Synthesis of 2S-Hydroxymethyl-3R, 4R-dihydroxypyrrolidine

The sythesis of 2S-hydroxymethyl-3R, 4R-dihydroxypyrrolidine from D-arabinose was described in this paper.

Evaluation of the effect of pyrrolidine dithiocarbamate in suppressing inflammation in mice with dextran sodium sulfate-induced colitis

AIM: To evaluate the effect of pyrrolidine dithio- carbamate (PDTC; an NF-κB inhibitor) administered at low (50 mg/kg) and high (100 mg/kg) doses in suppressing colitis in mice with dextran sodium sulfate (DSS)-induced colitis. METHODS: Mice were divided into a DSS-untreated group (normal group), DSS-treated control group, DSS+PDTC-treated groupⅠ(low-dose group), and DSS+PDTC-treated groupⅡ (high-dose group). In each group, the disease activity index score (DAI score), intestinal length, histological score, and the levels of activated NF-κB and inflammatory cytokines (IL-1β and TNF-α) in tissue were measured. RESULTS: The DSS+PDTC-treated groupⅡ exhibited suppression of shortening of intestinal length and reduction of DAI score. Activated NF-κB level and IL-1β and TNF-α levels were significantly lower in DSS+PDTC- treated groupⅡ. CONCLUSION: These findings suggest that PDTC is useful for the treatment of ulcerative colitis.

Activation of nuclear factor-kappa B and effects of pyrrolidine dithiocarbamate on TNBS-induced rat colitis

AIM: To explore the changes of nuclear factor-kappa B (NF-κB) DNA-binding activity, the expression of intercellular adhesion molecule-1(ICAM-1) regulated by IMF-κB at various times and to evaluate the effects of pyrrolidine dithiocarbamate (PDTC) on trinitrobenzene sulfonic acid (TNBS)-induced rat colitis. METHODS: TNBS of 0.6 mL was mixed with ethanol of 0.3 mL solution and instilled into the lumen of the rat colon. The rat models were divided into 6 groups, which were killed at 24 h, 3, 7,14, and 21 d after enema. Colonic inflammation and damage were assessed by macroscopical and histological criteria. Activity of NF-κB DNA-binding was analyzed by electrophoresis mobility shift assays (EMSA). Expression of ICAM-1 was detected by in situ hybridization (ISH) and immunohistochemistry (IH). Then various doses of PDTC were injected into rat abdomen 30 min before enema with TNBS/ethanol as pretreatment. The rats were killed 4 h after enema and the colonic inflammation, myeloperoxidase (MPO) activity, malondialdehyde (MDA) level, and DNA-binding activity of NF-κB were assessed. Finally, PDTC was injected intraperitoneally after colitis was induced. Changes of morphology were assayed. RESULTS: During the first week, hyperemia, hemorrhage, edema and ulceration of the colonic mucosa appeared with predominant infiltration of leukocytes. Neutrophils, macrophages, lymphocytes infiltrated in mucosa and submucosa 14 d later. Fibroblasts and granuloma-like structures were also obviously seen. The binding activity of NF-κB began to increase at 24 h time point and reached a peak at 14 d, then decreased but still was higher than control group at 21 d (P<0.01). Levels of ICAM-1 mRNA and protein significantly elevated at 24 h and the peak was at 21 d. Pretreatment with PDTC could attenuate the development of inflammation but not by reducing NF-KB activity. This attenuation of inflammation had a positive relationship with the dose of PDTC. PDTC at the dose of 100 mg/kg had no therapeutic effect after colitis was induced. CONCLUSION: NF-κB activation is an important event that may be involved in acute and chronic inflammation development and may contribute to self-protection against early inflammation damage. NF-κB also regulates ICAM-1 expression during colonic inflammation. Pretreatment of PDTC may attenuate the inflammation development. But PDTC has no therapeutic effect after the colitis is induced.

Pyrrolidine dithiocarbamate alleviates the anti-tuberculosis drug-induced liver injury through JAK2/STAT3 signaling pathway:An experimental study

Objective:To study the effect of pyrrolidine dithiocarbamate(PDTC) on the anti-tuberculosis drug-induced liver injury and the molecular mechanism. Methods:Clean male SD rats were selected as experimental animals and randomly divided into normal group,model group,PDTC group and AG490 group. Animal model of anti-tuberculosis drug-induced liver injury was established by intragastric administration isoniazid + rifampicin. PDTC group received intraperitoneal injection of PDTC,and AG490 group received intraperitoneal injection of AG490. Twenty-eight days after intervention,the rats were executed,and the liver injury indexes,inflammation indexes and oxidative stress indexes in serum as well as JAK2/STAT3 expression,liver injury indexes,inflammation indexes and oxidative stress indexes in liver tissue were determined. Results:p-JAK2,p-STAT3,TNF-α,IL-1β,IL-6,ROS,8-OHdG and MDA expression in liver tissue as well as TBIL,ALT,AST,γ-GT,TNF-α,IL-1β,IL-6,ROS,8-OHdG and MDA levels in serum of model group were significantly higher than those of normal group while p-JAK2,p-STAT3,TNF-α,IL-1β,IL-6,ROS,8-OHdG and MDA expression in liver tissu as well as TBIL,ALT,AST,γ-GT,TNF-α,IL-1β,IL-6,ROS,8-OHdG and MDA levels in serum of PDTC group and AG490 group were significantly lower than those of model group. Conclusions:PDTC can inhibit the inflammation and oxidative stress mediated by JAK2/STAT3 signaling pathway to alleviate the anti-tuberculosis drug-induced liver injury.

Pyrrolidine dithiocarbamate reduces ischemia-reperfusion injury of the small intestine

AIM： To evaluate whether pyrrolidine dithiocarbamate （PDTC）, an enhancer of HO production, attenuates intestinal IR injury. METHODS： Eighteen male rats were randomly allocated into three groups： （a） sham; （b） IR, consisting of 30 min of intestinal ischemia, followed by 2-h period of reperfusion; and （c） PDTC treatment before IR. Intestinal microvascular perfusion （IMP） was monitored continuously by laser Doppler flowmetry. At the end of the reperfusion, serum samples for lactate dehydrogenase （LDH） levels and biopsies of ileum were obtained. HO activity in the ileum was assessed at the end of the reperfusion period. RESULTS： At the end of the reperfusion in the IR group, IMP recovered partially to 42.5% of baseline （P〈0.05 vs sham）, whereas PDTC improved IMP to 67.3% of baseline （P〈0.01 vs IR）. There was a twofold increase in HO activity in PDTC group （2 062.66±106.11） as compared to IR （842.3±85.12） （P〈0.001）. LDH was significantly reduced （P〈0.001） in PDTC group （585.6±102.4） as compared to IR group （1 973.8±306.5）. Histological examination showed that the ileal mucosa was significantly less injured in PDTC group as compared with IR group. CONCLUSION： Our study demonstrates that PDTC improves the IMP and attenuates IR injury of the intestine possibly via HO production. Additional studies are warranted to evaluate the clinical efficacy of PDTC in the prevention of IR injury of the small intestine.

Protective effect of pyrrolidine dithiocarbamate on liver injury induced by intestinal ischemia-reperfusion in rats

BACKGROUND: The nuclear translocation of transcription factors may be a critical factor in the intracellular pathway involved in ischemia/reperfusion(I/R) injury. The aim of the study was to evaluate the role of nuclear factor-kappa B (NF-κB) in the pathogenesis of liver injury induced by intestinal ischemia/reperfusion (IIR) and to investigate the effect of pyrrolidine dithiocarbamate (PDTC) on this liver injury. METHODS: Male Wistar rats were divided randomly into three experimental groups (8 rats in each): sham operation group (control group); intestinal/reperfusion group(I/R group): animals received 1-hour of intestinal ischemia and 2-hour reperfusion; and PDTC treatment group (PDTC group): animals that received I/R subject to PDTC treatment (100 mg/kg). The histological changes in the liver and intestine were observed, and the serum levels of tumor necrosis factor-α (TNF-α), alanine aminotransferase (ALT), aspartate aminotransferase (AST), liver superoxide dismutase (SOD), and nitrite/nitrate (NO) were measured. The immunohistochemical expression and Western blot analysis of liver NF-κB and intercellular adhesion molecule-1(ICAM-1) were observed. RESULTS: IIR induced liver injury characterized by the histological changes of liver edema, hemorrhage, polymorphonuclear neutrophil (PMN) infiltration, and elevated serum levels of AST and ALT. The serum TNF-α level was significantly higher than that of the control group(P<0.01) and a high level of liver oxidant product was observed (P<0.01). These changes were parallel to the positive expression of NF-κB and ICAM-1. After the administration of PDTC, the histological changes after liver injury were improved; the levels of SOD and NO in the liver were elevated and reduced, respectively (P<0.01). The expressions of ICAM-1 and NF-κB in the liver were weakened (P<0.01). CONCLUSION: NF-κB plays an important role in the pathogenesis of liver injury induced by HR. PDTC, an agent known to inhibit the activation of NF-κB, can reduce and prevent this injury.

Pyrrolidine dithiocarbamate and saxagliptin ameliorate ulcerative colitis in rats

Objective: To evaluate the antioxidant, immunomodulatory and anti-inflammatory activities of pyrrolidine dithiocarbamate and saxagliptin in rats with thioacetamide-induced ulcerative colitis. Methods: Animals were orally administered with a vehicle, sulfasalazine(500 mg/kg), pyrrolidine dithiocarbamate(100 mg/kg), and saxagliptin(10 mg/kg) for two weeks. Ulcerative colitis was induced by a single intrarectal instillation of thioacetamide on day 8. Colon samples were collected to assess mitogen-activated protein kinase(MAPK), phosphorylated extracellular signal-regulated kinase(ERK), c AMP response element-binding protein(CREB), interleukin-12(IL-12), caspase-3, β-defensin, inducible nitric oxide synthase(i NOS) and glucagon like peptide-1(GLP-1). Moreover, histopathological examination was performed. Results: Rats treated with thioacetamide caused increases in colonic MAPK, phosphorylated ERK, CREB, caspase-3, IL-12, β-defensin, i NOS, as well as decreases in body weight and GLP-1. In addition, distortion of colonic structure was found by histopathological examination. Pyrrolidine dithiocarbamate and saxagliptin mitigated colitis severity by improving body weight decrease and GLP-1, and reducing colonic MAPK, phosphorylated ERK, CREB, caspase-3, IL-12, β-defensin and i NOS. Conclusions: Pyrrolidine dithiocarbamate and saxagliptin are efficient against thioacetamide induced colitis through improving inflammatory and oxidative changes.

Pyrrolidine Dithiocarbamate (PDTC) Attenuates Luteolin-Induced Apoptosis in Human Leukemia HL-60 Cells

Studies have indicated that flavonoid luteolin is a potential inhibitor of tumor cell proliferation and may function as an anticarcinogenic agent. Pyrrolidine dithiocarbamate (PDTC), a synthetic compound, may exhibit biphasic effects on apoptosis depending on the experimental context. Previously, we found that luteolin induced the activation of the proapoptotic proteins, such as Bad, Bid, and Bax, in HL-60 human leukemia cells. We also explored the modulatory effects and molecular mechanisms of PDTC on the cytotoxicity of luteolin in HL-60 cells;PDTC could interfere with luteolin’s ability to cleave poly(ADP-ribose)-polymerase (PARP) and DNA fragmentation of factor-45 (DFF-45). In the current study, we further investigated the effect of PDTC on the luteolin-induced death-receptor pathway and the cleavage of the Bcl-2 family members. We found that the combination of luteolin and PDTC increased the survival of the HL-60 cells such that PDTC inhibited both extrinsic and intrinsic pathways in luteolin-induced apoptosis.

Improved Electrochemical Synthesis of Nitro-substituted 1-Aryl-2-pyrrolidinecarbonitriles

In this paper, we described an improved electrochemical method for synthesis of some 1-aryl-2-pyrrolidinecarbonitrile derivatives bearing an electron-withdrawing group （NO2）. The electrochemical synthesis of titile compounds has been successfully performed in an undivided cell in reasonable yields.

One-Pot Synthesis of N-Boc-2, 5-bis(trimethylsilyl)pyrrolidine

N-Boc-2, 5-bis(trimethylsilyl)pyrrolidine 4 was synthesized from the reaction of N-Boc-pyrrolidine 1 with trimethylsilyl chloride (TMSCl) at optional temperature in one-pot in good yield.

N-Alkoxyl Templates for Diastereoselective Pyrrolidine Synthesis

Intramolecular cyclization of N-alkoxyl amines are studied for the stereoselective preparation of 2, 4-disubstituted pyrrolidine derivatives. Reduction of oximes under acidic conditions by NaBH3CN afforded the corresponding nucleophilic hydroxylamine derivatives, which subsequently cyclized via SN2' mechanism to give the desired N-alkoxyl pyrrolidines.

First Total Synthesis of Hyacinthacine A_6 from the Protected Derivative of Polyhydroxylated Pyrrolidine

（1S、2R、3R、5R、7aR）-1,2-Dihydroxy-3-hydroxy methyl-5-methylpyrrolizidine（hyacinthacine A6, I） was synthesized by Wittig＇s methodology via the reaction of aldehyde 6, prepared from the partially protected derivative of polyhydroxylated pyrrolidine, with appropriated ylides, followed by cyclization through the intemal reductive amination process of the resulting a,B-unsaturated ketone 7, and total deprotection.

Syntheses, Structures and Antitumor Activities of Tri(o-bromobenzyl)tin Diethyldithiocarbamate and Tri(m-fluorobenzyl)tin Pyrrolidine Dithiocarbamate

Tri(o-bromobenzyl)tin diethyldithiocarbamate(1) and tri(m-fluorobenzyl)tin pyrrolidine dithiocarbamate(2) have been synthesized and characterized by elemental analysis, IR spectroscopy, NMR(~1 H, ^(13)C and ^(119)Sn), thermogravimetric analysis and single-crystal X-ray diffraction. The two complexes crystallize in the triclinic system space group P1. For complex 1, a = 0.9770(1), b = 1.1011(1), c = 1.4583(1) nm, α = 78.431(1)°, β = 86.307(1)°, γ = 69.712(1)°, V = 1.4417(2) nm^3, Z = 2, Dc = 1.790 g/cm^3, m(Mo Kα) = 52.04 cm–1, F(000) = 756, R = 0.0434 and wR = 0.0593. For complex 2, a = 0.7055(1), b = 1.3349(3), c = 1.3782(3) nm, α = 89.216(2)°, β = 82.044(2)°, γ = 84.637(2)°, V = 1.2799(5) nm^3, Z = 2, Dc = 1.537 g/cm^3, m(Mo Kα) = 11.98 cm^(–1), F(000) = 596, R = 0.0313 and wR = 0.0333. The two complexes represent mononuclear structures with five-coordinated [SnC3S2] cores forming a distorted trigonal bipyramid. The quantum chemical calculations of 1 and 2 have been investigated. The antitumor activity shows that 1 and 2 have higher activities than cisplatinum against Colo205, HepG2, MCF-7, Hela and H460 cell line in vitro.

Synthesis of fulleropyrrolidine derivatives of C_(60)

1 Experimental ORGANIC chemical derivatization of fullerene by cycloaddition reactions has attracted in-tense interest. It has been found that C60 can undergo a series of cycloaddition reactions associ-ated with poorly-conjugated and electron-deficient alkenes, including [4+2], [3+2], [2+2] and [2+1] cycloaddition reaction, 1, 3-dipolar cycloaddition reactions. [3+2] cycloaddi-tion reactions of azomethine ylides to C60 have been widely used to prepare N-substituted

Therapeutic effects of salidroside vs pyrrolidine dithiocarbamate against severe acute pancreatitis in rats

OBJECTIVE:To evaluate the therapeutic effectiveness of salidroside(Sal)and pyrrolidine dithiocarbamate(PDTC)against severe acute pancreatitis(SAP)in a rat model.METHODS:Rat models of SAP were established by retrograde infusion of sodium taurocholate solution.SAP rats were randomly divided into 6 groups:SAP 3 h group,SAP 24 h group,low-dose Sal treatment group(Sal L+S),middle-dose Sal treatment group(Sal M+S),high-dose Sal treatment group(Sal H+S)and PDTC treatment group(PDTC+S).The serum amylase,tumor necrosis factor-α(TNF-α),interleukin-1β(IL-1β)and interleukin-10(IL-10)levels were determined by optical turbidimetry and enzyme-linked immunosorbent assay.The expression of Beclin-1,microtubule-associated protein light chain 3Ⅱ(LC3Ⅱ),lysosome associated membrane protein 2(LAMP2),interleukin-1 receptor associated kinase 1(IRAK1),inhibitorαof nuclear transcription factor-κB(IκBα),nuclear transcription factor-κB 65(p65)in the pancreas tissues were detected by quantitative real-time polymerase chain reaction and Western blot,while the pIκBαand p-p65 levels were detected by Western blot.Pathological changes of the pancreas and all the other indexes were observed at 3 and 24 h after operation.RESULTS:The serum IL-10 level,IκBαand LAMP2 levels in Sal M+S,Sal H+S and PDTC+S groups were higher than those in SAP 24 h group,while all the other indexes in these three groups were all lower significantly than those in SAP 24 h group.There was no significant difference in all indexes between Sal H+S and PDTC+S groups.CONCLUSION:High-dose Sal has an effectively therapeutic effect on SAP in rats,which was similar to PDTC.

Synthesis of bromoallenyl pyrrolidines via 1,4-addition to 1,3-enynes

The discovery of the novel reactivity of conjugated enynes,mediated by readily available halogenation reagents,opens a broad range of mechanistically unique pathways for the synthesis of highly functionalized chiral allene derivatives.Bromoallenyl pyrrolidines can be synthesized via 1,4-addition of sulfonamide nitrogen nucleophiles and halogens to conjugated enynes.This process can lead to simultaneous formation of a highly functionalized axially chiral allene and a stereogenic center under economical and environmentally friendly reaction conditions.

A Facile Access to Fluorinated Pyrrolidines via Catalytic Asymmetric 1,3-Dipolar Cycloaddition of Azomethine Ylides with Methyl a-Fluoroacrylate

Asymmetric 1,3-dipolar cycloaddition of methyl a-fluoroacrylate with azomethine ylides for the construction of optically active fluorinated pyrrolidines bearing one unique fluorinated quaternary and two tertiary stereogenic cen- ters has been achieved with Cu（CH3CN）4BF4/TF-BiphamPhos complexes for the first time. This catalytic system performs well over a broad scope of substrates, providing the synthetically useful adducts in good yields and excel- lent diastereoselectivities and good to high enantioselectivities.

Targeted isolation and identification of bioactive pyrrolidine alkaloids from Codonopsis pilosula using characteristic fragmentation-assisted mass spectral networking

Codonopsis pilosula(CP),a well-known food medicine homology plant,is commonly used in many countries.In our preliminary study,a series of pyrrolidine alkaloids with high MS responses were detected as characteristic absorbed constituents in rat plasma after oral administration of CP extract.However,their structures were unclear due to the presence of various isomers and the lack of reference standards.In the present study,an MS-guided targeted isolation of pyrrolidine alkaloids of CP extract was performed by ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry(UPLC/Q-TOF MS).For data analysis under fast data directed acquisition mode(Fast-DDA),an effective approach named characteristic fragmentation-assisted mass spectral networking was successfully applied to discover new pyrrolidine alkaloids with high MS response in CP extract.As a result,seven new pyrrolizidine alkaloids[codonopyrrolidiums C–I(3–9)],together with two known ones(1 and 2),were isolated and identified by NMR spectral analysis.Among them,codonopyrrolidium B(1),codonopyrrolidium D(4)and codonopyrrolidium E(5)were evaluated for lipid-lowering activity,and they could improve high fructose-induced lipid accumulation in HepG2 cells.In addition,the characteristic MS/MS fragmentation patterns of these pyrrolizidine alkaloids were investigated,and 17 pyrrolidine alkaloids were identified.This approach could accelerate novel natural products discovery and characterize a class of natural products with MS/MS fragmentation patterns from similar chemical scaffolds.The research also provides a chemical basis for revealing in vivo effective substances in CP.

Synthesis, Characterization, Optical and Electrochemical Properties of Fulleropyrrolidines Containing Trifluoromethyl Group

Four novel [60]fullerene pyrrolidines containing trifluoromethyl （--CF3） group have been synthesized via 1,3-dipolar cycloaddition reaction, which have been characterized by UV-Vis spectroscopy, fourier transform in- frared spectroscopy, matrix-assisted laser desorption ionization-time of flight mass spectroscopy, and IH, 13C, 19F nuclear magnetic resonance spectrometer （IH NMR, 13C NMR, 19F NMR）. Their optical and electrochemical prop- erties have been studied, and the results show that those fulleropyrrolidines containing --CF3 group have good fluo- rescence and electrochemical properties. Compared with C60, they have negative shifts in varying degrees for half-wave potentials, and may have potential applications for photovoltaic conversion materials since their lowest unoccupied molecular orbital （LUMO） levels are close to that of [6,6]-phenyl-C6：butyric acid methyl ester.

N-Unsubstituted and N-Arylated Fulleropyrrolidines： New Useful Building Blocks for C60 Functionalization

Two series of stable and soluble fulleropyrrolidines have been prepared from the reactions of C60, glycine or its N-arylated derivatives and aliphatic aldehydes or ketones in refluxing toluene or chlorobenzene. The new C60 derivatives represent new useful building blocks for further preparation of more funcionalized C60 derivatives.