Insight into the synthesis of <i>N</i>-methylated polypeptides

Muhl, Christian; Zengerling, Lydia; Groß, Joachim; Eckhardt, Paul; Opatz, Till; Besenius, Pol; Barz, Matthias

doi:10.1039/d0py01055c

Cited by 5 publications

(6 citation statements)

References 41 publications

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“…[73][74][75] In another work, Barz and co-workers investigated the polymerizations of N-methylated 𝛼-substituted amino acid NCAs (𝛼NNCAs) toward N,𝛼-disubstituted PAAs, whose properties and applications are still unknown. [76] 3. Amino Acid N-Thiocarboxyanhydride…”

Section: Advances In Polymerizations Of Ncasmentioning

confidence: 99%

An Inspection into Multifarious Ways to Synthesize Poly(Amino Acid)s

Zheng

Bai

Tao

et al. 2021

Macromol. Rapid Commun.

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Poly(𝜶-amino acid)s (PAAs) attract growing attention due to their essential role in the application as biomaterials. To synthesize PAAs with desired structures and properties, scientists have developed various synthetic techniques with respective advantages. Here, different approaches to preparing PAAs are inspected. Basic features and recent progresses of these methods are summarized, including polymerizations of amino acid N-carboxyanhydrides (NCAs), amino acid N-thiocarboxyanhydrides (NTAs), and N-phenoxycarbonyl amino acids (NPCs), as well as other synthetic routes. NCA is the most classical monomer to prepare PAAs with high molecular weights (MWs). NTA polymerizations are promising alternative pathways to produce PAAs, which can tolerate nucleophiles including alcohols, mercaptans, carboxyl acids, and water. By various techniques including choosing appropriate solvents or using organic acids as promoters, NTAs polymerize to produce polypeptoids and polypeptides with narrow dispersities and designed MWs up to 55.0 and 57.0 kg mol −1 , respectively. NPC polymerizations are phosgene-free ways to synthesize polypeptides and polypeptoids. For the future prospects, detail investigations into polymerization mechanisms of NTA and NPC are expected. The synthesis of PAAs with designed topologies and assembly structures is another intriguing topic. The advantages and unsettled problems in various synthetic ways are discussed for readers to choose appropriate approaches for PAAs.

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Section: Advances In Polymerizations Of Ncasmentioning

confidence: 99%

An Inspection into Multifarious Ways to Synthesize Poly(Amino Acid)s

Zheng

Bai

Tao

et al. 2021

Macromol. Rapid Commun.

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“…A submonomer solid-phase synthesis method has been applied for the preparation of N -methyl polyalanine; however, the coupling between the ( S )-2-bromopropionic acid and methylamine is inefficient that only low molecular weight (MW) polymers were obtained (DP < 10) (Scheme a) . Ring-opening polymerization (ROP) of α-amino acid-based N -methyl N -carboxyanhydrides (αNNCAs) has also been attempted to synthesize N -methyl polypeptides using primary amine as the initiator. , The polymerization, nevertheless, was very slow and uncontrolled, such that only low MW polymers were obtained (Scheme a). The polymers exhibited a high discrepancy between the actual and theoretical MWs.…”

Section: Introductionmentioning

confidence: 99%

“…5 Ring-opening polymerization (ROP) of α-amino acid-based Nmethyl N-carboxyanhydrides (αNNCAs) has also been attempted to synthesize N-methyl polypeptides using primary amine as the initiator. 6,7 The polymerization, nevertheless, was very slow and uncontrolled, such that only low MW polymers were obtained (Scheme 1a). The polymers exhibited a high discrepancy between the actual and theoretical MWs.…”

Section: ■ Introductionmentioning

confidence: 99%

“…The above-mentioned slow polymerization of αNNCAs is mainly attributed to the low reactivity of the monomer due to the electronic effect and steric hindrance added by the substituents at both α-carbon (α-CH) and nitrogen. , It is important to find an efficient catalyst to facilitate the nucleophilic addition of monomers with initiators and subsequent propagating chain end. Among the various catalysts (e.g., metal complexes, strong organic bases, − and thiourea/urea–amine combinations , ), strong organic bases have been widely used to promote the ROP of cyclic monomers including lactides, lactones, cyclic carbonates, O -carboxyanhydrides (OCAs), and NCAs.…”

Section: Introductionmentioning

confidence: 99%

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Efficient Synthesis of N-Methyl Polypeptides by Organic Acid Promoted Controlled Ring-Opening Polymerization of N-Methyl-α-Amino Acids N-Carboxyanhydrides

Yu,

Wang,

Dong

et al. 2023

Macromolecules

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N-Methyl peptides, which are widely found in nature, have emerged as an intriguing material in both polymer science and the biomedical field. The inefficient synthesis of Nmethyl peptides, however, has greatly impeded the progress toward their structure−property investigation and applications. Here, we report an efficient, moisture-tolerant, primary amine-initiated, and acetic acid-catalyzed ring-opening polymerization of enantiomerically pure N-methyl-α-amino acids N-carboxyanhydrides, yielding well-defined, stereoregular, and structurally diverse N-methyl polypeptides. The concentration of the acetic acid, polarity of solvents, and stiffness of polymer chains were found to be crucial to the rate of the polymerization. The acetic acid was proposed to activate the monomer through hydrogen bonding interaction, promote the release of CO 2 , and form an acid−base equilibrium with the secondary amine chain end. The obtained N-methyl polypeptides exhibited stable helix structures, revealing chain stiffness, consistent with the high glass transition temperatures (>250 °C) from DSC measurements. Moreover, preliminary studies indicated that N-methyl polypeptides are nontoxic both in vitro and in vivo and are enzymatically stable toward trypsin treatment. Together, this study provides a mild and efficient method for the preparation of N-methyl polypeptides, opening avenues for their further structure−property investigation and potential applications.

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“…In this study, a new type of non-ionic hydrophilic polypeptide called poly (n-methylated glycine) ( 18 , 19 ) or Polysarcosine (PSar) was used in the delivery of chemotherapeutic drugs by polymeric nanoparticles; which is the best alternative to corona-forming polymer, poly (ethylene glycol) (PEG) ( 20 ). Apart from PSar, the Poly D, L-lactic-co-glycolic acid (PLGA) ( 21 ) was also used; due to its excellent biodegradability and biocompatibility properties it is an excellent choice for drug delivery.…”

Section: Introductionmentioning

confidence: 99%

Unveiling the therapeutic potential of cabozantinib-loaded poly D,L-lactic-co-glycolic acid and polysarcosine nanoparticles in inducing apoptosis and cytotoxicity in human HepG2 hepatocellular carcinoma cell lines and in vivo anti-tumor activity in SCID female mice

Bhattacharya

Parihar²,

Prajapati³

2023

Front. Oncol.

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IntroductionThe study aimed to develop a nano-based drug delivery system for the treatment of hepatocellular carcinoma (HCC), a type of liver cancer that accounts for 90% of all liver malignancies. The study focused on the use of cabozantinib (CNB), a potent multikinase inhibitor that targets the VEGF receptor 2, as the chemotherapeutic drug. We developed CNB-loaded nanoparticles made from Poly D, L-lactic-co-glycolic acid, and Polysarcosine (CNB-PLGA-PSar-NPs) for use in human HepG2 cell lines.MethodsBy O/W solvent evaporation method, the polymeric nanoparticles were prepared. The various techniques, such as photon correlation spectroscopy, scanning electron microscopy, and transmission electron microscopy were used, to determine the formulation's particle size, zeta potential, and morphology. SYBR Green/ROX qPCR Master Mix and RT-PCR equipment used to measure liver cancer cell line and tissue mRNA expression and MTT assay to test HepG2 cell cytotoxicity. Cell cycle arrest analysis, annexin V assay, and ZE5 Cell Analyzer apoptosis assay were also performed.ResultsThe results of the study showed that the particle diameters were 192.0 ± 3.67 nm with 0.128 PDI and -24.18 ± 3.34 mV zeta potential. The antiproliferative and proapoptotic effects of CNB-PLGA-PSar-NPs were evaluated using MTT and flow cytometry (FCM). The IC50 value of CNB-PLGA-PSar-NPs was 45.67 µg/mL, 34.73 µg/mL, and 21.56 µg/mL for 24, 48, and 72 h, respectively. The study also found that 11.20% and 36.77% of CNB-PLGA-PSar-NPs-treated cells were apoptotic at 60 µg/mL and 80 µg/mL, respectively, suggesting that the nanoparticles were effective in inducing apoptosis in the cancer cells. It can also conclude that, CNB-PLGA-PSar-NPs inhibit human HepG2 hepatocellular carcinoma cells and kill them by upregulating the tumour suppressor genes MT1F, MT1X, and downregulating MTTP, APOA4. Further in vivo antitumor activity was well reported in SCID female mice.DiscussionOverall, this study suggests that the CNB-PLGA-PSar-NPs are a promising drug delivery system for the treatment of HCC, and further research is needed to investigate their potential in clinical treatment.

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Insight into the synthesis of N-methylated polypeptides

Abstract: The ring-opening polymerization of α-substituted N-methylated N-carboxy anhydrides is reported. The polymerization was tested using various amino acids and initiators, and was found to be limited by the steric demand of N-methylated compared to conventional amino acids.

Cited by 5 publications

References 41 publications

An Inspection into Multifarious Ways to Synthesize Poly(Amino Acid)s

An Inspection into Multifarious Ways to Synthesize Poly(Amino Acid)s

Efficient Synthesis of N-Methyl Polypeptides by Organic Acid Promoted Controlled Ring-Opening Polymerization of N-Methyl-α-Amino Acids N-Carboxyanhydrides

Unveiling the therapeutic potential of cabozantinib-loaded poly D,L-lactic-co-glycolic acid and polysarcosine nanoparticles in inducing apoptosis and cytotoxicity in human HepG2 hepatocellular carcinoma cell lines and in vivo anti-tumor activity in SCID female mice

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