- Formation of peptide disulfide bonds through a trans-dibromido-Pt(IV) complex oxidation reaction: Kinetic and mechanistic analyses
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A trans-dibromido-Pt(IV) complex [PtBr2(en)2]Br2 was synthesized and evaluated for the synthesis of peptide disulfide bonds in this work. The reactions between the Pt(IV) complex and dicysteine-containing peptides were carried out in various aqueous solutions. As a result, excellent yields with fast reaction rates were achieved. Methionine residue was intact when the Pt(IV) complex reacted with a dicysteine and methionine-containing peptide. 3,6-Dioxa-1,8-octanedithiol (DODT) was selected as a model compound of the dicysteine-containing peptide. Kinetic studies for the reaction between the Pt(IV) complex and DODT were performed in different pH solutions. It is first-order both in [Pt(IV)] and in [DODT]. A reaction mechanism was proposed accordingly. The kinetic and mechanistic results demonstrated that the reaction rate for the formation of peptide disulfide bond via the Pt(IV) oxidation is increased with the increase of pH of the reaction medium. The protolytic constants of the two thiol groups in peptide also play a critical role in reaction rate. On the other hand, kinetic studies demonstrated that the Pt(IV) complex trans-[PtBr2(en)2]2+ can be used in an acidic medium for the purpose of synthesis of disulfide bonds.
- Ma, Dongying,Song, Changying,Sun, Jingjing,Shen, Shigang,Huo, Shuying
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- Construction of disulfide bonds in peptides via immobilized platinum(IV) complex oxidation
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A novel TentaGel resin supported platinum(IV) complex named TentaGel-Pt(IV) was synthesized and characterized by SEM, XPS, ICP-MS and UV–vis spectrophotometry. The formation of intramolecular disulfides in eleven dithiol-containing peptides of variable lengths using TentaGel-Pt(IV) was investigated at room temperature. The disulfide-containing peptides were formed in excellent oxidation yields and were easily separated by filtration upon completion of the reaction. Excellent reusability of TentaGel-Pt(IV) was also achieved. The mechanism for construction of the disulfide bond in peptides via TentaGel-Pt(IV) oxidation was proposed.
- Sun, Jingjing,Zhang, Yamei,Huo, Shuying,Shen, Shigang
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supporting information
(2019/12/24)
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- A study to develop platinum(iv) complex chemistry for peptide disulfide bond formation
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Platinum(iv) complexes with a heterocyclic ligand and an ancillary ligand have been investigated and applied for treating various tumour cell lines. Another application of the Pt(iv) complexes in forming peptide disulfide bonds was investigated in this work. For development of Pt(iv) complex chemistry for disulfide bond formation in peptides, two Pt(iv) complexes, [PtCl2(phen)(en)]Cl2 and [PtCl2(bpy)(en)]Cl2, were synthesized and characterized using elemental analysis, ESI-MS and NMR. Subsequently, they were investigated as oxidants for the formation of disulfide bonds in various peptides. Excellent purities and yields of disulfide-containing peptides were achieved when the reactions were carried out in aqueous solution. The reactions were completed rapidly in a wide range of pH values even in acidic medium at room temperature. An intramolecular disulfide bond was formed in each of the peptides in a solution containing two dithiol-containing peptides, making the Pt(iv) complexes useful for generating disulfide-containing peptide libraries. In addition, the two Pt(iv) complexes can be used as oxidants for the synthesis of disulfide bonds on a resin, which is a more convenient method to synthesize disulfide-containing peptides through automation.
- Huo, Shuying,Shen, Shigang,Song, Changying,Sun, Jingjing,Zhao, Xiaowei
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supporting information
p. 1736 - 1741
(2020/02/20)
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- Robust synthesis of C-terminal cysteine-containing peptide acids through a peptide hydrazide-based strategy
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A new robust strategy was reported for the epimerization-free synthesis of C-terminal Cys-containing peptide acids through mercaptoethanol-mediated hydrolysis of peptide thioesters prepared in situ from peptide hydrazides. This simple-to-operate and highly efficient method avoids the use of derivatization reagents for resin modification, thus providing a practical avenue for the preparation of C-terminal Cys-containing peptide acids.
- Zuo, Chao,Yan, Bing-Jia,Zhu, Han-Ying,Shi, Wei-Wei,Xi, Tong-Kuai,Shi, Jing,Fang, Ge-Min
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supporting information
p. 5698 - 5702
(2019/06/18)
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- Fine-tuning the π-π Aromatic interactions in peptides: Somatostatin analogues containing mesityl alanine
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Going through the motions: Somatostatin analogues having greater conformational rigidity than somatostatin have been prepared by substituting Phe residues in the native sequence with mesityl alanine (Msa; see structure). The analogues show high affinity f
- Martin-Gago, Pablo,Gomez-Caminals, Marc,Ramon, Rosario,Verdaguer, Xavier,Martin-Malpartida, Pau,Aragon, Eric,Fernandez-Carneado, Jimena,Ponsati, Berta,Lopez-Ruiz, Pilar,Cortes, Maria Alicia,Colas, Begona,MacIas, Maria J.,Riera, Antoni
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supporting information; experimental part
p. 1820 - 1825
(2012/04/04)
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- Soluble-support-assisted electrochemical reactions: Application to anodic disulfide bond formation
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A soluble-support-assisted technique was successfully applied to electrochemical reactions, leading to anodic disulfide bond formation. The support-bound peptide was soluble in electrolyte solution, allowing electron transfer at the surface of the electrodes. After completion of the reaction, the support-bound product was recovered as a precipitate by simple dilution of the reaction mixture with poor solvent.
- Kitada, Shingo,Takahashi, Masahito,Yamaguchi, Yusuke,Okada, Yohei,Chiba, Kazuhiro
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supporting information
p. 5960 - 5963
(2013/02/26)
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- N-Imidazolebenzyl-histidine substitution in somatostatin and in its octapeptide analogue modulates receptor selectivity and function
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Despite 3 decades of focused chemical, biological, structural, and clinical developments, unusual properties of somatostatin (SRIF, 1) analogues are still being uncovered. Here we report the unexpected functional properties of 1 and the octapeptide cyclo(3-14)H-Cys-Phe-Phe-Trp8-Lys-Thr-Phe-Cys-OH (somatostatin numbering; OLT-8, 9) substituted by imBzl-l- or -d-His at position 8. These analogues were tested for their binding affinity to the five human somatostatin receptors (sst1-5), as well as for their functional properties (or functionalities) in an sst3 internalization assay and in an sst3 luciferase reporter gene assay. While substitution of Trp8 in somatostatin by imBzl-l- or -d-His8 results in sst3 selectivity, substitution of Trp8 in the octapeptide 9 by imBzl-l- or -d-His8 results in loss of binding affinity for sst1,2,4,5 and a radical functional switch from agonist to antagonist.
- Erchegyi, Judit,Cescato, Renzo,Waser, Beatrice,Rivier, Jean E.,Reubi, Jean Claude
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supporting information; experimental part
p. 5981 - 5987
(2011/10/31)
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- Pharmaceutical compositions containing growth-hormone inhibitors or their biologically active fragments for the treatment of uterine myomas
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Pharmaceutical compositions containing growth-hormone inhibitors or their biologically active fragments for the treatment of uterine myomas are described.
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- Trans-Dichlorotetracyanoplatinate(IV) as a Reagent for the Rapid and Quantitative Formation of Intramolecular Disulfide Bonds in Peptides
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Oxidation of cysteine thiol groups by trans-dichlorotetracyanoplatinate(IV) to form intramolecular peptide disulfide bonds has been studied for a series of dithiol peptides ranging from 4 to 15 amino acid residues in length. The dithiol peptides are rapidly and quantitatively transformed to their intramolecular disulfide forms by a slight excess of [Pt(CN)4Cl2]2-, as shown by HPLC. Quantitative analyses by HPLC and by spectrophotometric titration confirm a [Pt(IV)]:[dithiol peptide] stoichiometry of 1:1. Under the low pH conditions used, oxidation to form a 38-membered ring in the case of reduced somatostatin is as rapid as that to form much smaller rings, suggesting that ring closure is not the rate-determining step. The oxidation rates increase as the pH is increased. Time-resolved spectra show two isosbestic points, indicating that no peptide-platinum intermediates accumulate to a significant amount. A reaction mechanism similar to that for reduction of [Pt(CN)4Cl2]2- by monothiols is proposed. [Pt(CN)4Cl2]2- is a mild oxidant and essentially substitution inert; its reduction product, [Pt(CN)4Cl2]2-, is stable, has no redox chemistry with peptides, and does not form complexes with peptides. Moreover, [Pt(CN)4Cl2]2- and [Pt(CN)4Cl2]2- are nontoxic and readily separable from peptides by HPLC, and the cost of the Pt(IV) complex is negligible compared with that of peptides. The only unwanted side reaction observed with [Pt(CN)4Cl2]2- is oxidation of the sulfur of methionine to the sulfoxide form. These characteristics and the results of this study suggest that [Pt(CN)4Cl2]2- is an excellent reagent for the formation of intramolecular peptide disulfide bonds.
- Shi, Tiesheng,Rabenstein, Dallas L.
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p. 4590 - 4595
(2007/10/03)
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- Targeted cytotoxic anthracycline analogs
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This invention is in the field of the chemistry of targeting anticancer anthracycline derivatives. More particularly, it concerns doxorubicin (DOX) or its daunosamine modified derivatives (DM-DOX) linked covalently to analogs of peptide hormones such as LH-RH, bombesin and somatostatin. These covalent conjugates are targeted to various tumors bearing receptors for the peptide hormone analogs. The compounds of this invention are represented by General Formula Q14 --O--R--P wherein Q has the general formula STR1 wherein: Q14 signifies a Q moiety with a side chain at the 14 position, R-- is H or --C(O)--(CH2)n --C(O)-- and n=0-7, R' is NH2 or an aromatic, saturated or partially saturated 5 or 6 membered heterocyclic compounds having at least one ring nitrogen and optionally having a butadiene moiety bonded to adjacent carbon atoms of said ring to form a bicyclic system; P is H or a peptide moiety, suitably an LHRH, somatostatin or bombesin analogs. Nevertheless where R' is NH2 then R and P are other than H. When R and P are H, then R' is other than NH2. A novel synthetic reaction has been discovered in the course of this work to form partially saturated heterocyclic moieties from vicinal and disjunct i.e., α, β, or α, γ hydroxy primary amines.
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- Kinetics and equilibria of the thiol/disulfide exchange reactions of somatostatin with glutathione
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Rate and equilibrium constants are reported for the thiol/disulfide exchange reactions of the peptide hormone somatostatin with glutathione (GSH). GSH reacts with the disulfide bond of somatostatin to form somatostatin-glutathione mixed disulfides (Cys3-SH, Cys14-SSG and Cys3-SSG, Cys14-SH), each of which can react with another molecule of GSH to give the reduced dithiol form of somatostatin and GSSG. The mixed disulfides also can undergo intramolecular thiol/disulfide exchange reactions to re-form the disulfide bond of somatostatin or to interconvert to the other mixed disulfide. Analysis of the forward and reverse rate constants indicates that, at physiological concentrations of GSH, the intramolecular thiol/disulfide exchange reactions that re-form the disulfide bond of somatostatin are much faster than reaction of the mixed disulfides with another molecule of GSH, even though the intramolecular reaction involves closure of a 38-membered ring. Thus, even though the disulfide bond of somatostatin is readily cleaved by thiol/disulfide exchange, it is rapidly reformed by intramolecular thiol/disulfide exchange reactions of the somatostatin-glutathione mixed disulfides. By comparison with rate constants reported for analogous reactions of model peptides measured under random coil conditions, it is concluded that disulfide bond formation by intramolecular thiol/disulfide exchange in the somatostatin-glutathione mixed disulfides is not completely random, but rather it is directed to some extent by conformational properties of the mixed disulfides that place the thiol and mixed disulfide groups in close proximity. A reduction potential of -0.221 V was calculated for the disulfide bond of somatostatin from the thiol/disulfide exchange equilibrium constant.
- Rabenstein, Dallas L.,Weaver, Kim H.
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p. 7391 - 7397
(2007/10/03)
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- Process for the preparation of somatostatin
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The present invention relates to a new process for the stepwise preparation of somatostatin enabling a product of high purity to be obtained, with high yields, from cysteine in 14 position whose acid function is protected by the phenylazobenzylsulfonylethyloxy group and thiol function is protected by the acetamidomethyl group, all the peptide coupling reactions being effected in liquid phase in the dimethylformamide, the intermediate peptides being precipitated by addition of a second solvent and purified in solid phase by washing with the aid of suitable solvents dissolving the impurities.
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- Method for removal of thiol-protecting groups
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A novel method for removal of protective group(s) from an amino acid or peptide having thiol group(s) protected with p-methoxybenzyl, 1-adamantyl or t-butyl group by treating the protected amino acid or peptide with the mercuric salt of acetic acid or halogenoacetic acid, the removal being effected selectively and very smoothly in a good yield under extremely mild conditions without giving any undesirable influence upon other functional or protective group(s).
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