Histidine <italic style="font-style: italic">N</italic>-Thiocarboxyanhydride: Direct Synthesis and Polymerization without Protection towards Well-defined Polyhistidine

Song-Yi Xu; Tian-Wen Bai; Bo-Tuo Zheng; Ze-Hua Li; Jun Ling

doi:10.1007/s10118-025-3348-0

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Histidine N-Thiocarboxyanhydride: Direct Synthesis and Polymerization without Protection towards Well-defined Polyhistidine

RESEARCH ARTICLE | Updated：2025-06-16

- Histidine N-Thiocarboxyanhydride: Direct Synthesis and Polymerization without Protection towards Well-defined Polyhistidine
- Chinese Journal of Polymer Science Vol. 43, Pages: 1-9(2025)
- Affiliations：
  
  a.MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310058, China
  b.College of Biological, Chemical Sciences and Engineering, Jiaxing University, Jiaxing 314001, China
  c.College of Chemistry and Materials Science, Fujian Key Laboratory of Polymer Materials, Fujian Normal University, Fuzhou 350007, China
- Author bio：
  
  lingjun@zju.edu.cn
- Funds：
- DOI：10.1007/s10118-025-3348-0
  CLC：
- Received：24 February 2025，
  
  Revised：16 March 2025，
  
  Accepted：31 March 2025，
  
  Published Online：26 May 2025，
  
  Published：2025-04
- Accepted：
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Xu, S. Y.; Bai, T. W.; Zheng, B. T.; Li, Z. H.; Ling, J. Histidine N-thiocarboxyanhydride: direct synthesis and polymerization without protection towards well-defined polyhistidine. Chinese J. Polym. Sci. https://doi.org/10.1007/s10118-025-3348-0

Song-Yi Xu, Tian-Wen Bai, Bo-Tuo Zheng, et al. Histidine N-Thiocarboxyanhydride: Direct Synthesis and Polymerization without Protection towards Well-defined Polyhistidine[J/OL]. Chinese journal of polymer science, 2025, 431-9.
Xu, S. Y.; Bai, T. W.; Zheng, B. T.; Li, Z. H.; Ling, J. Histidine N-thiocarboxyanhydride: direct synthesis and polymerization without protection towards well-defined polyhistidine. Chinese J. Polym. Sci. https://doi.org/10.1007/s10118-025-3348-0 DOI：

Song-Yi Xu, Tian-Wen Bai, Bo-Tuo Zheng, et al. Histidine N-Thiocarboxyanhydride: Direct Synthesis and Polymerization without Protection towards Well-defined Polyhistidine[J/OL]. Chinese journal of polymer science, 2025, 431-9. DOI： 10.1007/s10118-025-3348-0.

摘要

Abstract

Consisting of natural histidine residues

polyhistidine (PHis) simulates functional proteins. Traditional approaches towards PHis require the protection of imidazole groups before monomer synthesis and polymerization to prevent degradation and side reactions. In the contribution

histidine

-thiocarboxyanhydride (His-NTA) is directly synthesized in aqueous solution without protection. With the self-catalysis of the imidazole side group

the ring-closing reaction to form His-NTA does not require any activating reagent (

e.g.

phosphorus tribromide)

hich is elucidated by density functional theory (DFT) calculations. His-NTA directly polymerizes into PHis bearing unprotected imidazole groups with designable molecular weights (4.2−7.7 kg/mol) and low dispersities (1.10−1.19). Kinetic experiments and Monte Carlo simulations reveal the elementary reactions and the relationship between the conversion of His-NTA and time during polymerization. Block copolymerization of His-NTA with sarcosine

-thiocarboxyanhydride (Sar-NTA) demonstrate versatile construction of functional polypept(o)ides. The triblock copoly(amino acid) PHis-

-PSar-

-PHis is capable to reversibly coordinate with transition metal ions (Fe

and Zn

) to form pH-sensitive hydrogels.

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Keywords

references

Holeček, M. Histidine in health and disease: metabolism, physiological importance, and use as a supplement. Nutrients 2020 , 12 , 848..

Abe, H. Role of histidine-related compounds as intracellular proton buffering constituents in vertebrate muscle. Biochemistry 2000 , 65 , 757−765..

Trombley, P. Q.; Horning, M. S.; Blakemore, L. J. Interactions between carnosine and zinc and copper: implications for neuromodulation and neuroprotection. Biochemistry 2000 , 65 , 807−816..

Dahl, T. A.; Midden, W. R.; Hartman, P. E. Some prevalent biomolecules as defenses against singlet oxygen damage. Photochem. Photobiol. 2008 , 47 , 357−362..

Qiu, L.; Li, Z.; Qiao, M.; Long, M.; Wang, M.; Zhang, X.; Tian, C.; Chen, D. Self-assembled pH-responsive hyaluronic acid- g -poly(L-histidine) copolymer micelles for targeted intracellular delivery of doxorubicin. Acta Biomater. 2014 , 10 , 2024−2035..

Kuo, W.-H. K.; Chase, H. A. Exploiting the interactions between poly-histidine fusion tags and immobilized metal ions. Biotechnol. Lett. 2011 , 33 , 1075−1084..

Zhang, Y.; Kim, I.; Lu, Y.; Xu, Y.;Yu, D.-G.; Song, W. Intelligent poly(L-histidine)-based nanovehicles for controlled drug delivery. J. Control. Release 2022 , 349 , 963−982..

Fullenkamp, D. E.; He, L.; Barrett, D. G.; Burghardt, W. R.; Messersmith, P. B. Mussel-inspired histidine-based transient network metal coordination hydrogels. Macromolecules 2013 , 46 , 1167−1174..

Tang, Q.; Zhao, D.; Zhou, Q.; Yang, H.; Peng, K.; Zhang, X. Polyhistidine-based metal coordination hydrogels with physiologically relevant pH responsiveness and enhanced stability through a novel synthesis. Macromol. Rapid Commun. 2018 , 39 , 1800109..

Bornhorst, J. A.; Falke, J. J. Purification of proteins using polyhistidine affinity tags. Methods Enzymol. 2000 , 326 , 245−254..

Athan asiou, V.; Thimi, P.; Liakopoulou, M.; Arfara, F.; Stavroulaki, D.; Kyroglou, I.; Skourtis, D.; Stavropoulou, I.; Christakopoulos, P.; Kasimatis, M.; Fragouli, P. G.; Iatrou, H. Synthesis and characterization of the novel N ε -9-fluorenylmethoxycarbonyl- L -lysine N -carboxy anhydride. Synthesis of well-defined linear and branched polypeptides. Polymers 2020 , 12 , 2819..

John, J. V.; Uthaman, S.; Augustine, R.; Manickavasagam Lekshmi, K.; Park, I. K.; Kim, I. Biomimetic pH/redox dual stimuli-responsive zwitterionic polymer block poly(L-histidine) micelles for intracellular delivery of doxorubicin into tumor cells. J. Polym. Sci. Polym. Chem. 2017 , 55 , 2061−2070..

Liu, R.; He, B.; Li, D.; Lai, Y.; Tang, J. Z.; Gu, Z. Synthesis and characterization of poly(ethylene glycol)- b -poly(L-histidine)- b -poly(L-lactide) with pH-sensitivity. Polymer 2012 , 53 , 1473−1482..

Mavrogiorgis, D.; Bilalis, P.; Karatzas, A.; Skoulas, D.; Fotinogiannopoulou, G.; Iatrou, H. Controlled polymerization of histidine and synthesis of well-defined stimuli responsive polymers. Elucidation of the structure-aggregation relationship of this highly multifunctional material. Polym. Chem. 2014 , 5 , 6256−6278..

Pan, J.; Lei, S.; Chang, L.; Wan, D. Smart pH-responsive nanoparticles in a model tumor microenvironment for enhanced cellular uptake. J. Mater. Sci. 2018 , 54 , 1692−1702..

Ramasamy, T.; Ruttala, H. B.; Chitrapriya, N.; Poudal, B. K.; Choi, J. Y.; Kim, S. T.; Youn, Y. S.; Ku, S. K.; Choi, H. G.; Yong, C. S.; Kim, J. O. Engineering of cell microenvironment-responsive polypeptide nanovehicle co-encapsulating a synergistic combination of small molecules for effective chemotherapy in solid tumors. Acta Biomater. 2017 , 48 , 131−143..

Skoulas, D.; Mangiapia, G.; Parisi, D.; Kasimatis, M.; Glynos, E.; Stratikos, E.; Vlassopoulos, D.; Frielinghaus, H.; Iatrou, H. Tunable hydrogels with improved viscoelastic properties from hybrid polypeptides. Macromolecules 2021 , 54 , 10786−10800..

Sun, Y.; Li, Y.; Huang, H.; Wang, Y.; Sa, Z.; Wang, J.; Chen, X. pH-sensitive poly(itaconic acid)-poly(ethylene glycol)-poly(L-histidine) micelles for drug delivery. J. Macromol. Sci. Part A 2015, 52 , 925-933..

Zhang, X.; Chen, D.; Ba, S.; Zhu, J.; Zhang, J.; Hong, W.; Zhao, X.; Hu, H.; Qiao, M. Poly(L-histidine) based triblock copolymers: pH induced reassembly of copolymer micelles and mechanism underlying endolysosomal escape for intracellular delivery. Biomacromolecules 2014 , 15 , 4032−4045..

Bauer, T. A.; Simić, L.; Van Guyse, J. F. R.; Duro-Castaño, A.; Nebot, V. J.; Barz, M. Polypept(o)ides―origins, synthesis, applications and future directions. Prog. Polym. Sci. 2024 , 158 , 101889..

Sugimoto, T.; Kuwahara, T.; Liang, F.; Wang, H.; Tsuda, A. Photo-on-demand synthesis of α -amino acid N -carboxyanhydrides with chloroform. ACS Omega 2022 , 7 , 39250−39257..

Tao, X.; Zheng, B.; Bai, T.; Li, M.-H.; Ling, J. Polymerization of n-substituted glycine n -thiocarboxyanhydride through regioselective initiation of cysteamine: a direct way toward thiol-capped polypeptoids. Macromolecules 2018 , 51 , 4494−4501..

Tao, X.; Zheng, B.; Bai, T.; Zhu, B.; Ling, J. Hydroxyl group tolerated polymerization of N -substituted glycine N -thiocarboxyanhydride mediated by aminoalcohols: a simple way to α -hydroxyl- ω -aminotelechelic polypeptoids. Macromolecules 2017 , 50 , 3066−3077..

Miao, Y.; Xie, F.; Cen, J.; Zhou, F.; Tao, X.; Luo, J.; Han, G.; Kong, X.; Yang, X.; Sun, J.; Ling, J. Fe 3+ @polyDOPA-b-polysarcosine, a T1-weighted MRI contrast agent via controlled NTA polymerization. ACS Macro Lett. 2018 , 7 , 693−698..

Zheng, B.; Bai, T.; Ling, J.; Sun, J. Direct N -substituted N -thiocarboxyanhydride polymerization towards polypeptoids bearing unprotected carboxyl groups. Commun. Chem. 2020 , 3 , 144..

Zheng, B.; Bai, T.; Tao, X.; Schlaad, H.; Ling, J. Identifying the hydrolysis of carbonyl sulfide as a side reaction impeding the polymerization of N -substituted glycine N -thiocarboxyanhydride. Biomacromolecules 2018 , 19 , 4263−4269..

Zheng, B.; Tao, X.; Ling, J. Water tolerated polymerization of N -substituted glycine N -thiocarboxyanhydride initiated by primary amines. Acta Polymerica Sinica (in Chinese) 2018 , 72−79..

Siefker, D.; Williams, A. Z.; Stanley, G. G.; Zhang, D. Organic acid promoted controlled ring-opening polymerization of α -amino acid-derived N -thiocarboxyanhydrides (NTAs) toward well-defined polypeptides. ACS Macro Lett. 2018 , 7 , 1272−1277..

Zheng, B.; Xu, S.; Ni, X.; Ling, J. Understanding acid-promoted polymerization of the N -substituted glycine N -thiocarboxyanhydride in polar solvents. Biomacromolecules 2021 , 22 , 1579−1589..

Zhou, P.; Shen, T.; Chen, W.; Sun, J.; Ling, J. Biodegradable polysarcosine with inserted alanine residues: synthesis and enzymolysis. Biomacromolecules 2022 , 23 , 1757−1764..

Dewey, R. S.; Schoenewaldt, E. F.; H. Joshua, W.; Paleveda, J.; JR.; Schwam, H.; Barkemeyer, H.; Arison, B. H.; Veber, D. F.; Strachan, R. G.; Milkowski, J.; Denkewalter, R. G.; Hirschmann, R. The synthesis of peptides in aqueous medium. VII. The preparation and use of 2,5-thiazolidinediones in peptide synthesis. J. Org. Chem. 1971 , 36 , 49−59..

Dewey, R. S.; Schoenewaldt, E. F.; Joshua, H.; Paleveda, W. J.; Jr. H. S.; Barkemeyer, H.; Arison, B. H.; Veber, D. F.; Denkewalter, R. G.; Hirschmann, R. Synthesis of peptides in aqueous medium. V. Preparation and use of 2,5-thiazolidinediones (NTA’s). Use of the 13 C-H nuclear magnetic resonance signal as internal standard for quantitative studies. J. Am. Chem. Soc. 1968 , 90 , 3254−3255..

Tao, X.; Zheng, B.; Kricheldorf, H. R.; Ling, J. Are N-substituted glycine N-thiocarboxyanhydride monomers really hard to polymerize. J. Polym. Sci. Polym. Chem. 2017 , 55 , 404−410..

Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Petersson, G. A.; Nakatsuji, H.; Li, X.; Caricato, M.; Marenich, A. V.; Bloino, J.; Janesko, B. G.; Gomperts, R.; Mennucci, B.; Hratchian, H. P.; Ortiz, J. V.; Izmaylov, A. F.; Sonnenberg, J. L.; Williams-Young, D.; Ding, F.; Lipparini, F.; Egidi, F.; Goings, J.; Peng, B.; Petrone, A.; Henderson, T.; Ranasinghe, D.; Zakrzewski, V. G.; Gao, J.; Rega, N.; Zheng, G.; Liang, W.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Throssell, K.; Montgomery Jr. J. A.; Peralta, J. E.; Ogliaro, F.; Bearpark, M. J.; Heyd, J. J.; Brothers, E. N.; Kudin, K. N.; Staroverov, V. N.; Keith, T. A.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A. P.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Millam, J. M.; Klene, M.; Adamo, C.; Cammi, R.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Farkas, O.; Foresman, J. B.; Fox, D. J. Gaussian 16 Rev. B.01 , Gaussian, Inc.; Wallingford, CT, 2016.

Bai, T.; Shen, B.; Cai, D.; Luo, Y.; Zhou, P.; Xia, J.; Zheng, B.; Zhang, K.; Xie, R.; Ni, X.; Xu, M.; Ling, J.; Sun, J. Understanding ring-closing and racemization to prepare α -amino acid NCA and NTA monomers: a DFT study. Phys. Chem. Chem. Phys. 2020 , 22 , 14868−14874..

Cao, J.; Siefker, D.; Chan, B. A.; Yu, T.; Lu, L.; Saputra, M. A.; Fronczek, F. R.; Xie, W.; Zhang, D. Interfacial ring-opening polymerization of amino-acid-derived N -thiocarboxyanhydrides toward well-defined polypeptides. ACS Macro Lett. 2017 , 6 , 836−840..

Bai, T.; Zhou, P.; Li, Z.; Zheng, B.; Ling, J. Seeding crystals, harvesting polypeptides: preparing long chiral-sequence controlled polypeptides by interlocked polymerization in cocrystals (iPiC) of N -thiocarboxyanhydride (NTA) at room temperature. Macromolecules 2021 , 54 , 6691−6697..

Ling, J.; Ni, X.; Zhang, Y.; Shen, Z. Monte Carlo simulation of gas phase polymerization of 1,3-butadiene Part I. Modeling and programming. Polymer 2000 , 41 , 8703−8707..

Gillespie, D. T. Exact stochastic simulation of coupled chemical reactions. J. Phys. Chem. 1977 , 81 , 2340−2361..

Birke, A.; Ling, J.; Barz, M. Polysarcosine-containing copolymers: synthesis, characterization, self-assembly, and applications. Prog. Polym. Sci. 2018 , 81 , 163−208..

Schmaljohann, D. Thermo- and pH-responsive polymers in drug delivery. Adv. Drug Deliv. Rev. 2006 , 58 , 1655−1670..

Irving H.; William R. J. P. The Stability of transition-metal complexes. J. Chem. Soc. Part III 1953, 3192-3210.

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Histidine N-Thiocarboxyanhydride: Direct Synthesis and Polymerization without Protection towards Well-defined Polyhistidine

DOI：10.1007/s10118-025-3348-0

摘要

Abstract

关键词

Keywords

references