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Innovations in Peptide Synthesis and Conjugation

Tools for Drug Discovery

sigma-aldrich.com/drugdiscovery

Proline Derivativesand Analogs

New Amino AcidBuilding Blocks

New GuanidinylationReagents

New MonoprotectedBifunctional Linkers

FunctionalizedPolyethylene Glycols

Fluorescent Labelingof Peptides


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To order: Contact your local Sigma-Aldrich office (see back cover),or visit sigma-aldrich.com. s

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IntroductionSigma-Aldrich is a leading supplier of products for peptide andpeptidomimetic synthesis. The increasing relevance of the designof peptidomimetics and peptide analogs in the pharmaceutical

industry prompted us to establish a really unique andcomprehensive portfolio of unnatural amino acids that can beutilized as building blocks, conformational constraints, molecularscaffolds, or pharmacologically active compounds, giving accessto a nearly infinite array of diverse structural elements for thedevelopment of new therapeutic drugs.

Sigma-Aldrich is pleased to introduce more than 60 recentadditions to the portfolio of unnatural amino acid derivatives,building blocks, and selected polyethylene glycols (PEGs) in thisChemFiles.

1. Proline Derivatives and Analogs 1.1 Introduction

1.2 Proline Derivatives

1.3 3-Homoprolines

1.4 Prolines with Substituents in -Position

1.5 Hydroxyproline Derivatives

1.6 4-substituted Proline Derivatives

1.7 Dehydroprolines

1.8 Proline Analogs with Ring Restrictions-Aziridine andAzetidine-2-Carboxylic Acids

1.9 Proline Analogues with Ring Expansions-Pipecolic Acids

1.10 Oxa- and Thia-Prolines

1.11 Prolinol Derivatives

2. New Amino Acid Building Blocks 2.1 New Cyclic -Amino Acid(s)

2.2 Unnatural Alanine and Cysteine Derivatives Obtainedby Fermentation

2.3 Miscellaneous New Amino Acid Building Blocks

Content of this ChemFiles

At Sigma-Aldrich we are committed to being your preferredsupplier of building blocks and tools for drug discovery. Ourbroad range of high-quality products, superior distribution

facilities, user-friendly ordering systems, and vast chemicalknowledge make us the ideal source for all of your research anddevelopment needs in this area.

A strong example of our commitment is the introduction ofseveral hundreds new products every year. Please visit sigma-aldrich.com/new for regular updates of the latest Sigma-Aldrichproducts. If you cannot find a building block, or any otherproduct you are looking for, we welcome your input and will useit to broaden our product range even further. Please contact usat [email protected] with your suggestions!

3. New Guanidinylation Reagents

4. New Monoprotected Bifunctional Linkers 4.1 Protected Aminoalkyl Bromides

4.2 Mono-Alloc-Protected Diamines

5. Functionalized Polyethylene Glycols (PEGs) 5.1 Introduction

5.2 Functionalized Oligoethylene Glycols

5.3 High Oligomer Purity PEGs, n=518

5.4 Homobifunctional PEGs

5.5 Monofunctional PEGs 5.6 PEG Handles and Soluble Polymer Supports

for Synthesis

6. Fluorescent Labeling of Peptides

Your Resource for Drug DiscoveryWhether your interest is Medicinal Chemistry, Polymer-Supported Reagents or Peptides and PeptidomimeticSynthesis, from complex building blocks like bifunctional heterocycles and other heterocyclic building blocks,to amines, alcohols, carboxylic acids and sulfonyl chlorides; we carry a wide range of functionalized resinsand silica gels for use in solid-phase and solution-phase organic synthesis and can solve your chemical needs.Our comprehensive portfolio includes the broad range of common and specialty building blocks, resins, andreagents for solid-phase peptide synthesis as well as solution phase.

For more information: visit sigma-aldrich.com/drugdiscovery


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ProlineDerivatives

a n d A n a l o g s

(1) Brandl, C. J.; Deber, C. M. Proc. Natl. Acad. Sci. USA 1986 ,83 , 917.

(2) Ramachandran, G. N.; Sasisekharan, V. Adv. Prot. Chem. 1968 ,

23 , 283.(3) Steward, D. E.; Sarkar, A; Wampler, J. E. J. Mol. Biol. 1990 ,

254 , 353.

(4) Weiss, M. S.; Jabs, A.; Hilgenfeld, R. Nature Struct. Biol. 1998 ,5 , 676.

(5) Schmid, F. X. Annu. Rev. Biophys. Biomol. Struct. 1993 ,22 ,123.

(6) Schmid, F. X. et al. Adv. Prot. Chem. 1993 , 44 , 25.

(7) Fischer G. et al. Biomed. Biochem. Acta 1984 , 43 , 4401.

(8) Fischer G. et al. Nature (London) 1987 , 329 , 268.

(9) Kern, D.; Schutkowski, M.; Drakenberg, T. J. Am. Chem. Soc.1997 , 119 , 8403.

(10) Bader, R. F. W.; Cheeseman, J. R.; Laidig, K. E.; Wiberg, K. B.;Breneman, C. J. Am. Chem. Soc. 1990 , 112 , 6530.

(11) Yamazaki, T.; Ro, S.; Goodman, M.; Chung, N. N.; Schiller, P. W. J. Med. Chem . 1993 , 36 , 708.

(12) Yu, W. F.; Tung, C. S.; Wang, H.; Tasayco, M. L. Protein Sci.2000 , 9, 20.

(13) Olsen, B. R.; Ninomiya, Y. In Guidebook to the ExtracellularMatrix and Adhesion Proteins ; Kreis, T., Vale, R., Eds; OxfordUniversity Press: Oxford, 1993; p 40.

(14) Mauger, A.B., In Chemistry and Biochemistry of Amino Acids,Peptide and Proteins ; Weinstein, B., Ed.; Marcel Dekker: NewYork, 1977; p 179.

(15) Wagner, I.; Musso, H. Angew. Chem., Int. Ed. Engl. 1983 , 22 ,816.

(16) Metzner, L. et al. JPET , 2004 , 309 , 28.

(17) Goodmann, M.; Niu, G. C.; Su, K. J. J . Am. Chem. Soc. 1970 ,92 , 5219.

(18) Goodman, M.; Chen, V.; Benedetti, E.; Perdone, C.; Corradini,P. Biopolymers 1972 , 11 , 1779.

(19) Shuman, R. T.; Rothenberger, R. B.; Campbell, C. S.; Smith,G. F.; Giffordmoore, D. S.; Paschal, J. W.; Gesellchen, P. D. J.Med. Chem. 1995 , 38 , 4446.

(20) Wnsch, E. et al. Int. J. Pept. Protein Res. 1990 , 36 , 401.

(21) Wnsch, E. et al. Int. J. Pept. Protein Res. 1990 , 36 , 418.

(22) Rahfeld, J.; Schutkowsky, M.; Faust, J.; Neubert, K.; Barth, A.;Heins, J. Biol. Chem. Hoppe-Seyler 1991 , 372 , 313.

(23) Samanen, J.; Cash, T.; Narindray, D.; Brandeis, E.; Adams, W.;Weidemann, H.; Yellin, T.; Regoli, D. J. Med. Chem. 1991 , 34 ,3036.

(24) Kiso, Y. Biopolymers 1996 , 40 , 235.

(25) Karanewsky, D. S.; Badia, M. C.; Cushman, D. W.; DeForrest,J. M.; Dejneka, T.; Lee, V. G.; Loots, M. J.; Petrillo, E. W. J. Med.Chem. 1990 , 33 , 1459.

(26) Einbond, A.; Sudol, M . FEBS Lett . 1996 , 384 , 1.

(27) Lubec, G. Life Sci.1995 , 57 , 2245.

(28) Nelson, R. D. et al. NIDA Research Monograph 1986 , 101.

(29) Chang, L. L. et al. Bioorg. Med. Chem. Lett. 2002 , 12 , 159.

(30) Alonso, E. et al. J. Org. Chem. 2001 , 66 , 6333.

References

1. Proline Derivatives and AnalogsContdComparative studies performed with proline analogues revealedthat the key step in the catalysis of the cis/trans-isomerizationof a peptidyl-prolyl bond is a reduction of the double bond

character of the planar, conjugated CN amide bond. Anyfactor that can weaken the double bond character of the amidebond by destabilizing the planar peptide bond, or shifting thehybridization of the prolyl nitrogen from sp 2 to sp 3, is expectedto accelerate the isomerization. 9,10

In order to understand the relationship between imide bondgeometry and bioactivity of peptides, 11,12 synthetic prolineanalogues have been developed that provide restrictions ofthe Xaa-Pro imide conformation. Such proline mimetics arebased on ring substitutions with alkyl and aromatic groups,incorporation of heteroatoms into the ring, or the expansion orcontraction of the proline ring ( Table 1 ). Those analogues arepromising candidates for conformational studies and for tuningthe biological, pharmaceutical, or physicochemical properties ofnaturally occuring, as well as de novo designed, linear, and cyclicpeptides.

Several proline analogs and homologs occur in nature.Trans-3-hydroxyproline and trans -4-hydroxyproline representconstituents of common proteins as a result of post-translationalhydroxylation, especially in collagens. 13 Various 3- and 4-alkylatedderivatives of proline and hydroxyproline as well as analogueswith ring restrictions, such as aziridine-2-carboxylic acid and

azetidine-2-carboxylic acid, and ring expansions, i.e. pipecolicacid, are found in natural products. 14,15 Derivatives such asL-azetidine-2-carboxylic acid, cis-4-hydroxy-L-proline, and 3,4-

dehydro- DL-proline prevent pro-collagen from folding into astable triple-helical conformation, thereby reducing excessivedeposition of collagen in fibrotic processes and the growth oftumors. 16

Thiazolidine-4-carboxylic acid thiaproline has also beenincorporated into collagen model compounds 17,18 and otherbioactive molecules such as thrombin inhibitors, 19 somatostatin, 20,21

dipeptidyl peptidase IV substrates, 22 angiotensin II, 23 HIVinhibitors, 24 ACE inhibitors, 25 and oxytocin. 26

-Methyl-proline is a bioactive molecule restoring normal levelsof bone collagen type I synthesis. 27 It can be looked at as aconformationally constrained aminoisobutyric acid analog. The -Methyl-proline residue has been inserted into morphiceptin toperform conformational studies on the bioactivity of the Xaa-Pro

cis-/trans -isomers.28

A -methyl-proline containing potential dual 4 1 integrin antagonist has been described recently. 29

-Benzyl-proline combines the conformational restrictions of aproline derivative with the electronic properties of phenylalanine.Spirolactams containing an -benzyl-proline substructure havebeen synthesized as potential beta-turn mimetics. 30


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1.3 3- Homoprolines

Boc- 3-Homopro-OH purum, 98.0% TLCC11 H19NO4

Boc

N

O

OHMW: 229.27

[56502-01-3 ]14982-250MG 82.00 250 mg14982-1G 229.50 1 g

Fmoc-L- 3-Homopro-OH purum, 98.0% HPLCC21H21NO4

N

Fmoc

O

OHMW: 351.4[193693-60-6 ]47912-250MG 89.50 250 mg47912-1G 254.50 1 g

L- 3-Homopro-OH HCl purum, 98.0% TLCC6H11 NO2 HCl

NH

O

OH

HCl

MW: 165.62

[53912-85-9 ]03768-250MG 124.50 250 mg03768-1G 366.00 1 g

1.4 Prolines with Substituents in -Position

Boc- -Me- DL-Pro-OH purum, 96.0% HPLCC11 H19NO4

N

Boc

O

OH

CH 3

MW: 229.27[203869-80-1 ]68691-500MG 167.50 500 mg

-Methyl- L-proline purum, 98.0% TLCC6H11NO2

NH

O

OH

CH 3

MW: 129.16[42856-71-3 ]17249-250MG 115.00 250 mg17249-1G 321.50 1 g

Boc- -propyl- DL-Pro-OH tech., 90% HPLC

C13H23NO4

N

Boc

O

OH

CH 3

MW: 257.33[ 351002-88-5 ]

95566-500MG 167.50 500 mg

Boc- -allyl- DL-Pro-OH purum, 96.0% HPLCC13H21NO4

N

Boc

O

CH 2

OH

MW: 255.31[ 315234-49-2 ]

58147-500MG 167.50 500 mg

Boc-(R )- -allyl-Pro-OH purum, 98.0% HPLC 8

C13H21NO4

N

Boc

OH

O

MW: 255.31[144085-23-4 ]

06538-500MG-F 245.00 500 mg

Boc-(S )- -allyl-Pro-OH purum, 98.0% HPLC 8C13H21NO4

N

Boc

OH

O

MW: 255.31[706806-59-9 ]

06486-500MG-F 245.00 500 mg

(R )- -Allyl-proline hydrochloride purum, 98.0% HPLC 8C8H13NO2 HCl

NH

OH

O

HCl

MW: 191.66[177206-69-8 ]

06541-500MG-F 245.00 500 mg

(S )- -Allyl-proline hydrochloride purum, 98.0% HPLC 8C8H13NO2

NH

OH

O

HCl

MW: 155.19[129704-91-2 ]

06594-500MG-F 245.00 500 mg

Boc- -benzyl- DL-Pro-OH purum, 96.0% HPLCC17H23NO4

N

Boc

O

OH

MW: 305.37[ 351002-72-7 ]

52969-500MG 167.50 500 mg

Boc-(R )- -benzyl-Pro-OH purum, 99.0% HPLC 8C17H23NO4

N

Boc

OH

O

MW: 305.37[706806-60-2 ]

47079-500MG-F 245.00 500 mg

Boc-(S )- -benzyl-Pro-OH purum, 97.0% HPLC 8C17H23NO4

N

Boc

OH

O

MW: 305.37[706806-61-3 ]

76896-500MG-F 245.00 500 mg

ProlineDerivatives

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To discuss how our expertise can benefit your next scale-up project or to obtain a quote,contact your local Sigma-Aldrich office or visit www.safcglobal.com

US $ 7

1.4 Prolines with Substituents in -PositionContd

Boc- -(2-bromobenzyl)- DL-Pro-OH purum, 96.0% HPLCC17H22BrNO4

N

Boc

O

OH

Br

MW: 384.26

[ 351002-85-2 ]

90682-500MG 167.50 500 mg

Boc- -(2-chlorobenzyl)- DL-Pro-OH purum, 96.0% HPLCC17H22ClNO4

N

Boc

O

OH

Cl

MW: 339.81[ 351002-86-3 ]

90683-500MG 167.50 500 mg

Boc- -(3-chlorobenzyl)- DL-Pro-OH purum, 96.0% HPLCC17H22ClNO4

N

Boc

O

OH

ClMW: 339.81

[ 351002-87-4 ]

90684-500MG 167.50 500 mg

Boc- -(4-bromobenzyl)- DL-Pro-OH purum, 96.0% HPLCC17H22BrNO4

N

Boc

O

OH

Br

MW: 384.26[ 336817-91-5 ]

94866-500MG 167.50 500 mg

Boc- -(4-fluorobenzyl)- DL-Pro-OH purum, 96.0% HPLCC17H22FNO4

N

Boc O

OH

F

MW: 323.36[ 351002-78-3 ]

74082-500MG 167.50 500 mg

Boc-(R )- -(4-fluorobenzyl)-Pro-OH purum, 98.0% HPLC 8C17H22FNO4

N

Boc

OH

O

F

MW: 323.36[706806-64-6 ]

67420-500MG-F 245.00 500 mg

Boc-(S )- -(4-fluorobenzyl)-Pro-OH purum, 98.0% HPLC 8C17H22FNO4

N

Boc

OH

O

F

MW: 323.36[706806-65-7 ]

14931-500MG-F 190.00 500 mg

Boc- -(4-methylbenzyl)- DL-Pro-OH purum, 96.0% HPLCC18H25NO4

N

Boc O

OH

H 3 C

MW: 319.4

[ 351002-82-9 ]

76501-500MG 167.50 500 mg

Boc- -(1-naphthylmethyl)- DL-Pro-OH purum, 96.0% HPLCC21H25NO4

N

Boc O

OH

MW: 355.43[ 351002-65-8 ]

36748-500MG 167.50 500 mg

Boc- -(diphenylmethyl)- DL-Pro-OH technical, 90% HPLC

C23H27NO4

N

Boc O

OH

MW: 381.46[ 351002-64-7 ]

30763-500MG 167.50 500 mg

Boc-(R )- -(4-trifluoromethylbenzyl)-Pro-OH purum, 898.0% HPLCC18H22F3NO4

N

Boc

OH

O

CF 3

MW: 373.37

42004-500MG-F 245.00 500 mg

Boc-(S )- -(4-trifluoromethylbenzyl)-Pro-OH purum, 898.0% HPLCC18H22F3NO4

N

Boc

OH

O

CF 3

MW: 373.37

05199-500MG-F 245.00 500 mg

Boc-(R )- -(4-tert -butylbenzyl)-Pro-OH purum, 97.0% 8HPLCC21H31NO4

N

Boc

OH

O

MW: 361.48

39793-500MG-F 245.00 500 mg

Boc-(S )- -(4-tert -butylbenzyl)-Pro-OH purum, 98.0% 8HPLCC21H31NO4

N

Boc

OH

O

CF 3MW: 361.48

39166-500MG-F 190.00 500 mg

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1.5 Hydroxyproline Derivatives

Boc-Hyp-OH purum, 98.0% TLCC10H17NO5

N

Boc

OH

O

HO

MW: 231.25

[13726-69-7 ]

15544-5G 51.20 5 g15544-25G 170.50 25 g

Boc-Hyp(Bzl)-OH purum, 98.0% HPLCC17H23NO5

N

Boc

OH

O

OMW: 321.37[54631-81-1 ]

15535-1G 39.60 1 g15535-5G 186.00 5 g15535-25G 620.00 25 g

Fmoc-Hyp-OH purum, 98.0% HPLC, sum of enantiomersC20H19NO5

N

Fmoc

HO

O

OH

MW: 353.37[88050-17-3 ]

47686-1G 20.10 1 g

Fmoc-Hyp( t Bu)-OH purum, 98.0% HPLCC24H27NO5

N

Fmoc

O

t-Bu

O

OH

MW: 409.47[122996-47-8 ]

47517-1G-F 48.50 1 g

47517-5G-F 162.00 5 g47517-25G-F 688.00 25 g

Z-Hyp-OH puriss., 99.0% TC130 H15NO5

N

Z

OH

O

HO

MW: 265.26[13504-85-3 ]

96310-5G 41.60 5 g96310-25G 138.50 25 g

N -Acetyl- L-hydroxyproline puriss., 99.0% TC7H11NO4

N

O

O

OH

HO

CH 3

MW: 173.17[ 33996-33- 7]

01192-10G-F 77.10 10 g01192-50G-F 257.00 50 g

trans -4-Hydroxy- L-proline 99.0% NTC5H9NO3

N

H

O

OH

HO

MW: 131.13

[51-35-4 ]56250-5G 25.00 5 g56250-25G 63.60 25 g56250-100G 223.00 100 g

N -Boc-cis-4-Hydroxy- L-proline 97%C10H17NO5

N

Boc

OH

O

HO

MW: 231.25[87691-27-8 ]

654019-1G 90.50 1 g654019-5G 317.00 5 g

cis-4-Hydroxy- L-proline puriss., 99.0% NTC5H9NO3

NH

O

OH

HO

MW: 131.13[618-27-9 ]56248-50MG 52.80 50 mg56248-250MG 158.50 250 mg56248-1G 444.50 1 g

cis-4-Hydroxy- D-proline 99.0% NTC5H9NO3

NH

O

OH

HO

MW: 131.13[2584-71-6 ]56246-250MG 35.50 250 mg56246-1G 104.50 1 g

trans -3-Hydroxy- L-proline purum, 98.0% NT

C5H9NO3NH

O

OH

OH

MW: 131.13[4298-08-2 ]56244-100MG 41.60 100 mg56244-500MG 138.50 500 mg

cis-3-Hydroxy- DL-proline purum, 97.0% TLCC5H9NO3

NH

O

OH

OH

[4298-05-9 ]

56245-10MG 212.00 10 mg

ProlineDerivatives

a n d A n a l o g u e s

P0868 Proteins, Peptides and Amino Acids SourceBookJ. S. White and D. C. White. Humana Press: Totowa, NJ, 2002, 1080pp. Hardcover.

Building on the success of their Source Book of Enzymes, the authors have assembled a catalog of over 26,000commercially available proteins, peptides, and amino acids. All are arranged alphabetically and by sequence forfast access, and are replete with technical details and vendor information. Compounds can be easily locatedby either directly searching the appropriate section by chemical name or by consulting the general index byname, synonym, or derivative formula. The data covers sequence, sequence modification, chemical derivatives,preparation form, purity, composition, activity, functionality, as well as applications and literature references.

Please visit sigma-aldrich.com/books for a complete list of over 1700 titles,

tables of contents, or to or der online.


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US $ 9

1.8 Proline Analogues with Ring RestrictionsAziridine- and Azetidine-2-Carboxylic Acids

Lithium L-aziridine-2-carboxylate purum, 97.0% NT dried materialC3H4LiNO2

NH

O

O

Li +[67413-27-8 ]

11558-50MG 93.60 50 mg11558-250MG 312.00 250 mg

L-Azetidine-2-carboxylic acid purum, 98.0% NTC4H7NO2

NH

O

OH[2133-34-8 ]

11542-500MG 95.40 500 mg11542-2.5G 368.00 2.5 g

1-Boc-L-azetidine-2-carboxylic acid purum, 98.0% TLCC9H15NO4

N

Boc

OH

O

[51077-14-6 ]

78324-500MG-F 57.80 500 mg

1-Fmoc-( S)-azetidine-2-carboxylic acid purum, 97.0% HPLCC19H17NO4

N

Fmoc

O

OH[136552-06-2 ]

70238-500MG-F 57.80 500 mg

1.6 4-substituted Proline Derivatives

N -Boc-cis-4-N -Fmoc-amino- L-proline 97%C25H28N2O6

N

Boc

OH

O

NHFmoc

[174148-03-9 ]

534404-1G 92.00 1 g

N -Boc-trans -4-N -Fmoc-amino- L-proline 97%C25H28N2O6

N

Boc

OH

O

NHFmoc

[176486-63-8 ]

534390-1G 179.00 1 g

Boc-(R)-4-[2-(trifluoromethyl)benzyl]-Pro-OH purum, 898.0% HPLCC18H22F3NO4

N

Boc

OH

O

CF 3

38455-500MG-F 340.00 500 mg

Boc-(R)-4-(3,4-difluorobenzyl)-Pro-OH purum, 97.0% 8HPLC C17H21F2NO4

N

Boc

OH

O

F

F

40372-500MG-F 340.00 500 mg

Boc-(R)-4-[4-(trifluoromethyl)benzyl]-Pro-OH purum, 898.0% HPLCC18H22F3NO4

N

Boc

OH

O

F 3 C

01336-500MG-F 340.00 500 mg

1.7 Dehydroprolines

3,4-Dehydro- DL-proline 99.0% TC5H7NO2

NH

O

OH[ 3395-35-5 ]

30900-250MG 286.00 250 mg

30900-1G 867.90 1 g

3,4-Dehydro- L-proline 99.0% TLCC5H7NO2

NH

O

OH[4043-88-3 ]

30890-10MG 38.10 10 mg30890-50MG 127.10 50 mg

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1.10 Oxa- and Thia-Prolines

(S)-()-3-(Boc)-4-oxazolidinecarboxylic acid 98%

C12H13NO5 ON

Z

OH

O[97534-82-2 ]

469467-1G 37.20 1 g469467-5G 123.00 5 g

(R)-(+)-3-(Boc)-4-oxazolidinecarboxylic acid 98%C12H13NO5 O

N

Z

OH

O[97534-84-4 ]

469475-1G 43.10 1 g469475-5G 142.50 5 g

Thiazolidine-2-carboxylic acid 97%C4H7NO2S S

NH

OH

O[65126-70-7 ]

467995-1G 14.20 1 g467995-5G 46.50 5 g

L-4-Thiazolidinecarboxylic acid purum, 99.0% TC4H7NO2S

NH

S

OH

O[ 34592-47-7 ]

88400-10G 16.20 10 g88400-50G 54.00 50 g

(R)-Boc-4-thiazolidinecarboxylic acid puriss. p.a., 99.0% HPLC

C9H15NO4S SN

Boc

OH

O[51077-16-8 ]

95471-1G-F 19.40 1 g95471-5G-F 64.80 5 g

(R)-Fmoc-4-thiazolidinecarboxylic acid puriss., 99.0% HPLCC19H17NO4S S

N

Fmoc

OH

O[133054-21-4 ]

94703-1G-F 25.40 1 g94703-5G-F 100.50 5 g

(R)-()-2-Oxothiazolidine-4-carboxylic acid purum, 97.0% TC4H5NO3S

NH

S O

O

OH

[19771-63-2 ]

75951-1G 19.70 1 g75951-5G 65.60 5 g

1.9 Proline Analogs with Ring ExpansionsPipecolic Acids

DL-Pipecolic acid purum, 99.0% NTC6H11NO2

NH

OH

O

[535-75-1 ]

80618-25G 55.00 25 g80618-100G 181.00 100 g

L-Pipecolic acid puriss., 99.0% NTC6H11NO2

NH

OH

O

[ 3105-95-1 ]

80615-100MG 62.20 100 mg80615-500MG 264.50 500 mg

D-Pipecolic acid puriss., 99.0% NTC6H11NO2

NH

OH

O

[1723-00-8 ]

80617-100MG 86.20 100 mg80617-500MG 366.50 500 mg

Boc-Pip-OH purum, 99.0% HPLCC11 H19NO4

Boc

N

O

OH[26250-84-0 ]

15558-1G 145.50 1 g15558-5G 485.50 5 g

Boc-D-Pip-OH purum, 99.0% HPLCC11H19NO4

Boc

N

O

OH[28697-17-8 ]

75748-250MG 62.10 250 mg75748-1G 182.50 1 g

Fmoc-Pip-OH purum, 98.0% HPLCC21H21NO4

N

Fmoc O

OH[86069-86-5 ]

09777-250MG 85.00 250 mg09777-1G 229.50 1 g

Fmoc-D-Pip-OH purum, 98.0% HPLCC21H21NO4

N

Fmoc

O

OH

[101555-63-9 ]

73418-250MG 62.10 250 mg73418-1G 182.50 1 g

ProlineDerivatives

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4. New Monoprotected Bifunctional Linkers4.1 New Protected Aminoalkyl Bromides

4-(Boc-amino)butyl bromide technical, 90% AT 8C9H18BrNO2

O

O NH

H 3 C

H 3 C

CH 3

Br[164365-88-2 ]

90303-500MG-F 56.30 500 mg90303-2.5G-F 187.50 2.5 g

6-(Boc-amino)hexyl bromide purum, 97.0% GC 8C11H22BrNO2

O

O NH

Br

H 3 C

H 3 C

CH 3

[142356-33-0 ]

89171-500MG-F 46.90 500 mg89171-2.5G-F 199.50 2.5 g

2-(Fmoc-amino)ethyl bromide purum, 95.0% AT 8C17H16BrNO2 O

O NH

Br

74291-1G-F 29.10 1 g74291-5G-F 116.50 5 g

3-(Fmoc-amino)propyl bromide purum, 97.0% HPLC 8C18H18BrNO2 O

O NH

Br

76061-1G-F 47.80 1 g76061-5G-F 191.50 5 g

4-(Fmoc-amino)butyl bromide purum, 95.0% CHN 8C19H20BrNO2 O

O NH

Br

73431-1G-F 47.80 1 g73431-5G-F 191.50 5 g

4.2 New Mono-Alloc-Protected Diamines

N -Alloc-ethylenediamine hydrochloride purum, 8

98.0% ATC6H12N2O2 HCl OO N

H

NH 2H 2 C

HCl

51036-1G-F 56.10 1 g51036-5G-F 238.50 5 g

N -Alloc-1,3-propanediamine hydrochloride purum, 897.0% ATC7H14N2O2 HCl O

O NH

H 2 CH

HCl

43303-1G-F 56.10 1 g43303-5G-F 224.50 5 g

N -Alloc-1,4-butandiamine hydrochloride purum, 898.0% ATC8H16N2O2 HCl O

O NH

H 2 C NH 2

HCl

04667-1G-F 57.20 1 g04667-5G-F 229.00 5 g

N -Alloc-1,5-pentanediamine hydrochloride purum, 8

98.0% ATC9H18N2O2 OO N

HNH 2

H 2 C

HCl

44911-1G-F 51.00 1 g44911-5G-F 204.00 5 g

N -Alloc-1,6-hexanediamine hydrochloride purum, 897.0% ATC10H20N2O2 HCl O

O NH

NH 2H 2 CHCl

[184292-16-8 ]

69285-1G-F 56.10 1 g69285-5G-F 224.50 5 g

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5. Functionalized Polyethylene Glycols (PEGs)5.1 Introduction

The chemical modification of biologically active compounds,such as peptides, proteins, antibody fragments, aptamers,enzymes, and small molecules with polyethylene glycol(referred to as PEGylation), is an effective method to tailormolecular properties to particular applications. The PEG moietywithin such conjugates provides, for example , water solubility,biocompatibility, and flexibility. PEGylation of a therapeutic agentcan prolong the half-life of the drug in the circulation, reduce itsimmunogenicity and antigenicity, prevent biological degradationby reducing proteolysis and finally, alter the pattern of drugdistribution. 1,2 After the first therapeutic PEG-protein conjugate(PEG-adenosine deaminase, PEG-ADA 3) had been approved bythe FDA in 1991, a large number of PEG-protein conjugates hadbeen described for therapeutic use against a range of diseases. 4,5

PEG-enzyme complexes found application in biotechnology

because they increase the solubility, stability, and activity of theenzymes in hydrophobic organic solvents. 4,6

Further important applications of functionalizedpolyethylene glycols:

Preparation of graft polymeric supports for Solid-Phase PeptideSynthesis (SPPS)7

Introduction of solubilizing handles in SPPS 8

Soluble polymer supports for Peptide Synthesis 9,10

Soluble polymer supports for Organic Synthesis 11

Introduction of hydrophilic amino acids in Peptide Synthesis 12

Preparation of PEG-ligand conjugates for affinity partitioningof macromolecules 13

Preparation of PEG-coated surfaces 14

Linking of macromolecules to surfaces 15

Synthesis of targetable polymeric drugs 16

Preparation of PEG-glycoprotein conjugates 17

Preparation of PEG-cofactor adducts for biorectors 18

Sigma-Aldrich offers a broad portfolio of PEG reagents withmolecular weights up to 20 kDa for efficient PEGylations.Numerous homobifunctionalized, heterobifunctionalized, andmono-methoxy endcapped monofunctionalized linear PEGsare available in high quality. We provide polyethylene glycolsactivated for the most widely used conjugations to primary

amines or thiols. The introduction of different protecting groupsleads to extremely useful macromolecular cross-linking agentsand spacers.

Please take a look at our unique series of monodispersepolyethylene glycols with an oligomer purity of more than 9095%. Sigma-Aldrich homo- and heterobifunctional PEG products(n=5-18) with high oligomer purity are superior reagents fordrug delivery formulations, affinity labeling, protein engineering,surface modification, combinatorial chemistry, and any productdevelopment whenever accuracy and control are essential.

References(1) Mehvar, R. Pharm. Pharmaceut. Sci. 2000 , 3, 125.

(2) Wang-Yi, L. J.Biochem. Cell Biology 2002 , 34 , 396.

(3) Levy, J. et al. J. Pediatr. 1988 , 113 , 312.

(4) Inada, Y. et al. TIBTECH , 1995 , 13 , 86.

(5) Harris, J. M.; Martin, N. E.; Madi, M. Clin. Pharmacokinet.2001 , 40 , 539.

(6) Nakamura, A. et al. J. Biol. Chem. 1986 , 261 , 16792.

(7) Zalipski, S. et al. In Peptides: Structure and Function ; Deber,C. M., Hruby, V. J., Kopple, K. H., Eds.; Pierce Chemical Co:Rockford, 1985; p 257.

(8) Seitz, O.; Kunz, H. J. Org. Chem. 1997 , 62 , 813.(9) Mutter, M.; Bayer, E. Angew. Chemie 1974 , 86 , 101.

(10) Pillai V. N. R.; Mutter, M. J. Org. Chem. 1980 , 45 , 5364.

(11) Gravert, D. J.; Janda, K. D. Chem. Rev. 1997 , 97 , 489.

(12) Koskinen, A. M. P. et al. Bioorg. Med. Chem. Lett. 1995 , 5 ,573.

(13) Cordes, A.; Kula, M.-R. J. Chromat. 1986 , 376 , 375.

(14) Harris, J. M. et al. J. Polym. Sci. Polym. Chem. Ed. 1984 ,22 , 341.

(15) Andreadis, J. D.; Chrisey, L. A. Nucleic Acids Res. 2000 , 28(2), e5.

(16) Zalipski, S.; Barany, G. J. Bioact. Compatible Polym. 1990 ,5 , 227.

(17) Urrutigoity, M.; Souppe, J. Biocatalysis 1989 , 2, 145.(18) Okada, H.; Urabe, I. Meth. Enzymol. 1987 , 136 , 34.

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6. Fluorescent Labeling of Peptides

Labeling peptides with fluorescent dyes or other labels providespowerful tools for the investigation of biological relevant interactionslike receptor-ligand-binding, 1-3 protein structures, 4-6 and enzyme activity.Fluorescence energy transfer (FRET) between a donor and an acceptorlabel is widely applied for such investigations. It can be determined bya number of different methods, e.g., quenching and other intensitymeasurements, donor or acceptor depletion kinetics, and fluorescencelifetime or emission anisotropy measurements. 3-13 A variety of enzymesubstrates have been designed and used, 14-22 partially based on quenchingof emission through a second label, that is eliminated through theseparation of label and quencher by cleavage of substrate.

Labeled peptides can be prepared by either modifying isolated peptidesor by incorporating the label during solid-phase synthesis. Three strategiesare used to label peptides with dyes:

(1) Labeling during synthesis of peptide. Dyes that are not damaged byunblocking procedures are incorporated onto the amino terminus ofthe peptide chain.

(2) Synthetic peptides can be covalently modified on specific residuesand labels incorporated following synthesis.

(3) Synthetic peptides may be covalently labeled by amine- or thiol-reactive protein labels.

Fluorophores can be conjugated to the N-terminus of a resin-boundpeptide before other protecting groups are removed and the labeledpeptide is released from the resin. Amine-reactive fluorophores are usedin about 5-fold molar excess relative to the amines of the immobilizedpeptide. Reactive fluorescein, sulforhodamine B, tetramethylrhodamine,coumarin, eosin, dabcyl, dabsyl, or biotin labels, as well as several of our

new atto labels, should be stable enough to resist the harsh deprotectionconditions. Dabcyl has been frequently used as quencher. Anotherpossibility is the use of fluorescence or chromophore labeled amino acidsto incorporate labels at specific sites of peptides.

Labeling can also be achieved indirectly by using a biotinylated aminoacid. If, for example, Fmoc-Lys(biotinyl)-OH, no. 73749 is used in peptidesynthesis, the biotin group allows specific binding of streptavidin oravidin-conjugate to that site. A variety of fluorophores are available as(strept)avidin conjugates, a selection of our products are listed in Table 2 .

Following the routine synthesis procedure, peptides can also be labeledby practically all labels used for protein labeling. This means mainly aminereactive labels, or thiol reactive labels, if a cystein has been used for thepeptide. Whereas the common standard procedures for protein labelingare based on aqueous solutions of target proteins, labeling peptides inorganic solvents like DMSO or DMF requires specific modifications. Use oftriethylamine can be added to ensure that the target amino groups of thepeptide are deprotonated, which is required for the labeling procedure.

Table 1 shows a selection of our fluorescent labels. If you are lookingfor different spectral properties, or other functionalities (e.g., thiol label),

please have a look at our catalog (capture Fluorescent probes) or visitour homepage.

Table 1. Amine reactive fluorescent labels

Cat.No. Name

ExcitationMax.

EmissionMax.

PackageSize

64949-25MG

64949-100MG

7-Methoxycoumarin-3-carboxylic acid N -succinimidyl ester 328 393 25 mg

100 mg57672-1G-F 1,5-I-AEDANS (N -(Iodacetaminoethyl)-1-naphthylamin-5-

sulfonsure)341 471 1 g

36801-25MG36801-100MG

N -Succinimidyl 7-(diethylamino)coumarin-3-carboxylate 430 482 25 mg100 mg

92846-1MG-F92846-5MG-F

5-Carboxyfluorescein N -succinimidyl ester 492 525 1 mg 5 mg

52352-1MG-F52352-5MG-F

6-Carboxyfluorescein N -succinimidyl ester 492 516 1 mg 5 mg

41969-5MG-F 5-Carboxy-X-rhodamine N -succinimidyl ester 492 520 5 mg44617-5MG-F 6-Carboxy-X-rhodamine N -succinimidyl ester 492 516 5 mg53048-1MG-F53048-5MG-F

5-Carboxy-tetramethylrhodamine N -succinimidyl ester 543 575 1 mg 5 mg

88997-1MG-F

88997-5MG-F

6-Carboxy-tetramethylrhodamine N -succinimidyl ester 543 575 1 mg

5 mg42024-1KT-F Fluorescent orange 548 reactive 548 565 5 vials for labeling

1 mg protein each62164-1KT-F Fluorescent red 646 reactive 640 666 5 vials for labeling

1 mg protein each53404-1MG-F Atto 465 NHS ester 449 503 1 mg41698-1MG-F Atto 488 NHS ester 501 523 1 mg00379-1MG-F Atto 495 NHS ester 499 535 1 mg77810-1MG-F Atto 520 NHS ester 525 545 1 mg88793-1MG-F Atto 532 NHS ester 532 553 1 mg92835-1MG-F Atto 550 NHS ester 554 576 1 mg72464-1MG-F Atto 565 NHS ester 563 592 1 mg79636-1MG-F Atto 590 NHS ester 598 634 1 mg07376-1MG-F Atto 647 NHS ester 645 673 1 mg76245-1MG-F Atto 655 NHS ester 665 690 1 mg


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FluorescentLabeling

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References

(1) Kenworthy, A. K. Imaging protein-protein interactions using fluorescenceresonance energy transfer microscopy. Methods 2001 , 24 , 289.

(2) Hoppe, A.; Christensen, K.; Swanson, J. A. Imaging protein-proteininteractions in living cells. Biophys. J. 2002 , 83 , 3652.

(3) Ozawa, T.; Umezawa, Y. Peptide assemblies in living cells. Methods for

detecting protein-protein interactions. Supramol. Chem. 2002 , 14 , 271.(4) Peled, H.; Shai, Y. Synthetic S-2 and H-5 segments of the Shaker K+

channel: secondary structure, membrane interaction, and assemblywithin phospholipid membranes. Biochemistry 1994 , 33 , 7211.

(5) Ben-Efraim, I.; Strahilevitz, J.; Bach, D.; Shai, Y. Secondary structure andmembrane localization of synthetic segments and a truncated form ofthe IsK (minK) protein. Biochemistry 1994 , 33 , 6966.

(6) Marm, N.; Knemeyer J. P.; Sauer, M.; Wolfrun, J. Inter- andIntramolecular Fluorescence Quenching of Organic Dyes Tryptophan.Bioconjugate Chem. 2003 , 14 , 1133.

(7) Wieb van der Meer, B.; Coker, G.; Simon, C. Resonance Energy Tranfer:Theory and Data. VCH: New York, 1994.

(8) Young, R. M.; Arnette, J. K.; Roess, D. A.; Barisas, B. G. Quantitationof fluorescence energy transfer between cell surface proteins viafluorescence donor photobleaching kinetics. Biophys. J. 1994 , 67 , 881.

(9) Chicester, U. K.; Andrews D. L.; Demidov A. A. Resonance EnergyTransfer. Wiley & Sons: New York, 1999.

(10) Widengren, J.; Schweinberger, E.; Berger, S.; Seidel, C. A. M. Twonew concepts to measure fluorescence resonance energy transfervia fluorescence correlation spectroscopy: theory and experimentalrealizations. J. Phys. Chem. A 2001 , 105 , 6851.

(11) Clayton, A. H. A.; Hanley, Q. X. Arndt-Jofin D. J.; Subramaniam, V.;Jovin, T. M. Dynamic fluorescence anisotropy imaging microscopy in thefrequency domain (rFLIM) Biophys. J . 2002 , 83 , 1631.

(12) Clegg, R. M; Holub, O.; Gohlke, C. Fluorescence lifetime-resolvedimaging: measuring lifetimes in an image. Methods Enzymol. 2003 , 360 ,509.

(13) Jares-Erijman, E. A.; Jovin, T. M. FRET imaging. Nat. Biotechnol. 2003 ,21 , 13871395.

(14) Matayoshi, E. D.; Wang, G. T.; Krafft G. A.; Erickson, J. Novel fluorogenicsubstrates for assaying retroviral proteases by resonance energy transfer.Science 1990 , 247 , 954.

(15) Wang, G. T. Design and Synthesis of New Fluorogenic HIV ProteaseSubstrates Based on Resonance Energy Transfer. Tetrahedron Lett. 1990 , 31 , 6493.

(16) Garcia-Echeverria, C.; Rich, D. H. New intramolecularly quenchedfluorogenic peptide substrates for the study of the kinetic specificity ofpapain. FEBS Lett.1992 , 297 , 100.

(17) Wang, G. T.; Krafft, G. A. Automated Synthesis of Fluorogenic ProteaseSubstrates: Design of Probes for Alzheimers Disease-AssociatedProteases. Bioorg. Med. Chem. Lett. 1992 , 2 , 1665.

(18) Maggiora, L. L.; Smith, C. W.; Zhang, Z. Y. A general method for thepreparation of internally quenched fluorogenic protease substrates usingsolid-phase peptide synthesis. J. Med. Chem . 1992 , 35 , 3727.

(19) Contillo, L. G., et al. General Strategy for the Synthesis of EosinFluorescein Energy Transfer Substrates for High Sensitivity Screening ofProtease Inhibitors. In Techniques in Protein Chemistry V , Crabb J. W.,Ed. Academic Press: New York, 1994; pp 493.

(20) Weder, J. K. P; Kaiser, K-P. Fluorogenic Substrates for HydrolaseDetection Following Electrophoresis. J. Chromatogr. A 1995 , 698 , 181.

(21) Cavrois, M.; de Noronah, C.; Greene, W. C. Nat. Biotechnol. 2002 , 20,11511154.

(22) Marm, N.; Knemeyer, J. P.; Wolfrun, J.; Sauer, M.; Highly SensitiveProtease Assay Using Fluorescence quenching of Peptide Probes Basedon Photoinduced Electron Transfer. Angew . Chem., Int. Ed. Engl. 2004 ,43 , 3798.

6. Fluorescent Labeling of PeptidesContd

Table 2. Fluorescent streptavidin conjugates

Cat.No. Name

ExcitationMax.

EmissionMax.

PackageSize

56304-1MG-F Atto 565-Streptavidin 563 592 1 mg40709-1MG-F Atto 590-Streptavidin 598 634 1 mg56767-1MG-F Atto 610-Streptavidin 605 646 1 mg02744-1MG-F Atto 655-Streptavidin 665 690 1 mg16630-1MG-F Atto 680-Streptavidin 680 702 1 mg04307-500UG-F Streptavidin-C-Phycocyanin 600 640 500 g61707-500UG-F Streptavidin C-Phycoerythrin 575 545 500 g

Table 3. Quenchers

Cat. No. Name Absorption Max. Package Size09278-25MG-F09278-100MG-F

DABCYL-N-succinimidylester 453 25 mg100 mg

42220-500MG 3,5-Dinitrophenyl isocyanate 348 500 mg61683-1MG-F Atto 540 Q NHS ester 540 1 mg44756-1MG-F Atto 580 Q NHS ester 580 1 mg53988-1MG-F Atto 612 Q NHS ester 612 1 mg


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Protein-AQUA is a powerful, enabling technologythat facilitates focused, quantitative studies of notonly specific protein expression, but specific amino acid modificationas well. The Protein-AQUA strategy, originally presented in 2003 by Dr.Steve Gygi and his team, 1 enables absolute protein quantitation usingstable isotope labeled peptides, and mass spectrometry. Protein-AQUAis based on a common principle: the use of a labeled molecule as aninternal standard. By applying this technique to protein and peptideanalysis, Gygis team has advanced the abilities of protein researchersto study complex biological samples quantitatively, and has provided avaluable new tool for Proteomics!To meet the specific requirements of AQUA experimentation, Sigmahas developed a specialized custom peptide offering.

95% peptide purity by reverse-phase HPLC >98 atom % 13C and 98 atom % 15N isotopically labeled

amino acid incorporation Confirmed molecular weight by MALDI-TOF mass spectrometry Confirmed peptide content Peptides supplied as trifluoroacetate salts (acetate salt form

also available) Phosphorylated amino acids available Available in 15 business days(1) Gerber, S. A.; Rush, J.; Stemman, O.; Kirschner, M. W.; Gygi, S. P. Proc. Natl. Acad.Sci. U.S.A. (PNAS) 2003 , 100 , 6940.

Custom AQUA Peptides

The Ultimate Methodfor Biomarker Quantitation

This method was developed by Dr. Steve Gygi and colleagues at Harvard MedicalSchool [Stemmann O, Zou H, Gerber SA, Gygi SP, Kirschner MW; Dual inhibitionof sister chromatid separation at metaphase, Cell 2001, Dec 14,107: 715-726]. Limited use of this method is permitted under a licensing arrangement with Harvard Medical School.

To learn more about AQUAPeptides, visit our Web site at:

sigma-aldrich.com/aquamethod .

I N P AR TN ER SH IP W IT H T HES I G M A A N D I S O T E C B R A N D S

Accurately quantitate low abundance proteins Measure phosphorylation states and splice variants Validate gene silencing

Unrivaled Sensitivity To:

L E A D E R S H I P I N L I F E S C I E N C E , H I G H T E C H N O L O G Y A N D S E R V I C ESIGMA-ALDRICH CORPORATION BOX 14508 ST. LOUIS MISSOURI 63178 USA

Protein-AQUA is a trademark of Harvard University. ISOTEC is a trademark and Sigma a registered trademark of Sigma-Aldrich Biotechnology, L.P.


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