaction was found to allow expedient access to an array of 2,5-dihydro-1,4,5-thiadiazepines. Libraries of highly functionalized sulfoxide and sulfone analogues of 2,5-dihydro-1,4,5-thiadiazepines were also obtained via selective oxidation with m-CPBA.

Sulfoxide Analogs of TAK-875 as G Protein Coupled Receptor 40 Agonists: Synthesis, Determination of Absolute Configuration and Biological Activity

Sulfoxide Analogs of TAK-875 as G Protein Coupled Receptor 40 Agonists: Synthesis, Determination of Absolute Configuration and Biological Activity

Antibacterial properties of 3-(phenylsulfonyl)-2-pyrazinecarbonitrile.

The emergence of multidrug-resistant bacterial strains has heightened the need for new antimicrobial agents based on novel chemical scaffolds that are able to circumvent current modes of resistance. We recently developed a whole-animal drug-screening methodology in pursuit of this goal and now report the discovery of 3-(phenylsulfonyl)-2-pyrazinecarbonitrile (PSPC) as a novel antibacterial effective against resistant nosocomial pathogens. The minimum inhibitory concentrations (MIC) of PSPC against Staphylococcus aureus and Enterococcus faecium were 4 μg/mL and 8 μg/mL, respectively, whereas the MICs were higher against the Gram-negative bacteria Klebsiella pneumoniae (64 μg/mL), Acinetobacter baumannii (32 μg/mL), Pseudomonas aeruginosa (>64 μg/mL), and Enterobacter spp. (>64 μg/mL). However, co-treatment of PSPC with the efflux pump inhibitor phenylalanine arginyl β-naphthylamide (PAβN) or with sub-inhibitory concentrations of the lipopeptide antibiotic polymyxin B reduced the MICs of PSPC against the Gram-negative strains by >4-fold. A sulfide analog of PSPC (PSPC-1S) showed no antibacterial activity, whereas the sulfoxide analog (PSPC-6S) showed identical activity as PSPC across all strains, confirming structure-dependent activity for PSPC and suggesting a target-based mechanism of action. PSPC displayed dose dependent toxicity to both Caenorhabditis elegans and HEK-293 mammalian cells, culminating with a survival rate of 16% (100 μg/mL) and 8.5% (64 μg/mL), respectively, at the maximum tested concentration. However, PSPC did not result in hemolysis of erythrocytes, even at a concentration of 64 μg/mL. Together these results support PSPC as a new chemotype suitable for further development of new antibiotics against Gram-positive and Gram-negative bacteria.

Carbonyl olefination of diaryl ketones with heteroaryl sulfoxides

Heteroaryl sulfones are capable of converting the carbonyl functionalities to alkenyl motifs, which is well-known as Julia–Kocienski olefination reaction. However, their sulfoxide analogues have failed in such an olefination reaction for over twenty years. In this Letter, we demonstrate that the heteroaryl sulfoxide-participated carbonyl olefination reaction can be realized under certain conditions. Furthermore, a novel defluorinative olefination of diaryl ketones has been achieved with 2-pyridyl sulfoxides.

4'-Modified Pyrimidine Nucleosides as Potential Anti-hepatitis C Virus (HCV) Agents

Herein, we have investigated novel pyrimidine nucleosides bearing a 4’-carboxyl functionality (6-10, 13 and 15) as anti-HCV agents. In this new class of compounds, 7, 9, 10 and 15 demonstrated in vitro anti-HCV activity similar to or better than a known anti-HCV drug, ribavirin. In this work, we also, surprisingly, identified a 3’-sulfoxide analog of 3’-thiacytidine (16), obtained as a side product during the synthesis of 15, as a potent inhibitor of HCV replication at the concentration similar to that of ribavirin. No detectable in vitro cytotoxicity was observed for the investigated compounds up to the highest concentration tested. Keywords: Hepatitis C virus, Anti-HCV effect, Synthesis, Nucleosides.

SnO2 Nanoparticles: Preparation and Evaluation of their Catalytic Activity in the Oxidation of Aldehyde Derivatives to their Carboxylic Acid and Sulfides to Sulfoxide Analogs

A variety of aromatic and aliphatic aldehydes were converted to the corresponding carboxylic acid derivatives with 30% H2O2 and tert-butyl hydroperoxide as the oxidant in the presence of a catalytic amount of SnO2 nanoparticles as a precursor. These nanoparticles were also used for the efficient catalytic oxidation of sulfides to sulfoxides using 30% H2O2. The present methodology offers several advantages such as applicability to a wide range of aldehydes/ sulfides, convenient work-up, mild reaction conditions as well as good yields and reasonable time of the reactions. Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.

Synthesis and biological studies of neopetrosiamides as inhibitors of cancer cell invasion

The tricyclic peptides neopetrosiamides A and B, isolated from the marine sponge Neopetrosia sp., are potential antimetastatic agents that inhibit tumour cell invasion by both amoeboid and mesenchymal migration pathways. They differ in the stereochemistry of the methionine sulfoxide at position 24. Our previously reported syntheses using an orthogonal sulfur protection strategy established the critical connectivity of the three disulfide bonds. In this report, fifteen analogues of neopetrosiamide A and B, six which replace selected disulfide bonds and nine which replace the diastereomeric methionine sulfoxide, have been prepared using Fmoc solid-phase peptide chemistry. Disulfide replacement analogues were shown to lose activity, and only one of the methionine sulfoxide analogues retained full bioactivity in morphological studies.

Simple Synthesis of Modafinil Derivatives and Their Anti-inflammatory Activity

Simple synthesis of modafinil derivatives and their biological activity are described. The key synthetic strategies involve substitution and coupling reactions. We determined the anti-inflammatory effects of modafinil derivatives in cultured BV2 cells by measuring the inhibition of nitrite production and expression of iNOS and COX-2 after LPS stimulation. It was found that for sulfide analogues introduction of aliphatic groups on the amide part (compounds 11a–d) resulted in lower anti-inflammatory activity compared with cyclic or aromatic moieties (compounds 11e–k). However, for the sulfoxide analogues, introduction of aliphatic moieties (compounds 12a–d) showed higher anti-inflammatory activity than cyclic or aromatic fragments (compounds 12e–k) in BV-2 microglia cells.

Cα–Cβ chromophore bond dissociation in protonated tyrosine-methionine, methionine-tyrosine, tryptophan-methionine, methionine-tryptophan and their sulfoxide analogs

C(α)-C(β) chromophore bond dissociation in some selected methionine-containing dipeptides induced by UV photons is investigated. In methionine containing dipeptides with tryptophan as the UV chromophore, the tryptophan side chain is ejected either as an ion or as a neutral fragment while in dipeptides with tyrosine, the tyrosine side chain is lost only as a neutral fragment. Mechanisms responsible for these fragmentations are proposed based on measured branching ratios and fragmentation times, and on the results of DFT/B3-LYP calculations. It appears that the C(α)-C(β) bond cleavage is a non-statistical dissociation for the peptides containing tyrosine, and occurs after internal conversion for those with tryptophan. The proposed mechanisms are governed by the ionization potential of the aromatic side chain compared to that of the rest of the molecule, and by the proton affinity of the aromatic side chain compared to that of the methionine side chain. In tyrosine-containing peptides, the presence of oxygen on sulfur of methionine presumably reduces the ionization potential of the peptide backbone, facilitating the loss of the side chain as a neutral fragment. In tryptophan-containing peptides, the presence of oxygen on methionyl-sulfur expedites the transfer of the proton from the side chain to the sulfoxide, which facilitates the loss of the neutral side chain.

A new sulfoxide analog of 1,2,3,6-tetrahydrophenylpyridine and antimicrobial activity.

Bioactivities of thiotetrahydropyridines were previously described. Herein, a novel bioactive sulfoxide analog; N-acetyl-2-(1-adamantylsulfoxo)-3-acetoxy-4-phenyl-6-hydroxy-1,2,3,6-tetrahydropyridine (3) from the deoxydative substitution of 4-phenylpyridine 1-oxide is reported. Its structure was elucidated using spectral data including 2D-NMR, MS, IR and UV. The sulfoxide 3 exhibited antibacterial activity against Moraxella catarrhalis and Streptococcus pyogenes with minimum inhibitory concentration of 128 and 256 µg/mL, respectively.

Abstract 2668: Detoxification of metabolites from antibody-maytansinoid conjugates by human liver microsomes

Abstract Six antibody-maytansinoid conjugates (AMCs) consisting of the cytotoxic maytansinoid, DM1 or DM4, linked to a tumor-targeting monoclonal antibody are undergoing clinical evaluation, with the most advanced in Phase III testing. In these AMCs, the maytansinoid is attached through its C3 side chain to the antibody via a thioether or disulfide bond. The antibody moiety of the conjugate binds specifically to a tumor cell after which the conjugate is internalized and processed to release one or more maytansinoid metabolites (MMs) which kill the cell. Some of these MMs are hydrophobic and highly potent against both the forming cell and neighboring dividing cells, while others are charged or polar compounds that are highly toxic to the cell that intracellularly released them, but have a relatively low toxicity to adjacent cells due to poor membrane permeability. Similar MMs are formed from AMCs inside cells of the reticulo-endothelial system (RES), the primary route of elimination of proteinaceous therapeutics such as AMCs. We have previously reported, from studies with radiolabeled MMs in mice, that the primary elimination route of RES-formed MMs is via the liver, and entails biliary excretion of relatively low potency charged or polar maytansinoids. It would be desirable to know if MMs generated from AMCs in the RES systems of patients can be inactivated by the oxidative processes of the human liver. To model this, MMs and other maytansinoids were synthesized and then exposed in vitro to human liver microsomes. The resulting microsomal metabolites were identified by HPLC/MS and their cytotoxicities were determined. In general, the major metabolites formed from microsome exposure occurred via oxidation on the C3 side chain, with only minimal microsome-dependent alterations noted in the macrocycle. Non-charged hydrophobic maytansinoids containing at least one sulfur atom were oxidized on the sulfur atom(s) to yield one or more products which were significantly less cytotoxic than the substrate. For example, the highly cytotoxic tumor cell metabolite, S-methyl DM4, was converted to its sulfoxide and sulfone analogues, which were more than 20-fold less potent than S-methyl DM4. Charged maytansinoids containing an amino acid or a carboxylic acid were poorly metabolized by the human liver microsomes even when these maytansinoids contained one or more sulfur atoms. These data suggest that the highly potent, non-charged MMs formed in the tumor cells or the RES systems of patients would be rendered less toxic through oxidation in the liver prior to biliary elimination. Furthermore, the less potent, charged MMs likely would not be further processed by liver in a way that would increase their systemic toxicity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2668.

Preparation of vinylglycines by thermolysis of homocysteine sulfoxides

The synthesis and efficacy of preparing Cbz-VG-OMe ( 1) by thermolysis of alkyl and aryl homocysteine sulfoxides were surveyed. This investigation determined that aryl sulfoxide analogs were more effective for the reaction and that the 2-nitrophenyl analog 10f possessed a unique ability to syn eliminate at temperatures as low as 100 °C. The thermolysis of sulfoxide 10f was additionally discovered to occur under toluene reflux and when sodium acetate was added, Cbz-VG-OMe ( 1) could be obtained in high purity by simple filtration of the precipitated sulfenic acid byproduct 12. This mild protocol which was also applied in the synthesis of VG dipeptide 13 would have utility in the general synthesis of olefins and alkenes from 2-nitrophenylsulfoxides.

Critical role of methionine-722 in the stimulation of human brain G-proteins and neurotoxicity induced by London familial Alzheimer’s disease (FAD) mutated V717G-APP714–723

We have demonstrated earlier that V717G-APP714–723, the membrane fragment of the V717G (“London”) familial Alzheimer’s disease (FAD) mutant of amyloid precursor protein (APP), is a potent stimulator of G-proteins in human brain membranes. In this study, we tested the hypothesis that Met-722 in the V717G-APP714–723 peptide (P2) plays a critical role in the P2-induced oxidative stimulation of G-proteins in the human temporal cortex membranes and in the neurotoxicity of the peptide in differentiated PC12 and cerebellar granular cells. We found that 10 μM P3, the Met-722 sulfoxide analog of P2, produced a twofold lower stimulation of G-proteins ([35S]-GTPγS binding) in control temporal cortex membranes compared with 10 μM P2. The stimulatory effect of 10 μM P4, the Met-722 sulfone analog of P2, was 2.5-fold lower than the effect of P2. In Alzheimer’s disease (AD) temporal cortex, the P3 and P4 stimulation of G-proteins was slightly weaker than the P2 stimulation. Substitution of the Met-722 S-atom in P2 by -CH2- group (P5) led to the disappearance of P2 stimulatory effect on G-proteins. Glutathione (GSH), melatonin (Mel), desferrioxamine (DFO) and 17-β-estradiol (17βE) significantly reduced P2 stimulatory effect on G-proteins in human brain. Only DFO and Mel were able to reduce the moderate stimulation of G-proteins by P3, whereas none of the tested antioxidants influenced the weak stimulation by P4. P2 at 100 μM induced a 40% decrease in PC12 cell viability as revealed by MTT assay, the effect being significantly higher than that of P3 or P4, whereas P1 (wild-type APP714–723) did not affect cell viability. Trypan Blue exclusion assay demonstrated that 10 μM P2 and P3 induced 3.8- and 3.5-fold death in the cerebellar granular cells as compared with the respective control values. P1 and P4 at 10 μM induced 1.7- and 2.3-fold increase in cell death, respectively. Treatment of the cerebellar granular cells with pertussis toxin decreased the high neurotoxicity of P2 and P3, whereas the low toxicity of P1 and P4 was not influenced. These results support the hypothesis that the G-protein stimulatory effect and neurotoxicity of “London”-mutated V717G-APP714–723 (P2) and its Met-722 oxidized analogs involve oxidative-dependent and oxidative-independent mechanisms and the oxidation state of Met-722 plays a critical role in determining the mechanism.

Racemic and chiral sulfoxides as potential prodrugs of 4-pyrone COX-2 inhibitors

The preparation of the sulfoxide analogues 7, 8, and 9 and their enantiomerically pure forms is discussed as well as their ability to act as prodrugs of the potent and selective sulfone-containing COX-2 inhibitors 1, 2, and 3. Sulfoxide derivatives 7 and 9 were shown to be rapidly transformed in vivo into the corresponding sulfone derivatives 1 and 3, after oral administration to rats.

Racemic and chiral sulfoxides as potential prodrugs of the COX-2 inhibitors Vioxx ® and Arcoxia ®

The preparation of the sulfoxide analogues 2 and 4, and their enantiomeric pure forms is discussed as well as their potential to act as prodrugs to the potent and selective sulfone-containing COX-2 inhibitors rofecoxib and etoricoxib. Sulfoxides 2 and 4 were shown to be effectively transformed in vivo into rofecoxib and etoricoxib, respectively, after oral administration in rats. In the case of sulfoxide 2, both a slightly improved pharmacokinetic profile and a better pharmacological activity in an arthritis model were seen when compared with rofecoxib.