- Synthesis, Stability and Direct Antiproliferative Effect of New Cysteine Modified GnRH Analogs
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It is demonstrated that gonadotropin-releasing hormone (GnRH) analogs can directly inhibit the proliferation of reproductive tissue cancer cells, but the poor pharmacokinetic properties still restrict their application in treating hormone-dependent diseases. Modifications in position 6 and 10 of natural GnRH can improve the metabolic stability. In order to study the effect of incorporation Cys6 substitution with C-terminal Pro9-NHEt modification and dimerization of linear peptides on metabolic stability and antiproliferative activity of GnRH analogs, two new GnRH analogs [l-Cys6, desGly10, Pro9-NHEt]-GnRH (1) and [d-Cys6, desGly10, Pro9-NHEt]-GnRH (2), and their corresponding dimer derivatives ([l-Cys6, desGly10, Pro9-NHEt]-GnRH)2 (3) and ([d-Cys6, desGly10, Pro9-NHEt]-GnRH)2 (4) were synthesized. Incubation of these analogs with human serum was carried out to evaluate their metabolic stability, and direct growth inhibitory effect of the two dimer derivatives 3 and 4 on MCF-7 human breast cancer cell line was examined by MTT assay. The metabolic stability of dimer derivatives 3 and 4 was remarkably improved in comparison with natural GnRH. The d-Cys6 substituted dimer derivative 4 exhibited higher inhibitory effect (29.6–39.7% growth reduction) on cell growth than its corresponding counterpart 3 (21.8–26.2% growth reduction) at concentration range of 50, 100 and 200 μΜ. The cell growth inhibition of leuprolide was 16.4–27.2% at the tested concentrations. The dimer derivative 4 was the most stable and active GnRH analog in this study and has the potential for future preclinical investigations as promising antitumor drug candidate.
- Li, Songtao,Zhao, Hongling,Wang, Ruxing,Wang, Jianping,Mao, Xiaoxia,Hao, Ting,Chang, Xiaomin,Zhao, Enhong,Yin, Zhifeng,Deng, Shuhua,Yang, Yaqi,Wang, Huina
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- Protein Modification at Tyrosine with Iminoxyl Radicals
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Post-translational modifications (PTMs) of proteins are a biological mechanism for reversibly controlling protein function. Synthetic protein modifications (SPMs) at specific canonical amino acids can mimic PTMs. However, reversible SPMs at hydrophobic amino acid residues in proteins are especially limited. Here, we report a tyrosine (Tyr)-selective SPM utilizing persistent iminoxyl radicals, which are readily generated from sterically hindered oximes via single-electron oxidation. The reactivity of iminoxyl radicals with Tyr was dependent on the steric and electronic demands of oximes; isopropyl methyl piperidinium oxime 1f formed stable adducts, whereas the reaction of tert-butyl methyl piperidinium oxime 1o was reversible. The difference in reversibility between 1f and 1o, differentiated only by one methyl group, is due to the stability of iminoxyl radicals, which is partly dictated by the bond dissociation energy of oxime O-H groups. The Tyr-selective modifications with 1f and 1o proceeded under physiologically relevant, mild conditions. Specifically, the stable Tyr-modification with 1f introduced functional small molecules, including an azobenzene photoswitch, to proteins. Moreover, masking critical Tyr residues by SPM with 1o, and subsequent deconjugation triggered by the treatment with a thiol, enabled on-demand control of protein functions. We applied this reversible Tyr modification with 1o to alter an enzymatic activity and the binding affinity of a monoclonal antibody with an antigen upon modification/deconjugation. The on-demand ON/OFF switch of protein functions through Tyr-selective and reversible covalent-bond formation will provide unique opportunities in biological research and therapeutics.
- Ishiyama, Takashi,Kanai, Motomu,Maruyama, Katsuya,Oisaki, Kounosuke,Sakai, Kentaro,Seki, Yohei,Togo, Takaya
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supporting information
p. 19844 - 19855
(2021/11/30)
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- A Vinylogous Photocleavage Strategy Allows Direct Photocaging of Backbone Amide Structure
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Side-chain modifications that respond to external stimuli provide a convenient approach to control macromolecular structure and function. Responsive modification of backbone amide structure represents a direct and powerful alternative to impact folding and function. Here, we describe a new photocaging method using histidine-directed backbone modification to selectively modify peptides and proteins at the amide N-H bond. A new vinylogous photocleavage method allows photorelease of the backbone modification and, with it, restoration of function.
- Mangubat-Medina, Alicia E.,Martin, Samuel C.,Hanaya, Kengo,Ball, Zachary T.
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supporting information
p. 8401 - 8404
(2018/06/29)
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- A catalytic one-step synthesis of peptide thioacids: the synthesis of leuprorelin via iterative peptide-fragment coupling reactions
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A catalytic one-step synthesis of peptide thioacids was developed. The oxygen-sulfur atom exchange reaction converted the carboxy group at the C-terminus of the peptides into a thiocarboxy group with suppressed epimerization. This method was successfully applied to the synthesis of the peptide drug leuprorelin via an iterative fragment-coupling protocol.
- Matsumoto, Takuya,Sasamoto, Koki,Hirano, Ryo,Oisaki, Kounosuke,Kanai, Motomu
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supporting information
p. 12222 - 12225
(2018/12/01)
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- Solution-phase synthesis of leuprolide
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The present application concerns a solution-phase method for the synthesis of leuprolin. Leuprolin is a nonapeptide having strong ovulation-inducing activity, and has the following formula: 5-oxo-L-prolyl- L-histidyl- L-tryptophyl- L-seryl- L-tyrosyl -D-leucyl -L-leucyl- L-arginyl- N-ethyl-L-prolinamide.
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- Methods for the production of peptide derivatives
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The invention relates to methods for the preparation of peptides which are a C-terminal amide derivatives by a combination of solid-phase synthesis and post assembly solution phase synthesis. The peptides which are a C-terminal amide derivatives are further converted to peptide acetates. The invention also relates to pure peptide acetates and to protected peptide precursors.
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Page/Page column 13
(2010/11/25)
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- 4-Methoxy-2,6-dimethylbenzenesulphonyl (Mds): a New Protecting Group of the Guanidino Function in Peptide Synthesis
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The 4-methoxy-2,6-dimethylbenzenesulphonyl (Mds) group for the protection of the guanidino function, which is readily removed with trifluoroacetic acid-thioanisole but is resistant to hydrogenolysis or treatment with dilute hydrogen chloride, can be used in the solution synthesis of arginine-containing peptides; this protecting group was effectively used in the synthesis of substance P and two LH-RH analogues.
- Fujino, Masahiko,Nishimura, Osamu,Wakimasu, Mitsuhiro,Kitada, Chieko
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p. 668 - 669
(2007/10/02)
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