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Reaction Information

Reaction Stages Notes Yield

4

_{1.1 R:HBTU} 1.2 R:HBTU 1.3 R:HBTU 1.4 R:HBTU 1.5 R:HBTU 1.6 R:HBTU 1.7 R:HBTU 1.8 R:HBTU 1.9 R:HF 1.10 S:H2O

literature preparation, in situ neutralization protocol used, Boc protocol used, attachment to MBHA resin in stage 1,

ammonium bicarbonate buffered solution used in stage 10, Reactants: 8, Reagents: 2, Solvents: 1, Stages: 10

References

Modulating Oxytocin Activity and Plasma Stability by Disulfide Bond Engineering

By Muttenthaler, Markus et al

From Journal of Medicinal Chemistry, 53(24), 8585-8596; 2010

CASREACT ®: Copyright © 2011 American Chemical Society. All Rights Reserved. CASREACT contains reactions from CAS and from: ZIC/VINITI database (1974-1999) provided by InfoChem; INPI data prior to 1986; Biotransformations database compiled under the direction of Professor Dr. Klaus Kieslich; organic reactions, portions copyright 1996-2006 John Wiley & Sons, Ltd., John Wiley and Sons, Inc., Organic Reactions Inc., and Organic Synthesis Inc. Reproduced under license. All Rights Reserved.

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Substance Information 13139-15-6

Absolute stereochemistry., Rotation (-). C11 H21 N O4 L-Leucine, N-[(1,1-dimethylethoxy)carbonyl]-~3322 References Reactions Commercial Sources Regulatory Information 13139-16-7 Absolute stereochemistry. C11 H21 N O4 L-Isoleucine, N-[(1,1-dimethylethoxy)carbonyl]-~1544 References Reactions Commercial Sources Regulatory Information 13726-85-7

Absolute stereochemistry., Rotation (-). C10 H18 N2 O5 L-Glutamine, N2-[(1,1-dimethylethoxy)carbonyl]-~796 References Reactions Commercial Sources Regulatory Information 15761-39-4

Absolute stereochemistry., Rotation (-). C10 H17 N O4 1,2-Pyrrolidinedicarboxylic acid, 1-(1,1-dimethylethyl) ester, (2S)-~3472 References Reactions Commercial Sources Regulatory Information 20887-95-0

Absolute stereochemistry., Rotation (+). C8 H15 N O4 S L-Cysteine, N-[(1,1-dimethylethoxy)carbonyl]-~202 References Reactions Commercial Sources Regulatory Information 3978-80-1

Absolute stereochemistry., Rotation (+). C14 H19 N O5 L-Tyrosine, N-[(1,1-dimethylethoxy)carbonyl]-~1026 References Reactions Commercial Sources Regulatory Information 4530-20-5 C7 H13 N O4 Glycine, N-[(1,1-dimethylethoxy)carbonyl]-~5193 References Reactions Commercial Sources Regulatory Information 50-56-6 Absolute stereochemistry. C43 H66 N12 O12 S2 Oxytocin Protein Sequence Sequence Length: 9 ~13566 References Reactions Commercial Sources Regulatory Information 7536-55-2

Absolute stereochemistry., Rotation (-). C9 H16 N2 O5 L-Asparagine, N2-[(1,1- dimethylethoxy)carbonyl]-~816 References Reactions Commercial Sources Regulatory Information

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References

Modulating Oxytocin Activity and Plasma Stability by Disulfide Bond Engineering

By Muttenthaler, Markus; Andersson, Asa; de Araujo, Aline D.; Dekan, Zoltan; Lewis, Richard J.; Alewood, Paul F. From Journal of Medicinal Chemistry (2010), 53(24), 8585-8596. Language: English, Database: CAPLUS,

DOI:10.1021/jm100989w

Disulfide bond engineering is an important approach to improve the metabolic half-life of cysteine-contg. peptides. Eleven analogs of oxytocin were synthesized including disulfide bond replacements by thioether, selenylsulfide, diselenide, and ditelluride bridges, and their stabilities in human plasma and activity at the human oxytocin receptor were assessed. The cystathionine (Ki = 1.5 nM, and EC50 = 32 nM), selenylsulfide (Ki = 0.29/0.72 nM, and EC50 = 2.6/154 nM), diselenide (Ki = 11.8 nM, and EC50 = 18 nM), and ditelluride analogs (Ki = 7.6 nM, and EC50 = 27.3 nM) retained considerable affinity and functional potency as compared to oxytocin (Ki = 0.79 nM, and EC50 = 15 nM), while shortening the disulfide bridge abolished binding and functional activity. The mimetics showed a 1.5-3-fold

enhancement of plasma stability as compared to oxytocin (t1/2 = 12 h). By contrast, the all-D-oxytocin and head to tail cyclic oxytocin analogs, while significantly more stable with half-lives greater than 48 h, had little or no detectable binding or functional activity.

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