AK-7_420831-40-9_DataSheet_MedChemExpress
Nipro PharmaPackaging预填充玻璃注射器质量等级说明书
FINE-TUNED TO YOUR NEEDSPRE-FILLABLE GLASS SYRINGESF INE-T UNED T O YOUR NEED SThe pre-fillable syringe market has grown significantly in the past years. Pharmaceutical companies are developing an increasing number of drug products in injectable formats, since this packaging type offers exceptional benefits: decreased total cost of ownership, improved drug-container compatibility, and increased patient safety.At Nipro PharmaPackaging, we understand the diverse quality requirements in the pharmaceutical industry. To address these various demands for quality and their intricacies, we present three distinct quality levels for our pre-fillable glass syringes.NIPRO QUALITY LEVELSThe process of defining the right quality level for primary packaging is a complex, involved process. In order to ensure the optimal match, there must be understanding and collaboration: specific data must be ex-changed, requirements discussed, and numerous parameters defined.Our Nipro Quality Levels form the perfect base to fine-tune your quality and service requirements, therebyproviding you with the optimal packaging solution.eNgage with Nipro to develop atailored packaging quality, wherebywe apply our profound analyticalcompetencies and align our cutting-edge production and inspectiontechnologies to satisfy your unmetdrug product requirements.eNable a packaging quality thatanswers to the prevailing drugproduct requirements.eNhance the pre-fillable syringequality to meet the requirements ofhighly sensitive drugs, administeredthrough manual injection or autoinjectors.2DATA SHARINGSIMPLY SELECT THE QUALITY LEVELFINE-TUNED TO YOUR SPECIFIC DRUG REQUIREMENTS!3Our state of the art production facility in Germany features advanced manufacturing and inspection technologies that are capable of controlling exceptionally tight tolerances, even for your most advanced drug products.Data sharing is key in understanding needs and facilitating both development and supply. Therefore, all necessary data is available and will be adapted to meet your processes.Simple LoA requestprocedure Adaptable CoC and CoARANGELUER SLIP SYRINGESComponents supplied by: Aptar Stelmi, Datwyler, West, NiproLUER LOCK SYRINGESComponents supplied by: Aptar Stelmi, Datwyler, West, Vetter, NiproSTAKED NEEDLE SYRINGESComponents supplied by: Aptar Stelmi, Datwyler, West, Nipro* Wall type = “Thin walled“ (TW). Other sizes upon request.4S T A K E D N E E D L E S Y R I N G EL U E R L O C K S Y R I N G EL U E R S L I P S Y R I N G E5S TERIL IZED PACK AGING S OLU TION SNipro PharmaPackaging manufactures D2F syringes in technologically advanced production sites that are certified according to ISO 9001, ISO 15378, ISO 14001, and ISO 50001. Our fully automated cleaning and packaging process takes place in an ISO 7 / ISO 8 cleanroom with 100% monitoring under laminar air flow.Tyvek ® lidTyvek ® insertNestTubLabel with ETO indicatorSealed tubWelded breather bagDIRECT-TO-FILLCardboard or PP-Well interlayers6 per outer boxStacking scheme 115 tubs per outer box; 5 layers; 3 tubs per layer, packed upside down1. Different stacking schemes are available (depending on type of tub)6D2F MANUFACTURING PROCESSNE S T S A ND T UB S A RE F IR S T CL E A NED W I T H IONIZED A IR T O MINIMIZE PA R T ICL E LOA D.Robots then load the washed, siliconized, and final assembled pre-fillable syringes into nests and tubs. The tubs are covered with a Tyvek ® insert, sealed with a corresponding Tyvek ® lid, and then entered into a breather bag which is welded closed (double inserts & breather bags optional).Our 100% in-line inspection systems allow for continuous quality monitoring as part of In Process Controls (IPC). This ensures that all pre-fillable syringes are foreseen with closures and that tubs are 100% filled and correctly sealed.Afterwards, machines transfer the tubs to a station for final packing. Tubs are stacked and placed in outer boxes.Outer boxes are placed on pallets, protective angle boards are applied, and fixation is ensured with PE-Bands. The total pallet is wrapped in plastic foil to ensure safe transportation.Final packed pre-fillable syringes are then ETO sterilized. Labels on the tubs and outer boxes are provided with a special ETO indicator (a color change from blue to green after ETO exposure). This allows for visual confirmation of ETO sterilization and subsequent exposure.Nipro’s D2F packaging design is a smart, efficient choice. It prevents glass to glass contact while enabling immediate and direct use on the filling line. In essence, Direct to Fill.Outer Cardboard or PP-Well Box 80 x 53 x 24 cmLabel with ETO indicator7NIPRO PHARMAPACKAGING INTERNATIONAL HEADQUARTERSBlokhuisstraat 42, 2800 Mechelen, Belgium |*******************************| Nipro PharmaPackaging is specialized in developing and manufacturing advanced pharma packaging products and complete packaging solutions for early development drugs or the enhancement of packaging solutions for existing drugs.With a worldwide manufacturing footprint of 15 plants, multiple sales offices, and internal lab services, Nipro PharmaPackaging offers an exceptional service platform. Through our personnel, products, and services, Nipro PharmaPackaging enables you to provide a safer and healthier administration to your customers.Nipro PharmaPackaging is part of Nipro Corporation Japan, established in 1954. As a leading global healthcare company with over 28.000 employees worldwide, Nipro serves the Pharmaceutical, Medical Device, and Pharma Packaging industries.B r o -P r e f i l l a b l e S y r i n g e s -26.O c t .18。
HOBT EDCI
Design,Synthesis,and Biological Activity of Boronic Acid-Based Histone Deacetylase Inhibitors Nobuaki Suzuki,†Takayoshi Suzuki,*,†Yosuke Ota,†Tatsuya Nakano,‡Masaaki Kurihara,§Haruhiro Okuda,§Takao Yamori,# Hiroki Tsumoto,†Hidehiko Nakagawa,†and Naoki Miyata*,†,§Graduate School of Pharmaceutical Sciences,Nagoya City Uni V ersity,3-1Tanabe-dori,Mizuho-ku,Nagoya,Aichi467-8603,Japan,Di V ision of Medicinal Safety Science,National Institute of Health Sciences,1-18-1Kamiyoga,Setagaya-ku,Tokyo158-8501,Japan,Di V ision of Organic Chemistry,National Institute of Health Sciences,1-18-1Kamiyoga,Setagaya-ku,Tokyo158-8501,Japan,and Di V ision of Molecular Pharmacology,Cancer Chemotherapy Center,Japanese Foundation for Cancer Research,3-10-6Ariake,Koto-ku,Tokyo135-8550,Japan Recei V ed February2,2009Guided by the proposed catalytic mechanism of histone deacetylases(HDACs),we designed and synthesizeda series of boronic acid-based HDAC inhibitors bearing an R-amino acid moiety.In this series,compounds(S)-18,20,and21showed potent HDAC-inhibitory activity,highlighting the significance of the(S)-aminoacid moiety.In cancer cell growth inhibition assays,compounds(S)-18,20,and21exerted strong activity,and the values of the ratio of the concentration causing50%growth inhibition(GI50)to the concentrationcausing50%enzyme inhibition(IC50),i.e.,GI50/IC50,were low.The potency of these compounds was similarto that of clinically used suberoylanilide hydroxamic acid(SAHA)(2).The results of Western blot analysisindicated that the cancer cell growth-inhibitory activity of compounds(S)-18,20,and21is the result ofHDAC inhibition.A molecular modeling study suggested that the hydrated boronic acid interacts with zincion,Tyr residue,and His residue in the active site of HDACs.Ourfindings indicate that these boronic acidderivatives represent an entry into a new class of HDAC inhibitors.IntroductionThe acetylation status of lysine residues in nucleosomal histones is tightly controlled by two counteracting enzyme families,the histone acetyl transferases and the histone deacety-lases(HDACs a).1The latter family can be divided into two categories:Zn2+-dependent enzymes and NAD+-dependent enzymes.2The Zn2+-dependent HDACs are closely connected with control of gene expression and cell cycle progression.3The inhibition of HDACs causes histone hyperacetylation and leads to transcriptional activation of genes such as p21WAF/CIP1,Gadd 45,FAS,and caspase-3,which are associated with growth arrest and apoptosis in tumor cells.4Indeed,HDAC inhibitors,such as trichostatin A(TSA,1),5suberoylanilide hydroxamic acid (SAHA,also known as vorinostat,2),6PXD-101(3),7and MS-275(4)8(Chart1),have been reported to inhibit cell growth, induce terminal differentiation in tumor cells,and prevent the formation of malignant tumors,and they have been developed as antitumor agents.Among them,SAHA has recently been approved by the FDA for treatment of cutaneous T-cell lymphoma.In addition,there are several lines of evidence indicating that HDAC inhibitors are effective as therapeutic agents for other diseases,including inflammation and neuro-degenerative diseases.9Moreover,it has recently been reported that HDAC inhibitors,such as TSA(1),SAHA(2),and valproic acid,improve the efficiency of induction of pluripotent stem cells without introduction of the oncogene c-Myc,suggesting the importance of HDAC inhibitors in regenerative medicine.10Consequently,there are many ongoing research programs to find more potent and selective HDAC inhibitors.11To date,X-ray crystal structures of human HDAC4,12 HDAC7,13HDAC8,14and archaebacterial HDAC-like protein (HDLP)15have been published.A number of potent and selective inhibitors have been identified by structure-based drug design using these crystal structures.11Recently,the catalytic mechanism of the deacetylation of acetylated lysine substrates by HDACs was proposed,based on a density functional theory QM/MM study of HDLP,16and this also offers many clues for the design of HDAC inhibitors.Herein we report the synthesis and biological activity of boronic acid-based HDAC inhibitors, which were designed on the basis of the proposed catalytic mechanism of HDACs.ChemistryCompounds5-26prepared for this study are shown in Tables 1-3.The routes used for the synthesis of the compounds are shown in Schemes1-5.Scheme1shows the preparation of R-amino acid derivatives5-10.These compounds were syn-thesized from diethyl pound27was treated with(Boc)2O to yield N-Boc pound 28was allowed to react with5-bromopent-1-ene in the presence of NaOEt in refluxing EtOH to give C-alkylated compound29. Hydrolysis of the ethyl ester of29with an equivalent amount of LiOH gave monocarboxylic acid30,and subsequent decar-boxylation reaction afforded R-amino acid derivative31. Compound31was hydrolyzed with LiOH followed by treatment with an appropriate aromatic amine in the presence of EDCI and HOBt to give amides33-38.The hydroboration reaction of amides33-38with pinacolborane using[Ir(cod)Cl]2catalyst and dppm or dppe ligand gave terminal boronic esters39-44.17 Hydrolysis of the boronic esters39-44using NH4OAc and NaIO4in acetone-water yielded boronic acids5-10.18 Scheme2shows the preparation of boronic acids11-16,in which the R-amino moiety of compounds5-10was removed.*To whom correspondence should be addressed.For T.S.:phone andfax,+81-52-836-3407;e-mail,suzuki@phar.nagoya-cu.ac.jp.For N.M.:phone and fax,+81-52-836-3407;miyata-n@phar.nagoya-cu.ac.jp.†Nagoya City University.‡Division of Medicinal Safety Science,National Institute of HealthSciences.§Division of Organic Chemistry,National Institute of Health Sciences.#Japanese Foundation for Cancer Research.a Abbreviations:HDAC,histone deacetylase;TSA,trichostatin A;SAHA,suberoylanilide hydroxamic acid;HDLP,HDAC-like protein.J.Med.Chem.2009,52,2909–2922290910.1021/jm900125m CCC:$40.75 2009American Chemical SocietyPublished on Web04/14/2009These compounds were synthesized from hept-6-enoic acid 45using the same synthetic approach as described for compounds 5-10.Scheme 3shows the preparation of R -amino acid derivatives 17-24,in which the Boc group of 6was replaced with various carbonyl moieties.These compounds were prepared from 40in three steps:deprotection of the Boc group,condensation with an appropriate aromatic carboxylic acid,and hydrolysis of the boronic esters.Scheme 4shows the preparation of malonic acid derivatives 25and 26,in which the R -aminocarbonyl moiety of compounds 18and 20was replaced with the corresponding carboxamide.These compounds were synthesized from tert -butyl ethyl malonate 66.Treatment of 66with 5-bromopent-1-ene in the presence NaH in THF yielded compound 67.The ethyl ester of 67was hydrolyzed with an equivalent amount of LiOH,followed by condensation with biphenyl-3-ylamine to give amide 69.Hydroboration,deprotection of tert -butyl ester using TFA,condensation with an appropriate aromatic amine,and hydrolysis of the boronic ester gave the malonic acid derivatives 25and 26.Scheme 5shows the preparation of optically active R -amino acid derivatives (S )-and (R )-18,20,21.These compounds were synthesized using the procedure reported by Nishino and co-workers.19Compound (RS )-31was subjected to the action of subtilisin from Bacillus licheniformis in a mixture of DMF and water to yield (S )-32as a white solid.The recovered (R )-31was hydrolyzed with LiOH to afford (R )-32.The synthesis of (S )-and (R )-18,20,21was accomplished from (S )-32or (R )-32using the procedure described for the synthesis of R -amino acid derivatives (shown in Schemes 1and 3).The enantiomeric excess of (S )-and (R )-18,20,21was determined to be >95%by chiral column chromatography.Results and DiscussionDrug Design.In 1999,Finnin et al.reported X-ray crystal structures of HDLP complexed with inhibitors.15The enzyme contains a zinc ion at the bottom of the active site,and the active center consists of a tyrosine,two aspartic acids,and three histidines.In 2006,Corminboeuf et al.carried out density functional theory QM/MM studies on the deacetylation reaction catalyzed by HDLP.16The proposed mechanism suggested by the calculation results is depicted in Figure 1a.In this mecha-nism,the carbonyl oxygen of the substrate binds the zinc ion and is located adjacent to a water molecule.The electrophilicity of the carbonyl carbon is increased by coordination to the zinc ion,and so the carbonyl carbon is attacked by the water molecule activated by His 140and His 141(HDAC1number-ing).This nucleophilic attack results in a tetrahedral transition state,which is stabilized by a zinc -oxygen interaction and by hydrogen bonds with Tyr 303and His 140.In the final step,proton transfer from His 141to the nitrogen of the intermediate triggers scission of the carbon -nitrogen bond to afford the acetate and lysine products.In designing selective HDAC inhibitors,we focused on the proposed deacetylation mechanism.On the basis of this mech-anism,we designed R -amino acid derivatives A (Figure 1b)in which the acetamide of the acetylated lysine substrate is replaced by boronic acid.Because the boron atom of the boronic acids A has a vacant p-orbital,it could be attacked by a water molecule in the active site.The generated boronic acid -H 2O “ate”complex could act as a transition state analogue of the deacetylation of acetylated lysine substrates.That is,the hydrated boronic acid would bind the zinc ion and form two hydrogen bonds with Tyr 303and His 140,which would lead to HDAC inhibition.Enzyme Assays.In our exploratory study on boronic acid-based HDAC inhibitors,we initially focused on the R 1group (Table 1and Supporting Information Figure S1).We chose various aromatic rings as the R 1group because we had already discovered that thiolate compounds bearing aromatic groups such as phenyl,3-biphenyl,and 3-quinolinyl potently inhibited HDACs both in enzyme assays and in cellular assays.11BoronicChart 1.Examples of HDACInhibitorsScheme 1aaReagents and conditions:(a)(Boc)2O,Et 3N,THF,room temp,81%;(b)NaOEt,5-bromopent-1-ene,EtOH,reflux,89%;(c)LiOH ·H 2O,EtOH,H 2O,0°C,94%for 32,99%for 30;(d)toluene,reflux,94%;(e)R 1-NH 2,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI),1-hydroxybenzo-triazole hydrate (HOBt ·H 2O),DMF,room temp,67-95%;(f)[Ir(cod)Cl]2,bis(diphenylphosphino)methane (dppm)or 1,2-bis(diphenylphosphino)ethane (dppe),pinacolborane,CH 2Cl 2,room temp,32-93%;(g)NH 4OAc,NaIO 4,acetone,H 2O,room temp,10-92%.2910Journal of Medicinal Chemistry,2009,Vol.52,No.9Suzuki et al.acids 5-10,in which R 1is various aromatic groups and R 2is -NHBoc,were initially tested with an in vitro assay using HeLa nuclear extract with high HDAC activity (Table 1and Figure S1).Compounds 5-10showed HDAC-inhibitory activity at a concentration of 100µM,while the 3-biphenyl 6,3-quinolinyl 7,and benzthiazole 8compounds were more potent (78-86%inhibition at 100µM).Compounds 6,7,and 8inhibited HDAC activity dose-dependently with IC 50values of 12,16,and 23µM,respectively;these values are much lower than those of the other aromatic analogues 5,9,and 10.We also tested compounds 11-16,which lack the NH-Boc group of com-pounds 5-10,and they were found to be much less potent inhibitors than compounds 5-10(Table 1and Figure S1),suggesting the significance of the R -amino acid moiety.To find more potent HDAC inhibitors,we next focused on the tert -butoxy group of compound 6,the most potent inhibitorScheme 2aaReagents and conditions:(a)R 2-NH 2,EDCI,HOBt,DMF,room temp,72-95%;(b)[Ir(cod)Cl]2,dppm or dppe,pinacolborane,CH 2Cl 2,room temp,13-74%;(c)NH 4OAc,NaIO 4,acetone,H 2O,room temp,35-94%.Scheme 3aaReagents and conditions:(a)HCl,AcOEt,CHCl 3,room temp,100%;(b)R 3-COOH,EDCI,HOBt,DMF,room temp,11-100%;(c)R 3-COCl,Et 3N,CH 2Cl 2,N,N -dimethyl-4-aminopyridine (DMAP),room temp,41%;(d)NH 4OAc,NaIO 4,acetone,H 2O,room temp,19-82%.Scheme 4aaReagents and conditions:(a)NaH,5-bromopent-1-ene,THF,reflux,52%;(b)LiOH ·H 2O,tert -BuOH,H 2O,0°C,100%;(c)biphenyl-3-ylamine,EDCI,HOBt,DMF,room temp,76%;(d)[Ir(cod)Cl]2,dppm,pinacolborane,CH 2Cl 2,room temp,70%;(e)TFA,room temp,100%;(f)(i)oxalyl dichloride,DMF,CH 2Cl 2,0°C;(ii)R 4-NH 2,Et 3N,CH 2Cl 2,0°C,29%for 71,51%for 72;(g)NH 4OAc,NaIO 4,acetone,H 2O,room temp,39%for 26,71%for 25.Boronic Acid-Based Inhibitors Journal of Medicinal Chemistry,2009,Vol.52,No.92911in Table 1.We initially changed the Boc group of compound 6to a Cbz group (compound 17)(Table 2and Supporting Information Figure S2).Compound 17exhibited about 3-fold higher potency than compound 6.We also examined the activity of compound 18,in which the benzyloxy group of compound 17was replaced with a simple benzene ring,and the activity of 18(IC 50) 2.0µM)was about 2-fold higher than that of compound 17.By the mimicking of the partial structure of TSA (1),we introduced the dimethylamino group at the 4-position of the phenyl ring of compound 18,but compound 19displayed a 6.5-fold decrease in potency compared to the parent compound 18.Next,we converted the phenyl ring of compound 18to various heteroaryl rings.The 2-indole 23and 2-quinoline 24compounds exhibited HDAC-inhibitory activity less potent than that of the phenyl compound 18,whereas the 3-pyridine 20,5-thiazole 21,and 4-thiazole 22derivatives showed potencies similar to or greater than that of the phenyl compound 18(IC 50values:20)2.0µM,21)1.4µM,22)4.7µM),highlighting the importance of small ring size.To confirm the importance of R -amino acid structure,we examined the activity of malonic acid derivatives 25and 26in which the R -aminocarbonyl moiety of compounds 18and 20is replaced by the corresponding carboxamide (Table 2and Figure S2).Compounds 25and 26showed about 15-and 25-fold decreases in potency compared with the parent compounds 18and 20,respectively.Scheme 5aaReagents and conditions:(a)subtilisin,H 2O/DMF (1:3),37°C,42%for (R )-31,50%for (S )-32;(b)LiOH ·H 2O,EtOH,H 2O,room temp,100%;(c)biphenyl-3-ylamine,EDCI,HOBt,DMF,room temp,56-65%;(d)[Ir(cod)Cl]2,dppm,pinacolborane,CH 2Cl 2,room temp,79-82%;(e)HCl,AcOEt,CHCl 3,room temp,100%;(f)R 5-COOH,EDCI,HOBt,DMF,room temp,64-90%;(g)NH 4OAc,NaIO 4,acetone,H 2O,room temp,4-87%.Figure 1.(a)Proposed mechanism for the deacetylation of acetylated lysine substrates.(b)Proposed mechanism of inhibition of HDACs by boronic acids A .2912Journal of Medicinal Chemistry,2009,Vol.52,No.9Suzuki et al.Next we examined the influence of optical -pounds (R )-18,20,21and (S )-18,20,21were prepared and evaluated for their inhibitory effects on HDAC1,HDAC2,HDAC6,and HDAC8,as well as total HDACs from nuclear extracts.As shown in Table 3and Supporting Information Figure S3,in all cases,(S )-18,20,and 21were at least 10-fold more active than (R )-18,20,and 21,respectively.Since the stereochemistry of (S )-18,20,and 21is the same as that of natural lysine,these results suggest that these boronic acids act in the active site of HDACs.Among (S )-18,20,and 21,(S )-21was found to be the most potent pound (S )-21inhibited all HDACs with IC 50values in the micromolar or submicromolar range.Although (S )-21was less potent than SAHA (2),the isoform inhibition profile of (S )-21was similar to that of 2,which is the only HDAC inhibitor currently used in clinical practice.Cellular Assays.To examine the effectiveness of boronic acid-based HDAC inhibitors as anticancer drugs and tools for biological research,compounds (S )-18,20,and 21,as well as SAHA (2),were tested in a cancer cell growth inhibition assay.For initial screening,we used stomach cancer MKN45cells because HDAC inhibitors have been reported to inhibit the cell growth of MKN45cells.20The results are summarized in Ta-ble 4.SAHA (2)and its derivatives have been reported to show potent HDAC-inhibitory activity in enzyme assays and cancer cell growth inhibition assays.21However,a relatively large shift in potency between enzyme assay and cellular assay (GI 50/IC 50,abbreviated as potency shift in this paper)was observed with those hydroxamate HDAC inhibitors.21Indeed,as shown in Table 4,SAHA (2)exhibited a large potency shift in the cancerTable 1.HDAC Inhibitory Activity of Boronic Acids 5-16aaValues are the mean of at least three experiments.IC 50of SAHA (2)is 0.28µM.Table 2.HDAC Inhibitory Activity of 17-26aaValues are the mean of at least three experiments.Table 3.HDAC Inhibitory Activity of (S )-and (R )-18,20,21aIC 50(µM)class Icompd HDAC (nuclear extract)HDAC1HDAC2HDAC8class II,HDAC620.280.350.25 1.70.028(S )-18 1.6>10b 3.6>100 1.1(R )-1817>100>100>10024(S )-20 1.4 2.80.83230.32(R )-2015>10099>10014(S )-210.92 2.20.53 6.60.11(R )-2124>100>100>1005.6aValues are the mean of at least three experiments.b 38%inhibition at 10µM.Table 4.Growth-Inhibitory Activity on MKN45Cells and GI 50/IC 50Values of SAHA (2)and (S )-18,20,21aGI 50/IC 50compd GI 50(µM)HDAC HDAC1HDAC227.3262129(S )-189.3 5.8<0.93 2.6(S )-20 5.5 3.9 2.0 6.6(S )-213.53.81.66.6aValues are the mean of two separate experiments.Boronic Acid-Based InhibitorsJournal of Medicinal Chemistry,2009,Vol.52,No.92913cell growth inhibition assay using MKN45cells.22The reason for the large potency shift of SAHA (2)is unclear,but it seems reasonable to assume that it is at least partly due to poor membrane permeability resulting from the highly polar character of hydroxamic ing Advanced Chemistry Development (ACD/Laboratories)software,version 8.14for Solaris,the log D (pH 7)values of methylhydroxamic acid (CH 3CONHOH)and methylboronic acid (CH 3B(OH)2)were calculated to be -1.59and 1.0,respectively.The calculation results suggest that boronic acid is more lipophilic than hydroxamic acid under physiological conditions,and boronic acid derivatives might permeate through the cell membrane more efficiently than hydroxamates;there-fore,they might not show such large potency shifts as hydroxamates like SAHA (2).We then evaluated the growth-inhibitory activity of (S )-18,20,and 21on MKN45cells.As we expected,(S )-18,20,and 21inhibited the growth of MKN45cells and showed smaller potency shift values than SAHA (2).Among (S )-18,20,and 21,compound (S )-21showed the highest activity,being more potent than SAHA (2).Next,we evaluated growth inhibition by SAHA (2)and compound (S )-21against nine human cancer cell lines (Table 5).Compound (S )-21exerted potent growth inhibition against various human cancer cells,with GI 50values ranging from 0.73to 9.1µM,and these inhibitory activities were similar to those of SAHA (2)(average GI 50of (S )-21is 4.0µM,that of SAHA is 6.0µM).In addition,compound (R )-21did not show strong activity against these cancer cell lines (Table S1and Figure S4in Supporting Information)with GI 50s values ranging from 13to 21µM,suggesting the responsibility of HDAC inhibition for cancer cell growth repression.Next,we performed Western blot analysis to examine the HDAC-inhibitory effects of boronic acid derivatives in cells.Since nuclear HDACs such as HDAC 1and HDAC2catalyze the deacetylation of histones,3d the acetylation level of histone H4in human colon cancer HCT116cells was analyzed after treatment of the cells with compounds (S )-18,20,and 21.As can be seen in Figure 2,the level of acetylated histone H4was elevated dose-dependently.The level of acetylated R -tubulin was also investigated because (S )-18,20,and 21displayed potent inhibition of HDAC6,which is reported to catalyze the deacetylation of R -tubulin.23As expected,compounds (S )-18,20,and 21caused a dose-dependent increase in acetylation of R -tubulin.These results suggest that the cancer cell growth inhibition by boronic acids (S )-18,20,and 21was the result of HDAC inhibition.Molecular Modeling.Since the results of the enzyme assays (Table 3)suggested that boronic acids act within the active center of HDACs,we studied the binding mode of hydrated (S )-21within this site.We calculated the low energy conforma-tion of the hydrated (S )-21complex docked in a model based on the crystal structure of HDAC8(PDB code 1T67)using Macromodel 9.6software (Figure 3).An inspection of the complex shows that one of the oxygen atoms of the hydrated boronic acid can coordinate to the zinc ion (distance between oxygen and zinc,2.04Å)(Figure 3,left).In addition,the hydrogen of the OH group of Tyr 306is located 1.95and 2.20Åfrom the two oxygen atoms of the hydrated boronic acid,Table 5.Growth Inhibition of Various Cancer Cells Using SAHA (2)and (S )-21aGI 50(µM)cell2(S )-21HBC-5breast cancer17 6.5SNB-78central nervous system 169.1HCT116colon cancer 0.580.73DMS114lung cancer 2.9 2.4LOX-IMVI melanoma 1.3 1.3SK-OV-3ovarian cancer 2.5 2.2RXF-631L renal cancer 2.0 3.2MKN45stomach cancer 7.3 3.5PC-3prostate cancer 4.6 6.7mean6.04.0aValues arethe mean of two separate experiments.Figure 2.Western blot detection of acetylated R -tubulin and histone H4levels in HCT116cells after 8h treatment with (S )-18,20,21and reference compound 2.Figure 3.View of the conformation of (S )-21(ball-and-stick)docked in the HDAC8catalytic core.Residues within 5Åfrom the zinc ion are displayed in the tube graphic (left),and the surface of the enzyme is displayed in gray (right).2914Journal of Medicinal Chemistry,2009,Vol.52,No.9Suzuki et al.which suggests that Tyr306can form two hydrogen bonds with the hydrated boronic acid.Moreover,a short distance(2.22Å) between one of the hydrogens of the hydrated boronic acid and the nitrogen of His142was also observed.This indicates that hydrated boronic acids inhibit HDACs by interacting with the zinc ion,Tyr residue,and His residue in the active center.On the surface of HDAC8,the biphenyl ring is located in the hydrophobic region formed by the benzene rings of Tyr100 and Phe152and the alkyl chain of Lys33,and the thiazole ring lies in the hydrophobic area formed by the benzene ring of Tyr100and the methylene groups of Asp101,Gly151,and Phe208(Figure3,right).It is also suggested that two hydrogen bonds can be formed between the two NH groups and the carboxylate anion of Asp101(the distances are1.72and1.74Å).The observed interactions between(S)-21and HDAC8on the surface of the enzyme suggest the importance of the amino acid structure and the(S)-configuration of the inhibitor. ConclusionOn the basis of the proposed catalytic mechanism for the deacetylation of acetylated lysine substrates by HDACs,we designed a series of boronic acids bearing an R-amino acid moiety as candidate mechanism-based HDAC inhibitors.Among the synthesized compounds,compounds(S)-18,20,and21 displayed potent HDAC-inhibitory activities,suggesting that these boronic acids act in the active site of pounds (S)-18,20,and21also showed cancer cell growth-inhibitory activities as potent as SAHA(2).Intracellular HDAC inhibition by compounds(S)-18,20,and21was confirmed by Western blot analysis of acetylated histone H4and acetylated R-tubulin.A molecular modeling study of the HDAC8/(S)-21complex suggested that the hydrated boronic acid interacts with zinc ion, Tyr residue,and His residue in the active site of HDACs. Thus,we have identified a novel lead structure from which it should be possible to develop more potent HDAC inhibitors. Although boronic acids have been used as inhibitors for various hydrolytic enzymes such as serine protease,24arginase,25and proteasome,26this is thefirst report of HDAC inhibitors containing a boronic acid moiety.The results obtained in this study suggest that boronic acid-based inhibitors of HDACs have considerable potential for the development of novel therapeutic agents and tools for biological research.Experimental SectionChemistry.Melting points were determined using a Yanagimoto micro melting point apparatus or a Bu¨chi545melting point apparatus and were left uncorrected.Proton nuclear magnetic resonance spectra(1H NMR)and carbon nuclear magnetic resonance spectra(13C NMR)were recorded with a JEOL JNM-LA500,JEOL JNM-A500,or Bruker Avance600spectrometer in solvents as indicated.Chemical shifts(δ)are reported in parts per million relative to the internal standard tetramethylsilane.Elemental analysis was performed with a Yanaco CHN CORDER NT-5analyzer,and all values were within(0.4%of the calculated values,which indicates>95%purity of the tested compounds.Fast atom bombardment(FAB)mass spectra were recorded on a JEOL JMS-SX102A mass spectrometer.In positive-mode MS analysis using 3-nitrobenzyl alcohol(NBA)as a matrix,boronic acids are esterified with NBA and the molecular weight detected corresponds to(M+2NBA-2H2O+H)+or(M+2NBA-2H2O)+.In negative-mode analysis using glycerol(Gly)as a matrix,the molecular weight detected corresponds to(M+Gly-2H2O-H)-.HPLC was performed with a Shimazu instrument equipped with a CHIRALPAK IA column(4.6mm×250mm,Daicel Chemical Industries),and the samples eluted at1mL/min with ethanol and n-hexane.Reagents and solvents were purchased from Aldrich,Tokyo Kasei Kogyo,Wako Pure Chemical Industries,and Kanto Kagaku and used without purification.Flash column chromatog-raphy was performed using silica gel60(particle size0.046-0.063 mm)supplied by Merck.6-tert-Butoxycarbonylamino-7-oxo-7-phenylaminoheptylbo-ronic Acid(5).Step1:Preparation of Diethyl2-tert-Butoxy-carbonylaminomalonate(28).To a suspension of diethyl ami-nomalonate(27;10.0g,47.2mmol)and Et3N(32.9mL,236mmol) in THF(20mL)was added a solution of(Boc)2O(20.6g,94.4 mmol)in THF(10mL),and the solution was stirred overnight at room temperature.The reaction mixture was poured into water and extracted with AcOEt.The AcOEt layer was washed with water and brine and dried over Na2SO4.Filtration and concentration in vacuo and purification by silica gelflash column chromatography (AcOEt/n-hexane)1/5)gave10.5g(81%)of28as a colorless oil:1H NMR(CDCl3,500MHz,δ,ppm)5.56(1H,d,J)6.7Hz), 4.95(1H,d,J)7.6Hz),4.27(4H,m),1.45(9H,s),1.30(6H,t, J)7.3Hz).Step2:Preparation of Diethyl2-tert-Butoxycarbonylamino-2-(penten-4-yl)malonate(29).To a solution of28(10.2g,37.2 mmol)obtained above in EtOH(15mL)was added NaOEt(2.78 g,40.9mmol)under Ar gas at0°C.The reaction mixture was stirred at0°C for7min.After that,to the solution was added 5-bromopent-1-ene(8.32g,55.8mmol),and the mixture was refluxed for10h.It was then poured into water and extracted with AcOEt.The AcOEt layer was washed with water and brine and dried over Na2SO4.Filtration and concentration in vacuo and purification by silica gelflash column chromatography(AcOEt/n-hexane)1/6)gave11.3g(89%)of29as a colorless oil:1H NMR (CDCl3,500MHz,δ,ppm)5.94(1H,broad s),5.76(1H,ddt,J) 17,10,6.4Hz),5.00(1H,dd,J)15,1.8Hz),4.95(1H,d,J)10 Hz),4.26-4.18(4H,m),2.28(2H,m),2.07(2H,q,J)7.3Hz), 1.43(9H,s),1.30-1.19(8H,m).Step3:Preparation of2-tert-Butoxycarbonylamino-2-(ethoxy-carbonyl)hept-6-enoic Acid(30).To a solution of29(11.3g,33.0 mmol)obtained above in EtOH/H2O(20mL/10mL)was added LiOH·H2O(1.52g,36.3mmol),and the solution was stirred overnight at0°C.The reaction mixture was neutralized with10% citric acid and extracted with AcOEt.The AcOEt layer was washed with brine and dried over Na2SO4.Filtration and concentration in vacuo gave10.3g(99%)of30as a yellow oil:1H NMR(CDCl3, 500MHz,δ,ppm)5.80-5.71(2H,m),5.01(1H,dd,J)17,1.5 Hz),4.97(1H,dd,J)10,1.8Hz),4.31-4.18(2H,m),2.22(2H, m),2.07(2H,m),1.44(9H,s),1.39-1.22(5H,m).Step4:Preparation of Ethyl2-tert-Butoxycarbonylamino-hept-6-enoate(31).A solution of30(10.3g,32.6mmol)obtained above in toluene(40mL)was refluxed for9h.The reaction mixture was concentrated and purified byflash column chromatography (AcOEt/n-hexane)1/6)to give8.51g(94%)of31as a yellow oil:1H NMR(CDCl3,500MHz,δ,ppm)5.77(1H,ddt,J)17, 10,6.7Hz),5.04-4.94(3H,m),4.28(1H,m),4.19(2H,m),2.07 (2H,m),1.81(1H,m,),1.63(1H,m),1.53-1.37(11H,m),1.28 (3H,t,J)7.3Hz).Step5:Preparation of2-tert-Butoxycarbonylaminohept-6-enoic Acid(32).To a solution of31(8.34g,30.8mmol)obtained above in EtOH/H2O(20mL/10mL)was added LiOH·H2O(1.25 g,29.8mmol),and the solution was stirred overnight at0°C.The reaction mixture was neutralized with10%citric acid and extracted with AcOEt.The AcOEt layer was washed with brine and dried over Na2SO4.Filtration and concentration in vacuo gave7.01g (94%)of32as a white solid:1H NMR(CDCl3,500MHz,δ,ppm) 5.78(1H,ddt,J)17,10,6.7Hz),5.06-4.94(3H,m),4.32(1H, m),2.09(2H,m),1.87(1H,m),1.68(1H,m),1.57-1.37(11H, m).Step6:Preparation of tert-Butyl1-(Phenylaminocarbonyl) hex-5-en-1-ylcarbamate(33).To a solution of32(1.00g,4.11 mmol)and aniline(560µL,6.17mmol)in DMF(15mL)were added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochlo-ride(EDCI;1.18g,6.17mmol)and1-hydroxy-1H-benzotriazole monohydrate(HOBt·H2O;834mg,6.17mmol),and the mixture was stirred overnight at room temperature.The reaction mixtureBoronic Acid-Based Inhibitors Journal of Medicinal Chemistry,2009,Vol.52,No.92915。
AKT蛋白酶联免疫分析试剂盒使用说明书
人AKT蛋白（AKT）酶联免疫分析(ELISA)试剂盒使用说明书本试剂仅供研究使用目的：本试剂盒用于测定人血清、血浆、组织等样本中AKT蛋白（AKT）的含量。
实验原理：本试剂盒应用双抗体夹心法测定标本中人AKT蛋白（AKT）水平。
用纯化的人AKT蛋白（AKT）捕获抗体包被微孔板，制成固相抗体，往包被的微孔中依次加入人AKT蛋白（AKT），再与HRP标记的检测抗体结合，形成抗体-抗原-酶标抗体复合物，经过彻底洗涤后加底物TMB显色。
TMB在HRP酶的催化下转化成蓝色，并在酸的作用下转化成最终的黄色。
颜色的深浅和样品中的人AKT蛋白（AKT）呈正相关。
用酶标仪在450nm波长下测定吸光度（OD值），通过标准曲线计算样品中人AKT蛋白（AKT）含量。
试剂盒组成：样本处理及要求：1. 血清：室温血液自然凝固10-20分钟，离心20分钟左右（2000-3000转/分）。
仔细收集上清，保存过程中如出现沉淀，应再次离心。
2. 血浆：应根据标本的要求选择EDTA或柠檬酸钠作为抗凝剂，混合10-20分钟后，离心20分钟左右（2000-3000转/分）。
仔细收集上清，保存过程中如有沉淀形成，应该再次离心。
3. 尿液：用无菌管收集，离心20分钟左右（2000-3000转/分）。
仔细收集上清，保存过程中如有沉淀形成，应再次离心。
胸腹水、脑脊液参照实行。
4. 细胞培养上清：检测分泌性的成份时，用无菌管收集。
离心20分钟左右（2000-3000转/分）。
仔细收集上清。
检测细胞内的成份时，用PBS（PH7.2-7.4）稀释细胞悬液，细胞浓度达到100万/ml左右。
通过反复冻融，以使细胞破坏并放出细胞内成份。
离心20分钟左右（2000-3000转/分）。
仔细收集上清。
保存过程中如有沉淀形成，应再次离心。
5. 组织标本：切割标本后，称取重量。
加入一定量的PBS，PH7.4。
用液氮迅速冷冻保存备用。
标本融化后仍然保持2-8℃的温度。
美国贝克曼库尔特流式细胞分析仪
美国贝克曼库尔特流式细胞分析仪（Beckman coulter cell）产品型号：Cell Lab Quanta SC当前价格：0.00元产品数量：0新旧程度：全新有效期至：0000-00-00所在地：产品简介：仪器简介：T细胞亚群检测的CD45/CD4/CD8/CD3、CD45/CD56/CD19/CD3；阵发性血红蛋白尿（PNH）检测的CD55、CD59；血小板无力症（GT）检测的CD41、CD61等等详细信息仪器简介：T细胞亚群检测的CD45/CD4/CD8/CD3、CD45/CD56/CD19/CD3；阵发性血红蛋白尿（PNH）检测的CD55、CD59；血小板无力症（GT）检测的CD41、CD61等等。
但对于白血病/淋巴瘤免疫分型，国际上迄今为止也没有统一的抗体组合。
在2000年国际细胞分析学会（ISAC）大会上，临床血细胞计数协会组织了一次国际专家会议，以期对检测血液淋巴系统肿瘤所需最少、最有效的单抗数达成共识。
75%与会者一致认为，对于慢性淋巴系统增殖性疾病（CLD）有9种单抗：CD5,CD19,κ,λ,CD3,CD20,CD23,CD10,CD45对初诊来说是最基本的。
淋巴瘤和CLD相似，需要至少12-16种单抗。
对于急性白血病（AL），75%的与会者认为大约13-15种单抗是最基本的：CD10,CD19,CD79a,CD13,CD33,CD34,CD45,CD2,MPO，CD7,CD14,CD3,HLA-DR等，对初步鉴别白血病系列是必需的。
其他一些（CD16,CD56,CDw65,TdT,cyCD3）可能对某些病例有用。
几乎所有的投票者都认为，要对急性白血病完善分类所需单抗的恰当数量平均为20-24种。
但这些抗体之间组合也是一大难题，目前也无统一规定（如表二）。
大会多数发言者(11/13)指出，对已确诊病人的监护和分期来说，仅需较少单抗。
抗体的质量控制是实验的关键环节。
抗体的质量包括其特异性、灵敏度、精密度。
GENMED 柠檬酸化学法冰冻组织抗原修复处理试剂盒 产品说明书（中文版）
GENMED SCIENTIFICS INC. U.S.A GMS40039.3 v.A GENMED柠檬酸化学法冰冻组织抗原修复处理试剂盒产品说明书（中文版）主要用途GENMED柠檬酸化学法冰冻组织抗原修复处理试剂是一种旨在通过柠檬酸缓冲系统，辅以物理加热的强化处理，进行醛类固定的冰冻组织块的抗原修复和暴露，增强免疫化学的染色强度，降低背景噪音的权威而经典的技术方法。
该技术由大师级科学家精心改良、成功实验证明的。
主要适用于醛类处理的冰冻动物组织块的各种抗原的修复，尤其是核蛋白的修复。
产品即到即用，操作简捷，性能稳定，修复显著，敏感可靠。
技术背景组织制片固定时，使用醛类固定剂（例如福尔马林等），会导致醛类分子与组织蛋白产生分子交联，遮蔽了组织抗原。
其原理是在组织蛋白的反应部位（胺、氨类基团、巯基、氢氧基团、芳香环等）形成了亚甲基桥（methylene bridges）。
通过物理热处理和化学处理方法，破坏醛类分子交联，暴露和修复抗原。
产品内容GENMED清理液（Reagent A）XX毫升GENMED固着液（Reagent A）XX毫升GENMED修复液（Reagent B）XX毫升GENMED保护液（Reagent B）XX毫升产品说明书1份保存方式保存在4℃冰箱里，有效保证6月用户自备小型染色缸：用于清理的容器200毫升烧杯：用于修复操作的容器实验步骤1．准备1个6孔细胞培养板2．放进新鲜切除的或冰冻保存的动物组织样本（注意：建议组织大小为0.5厘米厚，1厘米长；如果过大，最好刀切处理一下）3．将组织压平4．小心加入XX毫升GENMED清理液（Reagent A），清洗组织样本5．小心抽去清理液6．小心加入XX毫升GENMED固定液（Reagent B），浸没整个组织7．在4℃条件下孵育2小时8．小心抽去固定液9．小心加入XX毫升GENMED清理液（Reagent A），清洗组织样本10．小心抽去清理液11．小心加入XX毫升GENMED修复液（Reagent C），浸没整个组织12．在4℃条件下孵育16小时13．准备一个200毫升的烧杯14．加入XX毫升GENMED修复液（Reagent C）15．煮沸16．用镊子取出组织，放入到煮沸的GENMED修复液（Reagent C）中17．孵育5分钟18．用镊子取出组织，放入到预冷的XX毫升GENMED保护液（Reagent D）里，浸没整个组织19．在4℃条件下孵育，直至组织块沉入底部20．即刻包埋和冰冻21．放进－80℃冰箱保存22．进行冰冻切片23．继续后续免疫化学染色操作注意事项1．本产品为20次操作2．操作时，须戴手套3．操作时，避免污染母液，尤其是GENMED保护液（Reagent D）4．本公司提供系列组织抗原修复试剂产品质量标准1．本产品经鉴定性能稳定2．本产品经鉴定修复效果显著使用承诺杰美基因秉着“信誉至上、客户满意、质量承诺”的宗旨为我们的用户提供优质产品和服务。
抗体公司
赛信通（上海）生物试剂有限公司
上海市浦东南路1101号远东大厦514室，200120 info@cst www.cst 2158356288 公司总部: 美国
Established in Beverly, MA in 1999, Cell Signaling Technology (CST) is a privatelyowned company with over 400 employees worldwide. We are dedicated to providing innovative research tools that are used to help define mechanisms underlying cell function and disease. Since its inception, CST has become the world leader in the production of the highest quality activationstate and total protein antibodies utilized to expand knowledge of cell signaling pathways. Our mission is to deliver the world's highest quality research tools that accelerate progress in biological research and personalized medicine. 总引用数为4670，来自于1966篇文章。最常引用的试剂包括： Akt, ERK2, ERK1, p38, Akt1。
AbD Serotec (BioRad)
抗酒石酸酸性磷酸酶(TRAP)检测试剂盒(PNP比色法)
抗酒石酸酸性磷酸酶(TRAP)检测试剂盒(PNP微板法)简介：酸酸性磷酸酶(acid phosphatase，ACP)分布极广泛，遍布各种组织，主要存在于细胞的溶酶体内，所以常作为溶酶体标志酶。
溶酶体外的酸性磷酸酶存在于内质网和胞质内，各种动物中的酸性磷酸酶各有不同，酸性磷酸酶的适宜pH为4.5～5.5。
存在于正常人肺泡巨噬细胞和白血病人脾脏的抗酒石酸酸性磷酸酶(Tartrate-resistnt acid phosphatase，TRAP)均在细胞滤泡中，并不是释放入血液，血液中的TRAP绝大多数来源于破骨细胞，因此可以通过测量血液中的TRAP了解破骨细胞的功能状态，几乎被认为是是机体破骨活性的唯一血液指标。
TRAP一种糖基化的含金属蛋白酶，在破骨细胞(osteoclast)和破软骨细胞(chondroclast)中高表达，在活化的巨噬细胞和神经元中也有表达。
Leagene抗酒石酸酸性磷酸酶检测试剂盒(Tartrate Resistnt Acid Phosphatase Colorimetric Assay Kit)检测原理是利用Para-nitrophenyl phosphate(pNPP)为一种常用的磷酸酶显色底物，在酸性条件下，可在酸性磷酸酶的作用下生成p-nitrophenol。
在碱性条件下p-nitrophenol呈黄色，产物黄色越深，说明酸性磷酸酶活性越高，反之则酶活性越低，通过分光光度比色法(酶标仪)测定吸光度，据此通过比色分析就可以计算出酸性磷酸酶活性水平。
在适量的酒石酸存在的情况下进行酸性磷酸酶的活性检测，检测得到的酸性磷酸酶的活性就是抗酒石酸酸性磷酸酶的活性。
该试剂盒可用于检测细胞或组织的裂解液或匀浆液、血浆、血清、尿液等样品中内源性的抗酒石酸酸性磷酸酯酶活性。
该试剂盒仅用于科研领域，不宜用于临床诊断或其他用途。
组成：自备材料：1、96孔板2、水浴锅或恒温箱3、酶标仪编号名称TE0043120TStorage试剂(A): ACP Assay buffer15ml 4℃试剂(B): pNPP 2支-20℃避光试剂(C): T artrate Solution 1ml 4℃试剂(D): p-nitrophenol(10mM) 0.1ml -20℃避光使用说明书1份操作步骤(仅供参考)：1、配制检测工作液：①配制显色工作液：取出pNPP，恢复至室温后溶解于ACP Assay buffer，混匀，冰上预冷备用。
Perkadox 14-40B-PD-S 产品数据表说明书
Product Data SheetPerkadox 14-40B-PD-S Di(tert-butylperoxyisopropyl) benzenePerkadox® 14-40B-PD-S is a 40% formulation on an inert carrier system in powder form.CAS number2212-81-9, 25155-25-3EINECS/ELINCS No.218-664-7TSCA statuslisted on inventoryMolecular weight338.5Active oxygen contentperoxide9.45%Concentration3.7-3.9%SpecificationsAppearance Off-white powderAssay39.0-41.0 %ApplicationsPerkadox® 14-40B-PD-S is a bifunctional peroxide which is used for the crosslinking of natural rubber and synthetic rubbers, as well as polyolefins. Rubber compounds containing Perkadox® 14-40B-PD-S have excellent scorch safety, and under certain conditions one step mixing is possible. Safe processing temperature: 135°C (rheometer ts2 > 20 min.). Typical crosslinking temperature: 175°C (rheometer t90 about 12 min.).Thermal stabilityOrganic peroxides are thermally unstable substances, which may undergo self-accelerating decomposition. The lowest temperature at which self-accelerating decomposition of a substance in the original packaging may occur is the Self-Accelerating Decomposition Temperature (SADT). The SADT is determined on the basis of the Heat Accumulation Storage Test.SADT80°CMethod The Heat Accumulation Storage Test is a recognized test method for thedetermination of the SADT of organic peroxides (see Recommendations on theTransport of Dangerous Goods, Manual of Tests and Criteria - United Nations, NewYork and Geneva).StorageDue to the relatively unstable nature of organic peroxides a loss of quality can be detected over a period of time. To minimize the loss of quality, Nouryon recommends a maximum storage temperature (Ts max.) for each organic peroxide product.Ts max.30°CNote When stored under strictly recommended storage conditions, Perkadox® 14-40B-PD-S will remain within the Nouryon specifications for a period of at least 12months after delivery.Packaging and transportThe standard packaging is a cardboard box for 25 kg peroxide formulation. Both packaging and transport meet the international regulations. For the availability of other packed quantities consult your Nouryon representative. Perkadox®14-40B-PD-S is classified as Flammable solid, class 4. 1, UN 1325.Safety and handlingKeep containers tightly closed. Store and handle Perkadox® 14-40B-PD-S in a dry well-ventilated place away from sources of heat or ignition and direct sunlight. Never weigh out in the storage room. Avoid contact with reducing agents (e. g. amines), acids, alkalines and heavy metal compounds (e. g. accelerators, driers and metal soaps). Please refer to the Safety Data Sheet (SDS) for further information on the safe storage, use and handling of Perkadox® 14-40B-PD-S. This information should be thoroughly reviewed prior to acceptance of this product. The SDS is available at /sds-search.Major decomposition productsMethane, Acetone, tert-Butanol, Di(2-hydroxyisopropyl)benzene, Diacetylbenzene, Acetyl 2-hydroxyisopropyl benzeneAll information concerning this product and/or suggestions for handling and use contained herein are offered in good faith and are believed to be reliable.Nouryon, however, makes no warranty as to accuracy and/or sufficiency of such information and/or suggestions, as to the product's merchantability or fitness for any particular purpose, or that any suggested use will not infringe any patent. Nouryon does not accept any liability whatsoever arising out of the use of or reliance on this information, or out of the use or the performance of the product. Nothing contained herein shall be construed as granting or extending any license under any patent. Customer must determine for himself, by preliminary tests or otherwise, the suitability of this product for his purposes.The information contained herein supersedes all previously issued information on the subject matter covered. The customer may forward, distribute, and/or photocopy this document only if unaltered and complete, including all of its headers and footers, and should refrain from any unauthorized use. Don’t copythis document to a website.Perkadox® is a registered trademark of Nouryon Functional Chemicals B. V. or affiliates in one or more territories.Contact UsPolymer Specialties Americas************************Polymer Specialties Europe, Middle East, India and Africa*************************Polymer Specialties Asia Pacific************************2022-12-5© 2022Polymer crosslinking Perkadox 14-40B-PD-S。