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Rong Zeng - One of the best experts on this subject based on the ideXlab platform.
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A zwitterionic serine modified chitosan derivative for improving protein stability and activity
International journal of biological macromolecules, 2020Co-Authors: Guanglin Zhang, Xingwen Huang, Wenrui Zhang, Rong ZengAbstract:Abstract A zwitterionic phosphoryldiserine (PDS)- chitosan conjugate was synthesized via Atherton-Todd Reaction, and its degree of substitution of PDS and structure were characterized by 1H and 31P NMR spectra, ICP, FTIR and XRD. Thermal analysis confirmed that there existed the freezing bound water surrounding PDS-chitosan due to the introduction of zwitterionic PDS groups onto chitosan backbone. In vitro cytotoxicity and hemolysis assay demonstrated that PDS-chitosan had excellent cell compatibility. UV adsorption and fluorescence spectra revealed that the model protein, bovine serum albumin (BSA) tended to keep its native conformation and showed better thermal stability in aqueous media in the presence of PDS-chitosan. We also found that the esterase-like activity of BSA could be enhanced by low concentration of PDS-chitosan (CBSA = 0.33 mg/mL, CPDS-chitosan = 0.0625 and 0.125 mg/mL, pH = 7.4, T = 25 °C). The results indicated that zwitterionic PDS-chitosan showed great potential for maintaining protein function in biomedical applications.
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Branched dicationically-charged phosphodicholine (PdC) modified chitosan with specific associated water structure and unique interactions with biocomponents
Reactive and Functional Polymers, 2018Co-Authors: Xingwen Huang, Rong Zeng, Zhaoyu Cao, Bangren Fang, Jianhao ZhaoAbstract:Abstract Cationic polymers possess significant potential in various biomedical applications due to their favorable interactions with biocomponents in aqueous media, which is related to their inherent structure and associated water structure. This work presents the development of a novel biodegradable cationic polymer with specific associated water structure and unique interactions with biocomponents. Bioinspired branched dicationically-charged phosphodicholine-chitosan (PdCCs) with different substitute degree were synthesized via Atherton-Todd Reaction. As compared with monocationically charged N-(2-hydroxyl) propyl-3-trimethyl ammonium chitosan chloride (HTCC), thermal analysis confirmed the existence of the freezing bound water surrounding PdCCs due to the introduction of branched dicationically-charged PdC moiety. Fluorescence spectra revealed that PdCCs induced much less conformational change of bovine serum albumin than HTCC. Antibacterial and hemolysis assay showed that PdCCs and HTCC displayed high antibacterial activities against Escherichia coli and Staphylococcus aureus with different bacterial-type selectivity, and PdCCs showed higher selectivity to kill bacteria over red blood cell than HTCC. Furthermore, PdCCs-immobilized antibacterial surfaces exhibited better hydrophilicity and less protein adsorption than HTCC-immobilized antibacterial surfaces. These results indicated that branched dicationic PdC with capacity to restrain the freezing bound water may provide a good choice for developing cationic polymers for therapeutic applications.
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Preparation, characterization and protein sorption of photo-crosslinked cell membrane-mimicking chitosan-based hydrogels
Carbohydrate polymers, 2016Co-Authors: Yunfei Zhao, Rong Zeng, Jianhao ZhaoAbstract:Photocrosslinkable biomimetic chitosan derivative, glycidyl methacrylate-phosphorylcholine-chitosan (PCCs-GMA) was synthesized through the combination of Atherton-Todd Reaction for coupling phosphorylcholine and ring opening Reaction of epoxides for attaching GMA, and confirmed by (1)H and (31)P NMR and Fourier transform infrared (FTIR) spectroscopy. The photo-crosslinking Reaction of PCCs-GMA with different degree of substitution (DS) of GMA allowed the formation of biomimetic hydrogels with tunable mechanical and swelling properties. Cold crystallization behaviors ascribed to their restrained freezing bound water were investigated using differential scanning calorimetry (DSC). The rheological and swelling behaviors, hemolysis as well as protein sorption of PCCs-GMA hydrogels were investigated in terms of the DS of GMA, using fibrinogen, bovine serum albumin and lysozyme as model proteins. Low irreversible protein sorption and non hemolytic results indicated that photo-crosslinked PCCs-GMA hydrogels may offer a promising candidate material with resistance to protein fouling in biomedical applications.
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Novel self-assembled pH-responsive biomimetic nanocarriers for drug delivery
Materials science & engineering. C Materials for biological applications, 2016Co-Authors: Zhaoyu Cao, Yunfei Zhao, Rong Zeng, Jianhao ZhaoAbstract:Novel pH-responsive biodegradable biomimetic nanocarriers were prepared by the self-assembly of N-acetyl-l-histidine-phosphorylcholine-chitosan conjugate (NAcHis-PCCs), which was synthesized via Atherton-Todd Reaction to couple biomembrane-like phosphorylcholine (PC) groups, and N,N'-carbonyldiimidazole (CDI) coupling Reaction to link pH-responsive N-acetyl-l-histidine (NAcHis) moieties to chitosan. In vitro biological assay revealed that NAcHis-PCCs nanoparticles had excellent biocompatibility to avoid adverse biological response mainly owing to their biomimetic PC shell, and DLS results confirmed their pH-responsive behavior in acidic aqueous solution (pH≤6.0). Quercetin (QUE), an anti-inflammatory, antioxidant and potential anti-tumor hydrophobic drug, was effectively loaded in NAcHis-PCCs nanocarriers and showed a pH-triggered release behavior with the enhanced QUE release at acidic pH5.5 compared to neutral pH7.4. The results indicated that pH-responsive biomimetic NAcHis-PCCs nanocarriers might have great potential for site-specific delivery to pathological acidic microenvironment avoiding unfavorable biological response.
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Bioinspired double-positively charged phosphodicholine-chitosan and zwitterionic phosphorylcholine-chitosan conjugates: The associated water structure, biocompatibility and antibacterial action
Reactive and Functional Polymers, 2016Co-Authors: Zhaoyu Cao, Yunfei Zhao, Rong Zeng, Lisha Dai, Jianhao ZhaoAbstract:Abstract Bioinspired double-positively charged phosphodicholine (PdC)-chitosan conjugate was synthesized via Atherton-Todd Reaction, which can hydrolyze to zwitterionic phosphorylcholine (PC)-chitosan in basic solutions, confirmed by 1 H and 31 P NMR spectra. Thermal analysis revealed that there existed the freezing bound water due to the introduction of PdC and PC groups for both PdC-chitosan and PC-chitosan, implying that double-positively charged PdC-chitosan may exhibit excellent biocompatibility as zwitterionic PC-chitosan. Cytotoxicity, hemolysis and antibacterial activity evidenced that PdC-chitosan displayed high antibacterial activity against Escherichia coli and Staphylococcus aureus under physiological conditions, and very low cytotoxicity and hemolytic activity, owing to its highly selective lysis of bacterial membranes over mammalian cell membranes mainly resulting from the competition of electrostatic interactions and shielding effect of the restrained water of PdC, while biocompatible PC-chitosan showed no antibacterial activity due to its non-fouling property. The results indicated that biocompatible double-positively charged PdC-containing bioinspired polymers may provide a promising approach for developing safe and effective antibacterial agents.
Yufen Zhao - One of the best experts on this subject based on the ideXlab platform.
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Progress in the Atherton-Todd Reaction and its stereochemical mechanism
SCIENTIA SINICA Chimica, 2015Co-Authors: Shuxia Cao, Yufen ZhaoAbstract:In this review, we summarize the literatures in the latest decades on the Atherton-Todd Reaction of the tetracoordinated and pentacoordinated phosphorus compounds containing P-H bond. Especially, the review focuses on the development of the stereochemical mechanism of the Atherton-Todd Reaction. Although the Reaction mechanism has been investigated for decades after the discovery of the Reaction, the earlier studies mainly concentrated on the Reaction intermediate. Up to the past dozen years, the stereochemical mechanism of the Atherton-Todd Reaction was studied in detail. However, up to now, there is few review and introduction to the stereochemical mechanism of the Atherton- Todd Reaction. We hope this article could compensate for this limitation, and it not only summarizes the general Atherton-Todd Reaction, but also introduces the recent research results on the stereochemical mechanism. It is considered that the further investigation on the stereochemical mechanism of the Atherton-Todd Reaction will be helpful to design and synthesize the novel tetracoordinated or pentacoordinated compounds with phosphorus chiral centers.
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Synthesis and Characterization of New Pyrospirophosphoranes Containing a P‐O‐P Bond by the Atherton–Todd Reaction
Heteroatom Chemistry, 2014Co-Authors: Xiaohui You, Yufen Zhao, Jia Zheng, Wang Dai, Yanchun Guo, Shuxia CaoAbstract:The classical Atherton–Todd Reaction has been successfully applied to the synthesis of pentacoordinate pyrospirophosphoranes containing a P-O-P bond under mild conditions. The absolute configurations of the products were confirmed by X-ray diffraction analysis and spectroscopic identification. And 31P NMR chemical shifts of the products were correlated with stereochemistry. A possible mechanism for explaining the stereochemistry of the Reaction was proposed, and it could well explain the results of the Reactions of different pentacoordinate hydrospirophosphoranes.
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Highly Regioselective Synthesis of Novel 4-O-Phosphorylated Paeonol Analogs
Phosphorus Sulfur and Silicon and the Related Elements, 2012Co-Authors: Jie Wang, Fengling Yang, Yufen ZhaoAbstract:Abstract 4-O-phosphorylated paeonol derivatives were conveniently prepared by a facile method. Resacetophenone was prepared by the Friedel–Crafts acylation Reaction of acetic acid with resorcinol. It was then phosphorylated regioselectively at the 4-O position using the Atherton–Todd Reaction. An efficient, highly regioselective method to synthesize 4-O-phosphorylated paeonol derivatives is provided, and the approach has the merits of mild Reaction conditions. Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.
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the synthesis of amino acid methyl ester 5 phosphoamidates of protected uridine
Phosphorus Sulfur and Silicon and The Related Elements, 2010Co-Authors: Yufen Zhao, W Z ChenAbstract:In this article, we used the Atherton–Todd Reaction to synthesize amino acid methyl ester 5′-phosphoamidates of uridine as prodrugs. Their structures were confirmed by 1H NMR, 31P NMR, 13C NMR, IR,...
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The Synthesis of Amino Acid Methyl Ester 5′-Phosphoamidates of Protected Uridine
Phosphorus Sulfur and Silicon and the Related Elements, 2010Co-Authors: W Z Chen, Yufen ZhaoAbstract:In this article, we used the Atherton–Todd Reaction to synthesize amino acid methyl ester 5′-phosphoamidates of uridine as prodrugs. Their structures were confirmed by 1H NMR, 31P NMR, 13C NMR, IR,...
Jianhao Zhao - One of the best experts on this subject based on the ideXlab platform.
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Branched dicationically-charged phosphodicholine (PdC) modified chitosan with specific associated water structure and unique interactions with biocomponents
Reactive and Functional Polymers, 2018Co-Authors: Xingwen Huang, Rong Zeng, Zhaoyu Cao, Bangren Fang, Jianhao ZhaoAbstract:Abstract Cationic polymers possess significant potential in various biomedical applications due to their favorable interactions with biocomponents in aqueous media, which is related to their inherent structure and associated water structure. This work presents the development of a novel biodegradable cationic polymer with specific associated water structure and unique interactions with biocomponents. Bioinspired branched dicationically-charged phosphodicholine-chitosan (PdCCs) with different substitute degree were synthesized via Atherton-Todd Reaction. As compared with monocationically charged N-(2-hydroxyl) propyl-3-trimethyl ammonium chitosan chloride (HTCC), thermal analysis confirmed the existence of the freezing bound water surrounding PdCCs due to the introduction of branched dicationically-charged PdC moiety. Fluorescence spectra revealed that PdCCs induced much less conformational change of bovine serum albumin than HTCC. Antibacterial and hemolysis assay showed that PdCCs and HTCC displayed high antibacterial activities against Escherichia coli and Staphylococcus aureus with different bacterial-type selectivity, and PdCCs showed higher selectivity to kill bacteria over red blood cell than HTCC. Furthermore, PdCCs-immobilized antibacterial surfaces exhibited better hydrophilicity and less protein adsorption than HTCC-immobilized antibacterial surfaces. These results indicated that branched dicationic PdC with capacity to restrain the freezing bound water may provide a good choice for developing cationic polymers for therapeutic applications.
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Preparation, characterization and protein sorption of photo-crosslinked cell membrane-mimicking chitosan-based hydrogels
Carbohydrate polymers, 2016Co-Authors: Yunfei Zhao, Rong Zeng, Jianhao ZhaoAbstract:Photocrosslinkable biomimetic chitosan derivative, glycidyl methacrylate-phosphorylcholine-chitosan (PCCs-GMA) was synthesized through the combination of Atherton-Todd Reaction for coupling phosphorylcholine and ring opening Reaction of epoxides for attaching GMA, and confirmed by (1)H and (31)P NMR and Fourier transform infrared (FTIR) spectroscopy. The photo-crosslinking Reaction of PCCs-GMA with different degree of substitution (DS) of GMA allowed the formation of biomimetic hydrogels with tunable mechanical and swelling properties. Cold crystallization behaviors ascribed to their restrained freezing bound water were investigated using differential scanning calorimetry (DSC). The rheological and swelling behaviors, hemolysis as well as protein sorption of PCCs-GMA hydrogels were investigated in terms of the DS of GMA, using fibrinogen, bovine serum albumin and lysozyme as model proteins. Low irreversible protein sorption and non hemolytic results indicated that photo-crosslinked PCCs-GMA hydrogels may offer a promising candidate material with resistance to protein fouling in biomedical applications.
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Novel self-assembled pH-responsive biomimetic nanocarriers for drug delivery
Materials science & engineering. C Materials for biological applications, 2016Co-Authors: Zhaoyu Cao, Yunfei Zhao, Rong Zeng, Jianhao ZhaoAbstract:Novel pH-responsive biodegradable biomimetic nanocarriers were prepared by the self-assembly of N-acetyl-l-histidine-phosphorylcholine-chitosan conjugate (NAcHis-PCCs), which was synthesized via Atherton-Todd Reaction to couple biomembrane-like phosphorylcholine (PC) groups, and N,N'-carbonyldiimidazole (CDI) coupling Reaction to link pH-responsive N-acetyl-l-histidine (NAcHis) moieties to chitosan. In vitro biological assay revealed that NAcHis-PCCs nanoparticles had excellent biocompatibility to avoid adverse biological response mainly owing to their biomimetic PC shell, and DLS results confirmed their pH-responsive behavior in acidic aqueous solution (pH≤6.0). Quercetin (QUE), an anti-inflammatory, antioxidant and potential anti-tumor hydrophobic drug, was effectively loaded in NAcHis-PCCs nanocarriers and showed a pH-triggered release behavior with the enhanced QUE release at acidic pH5.5 compared to neutral pH7.4. The results indicated that pH-responsive biomimetic NAcHis-PCCs nanocarriers might have great potential for site-specific delivery to pathological acidic microenvironment avoiding unfavorable biological response.
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Bioinspired double-positively charged phosphodicholine-chitosan and zwitterionic phosphorylcholine-chitosan conjugates: The associated water structure, biocompatibility and antibacterial action
Reactive and Functional Polymers, 2016Co-Authors: Zhaoyu Cao, Yunfei Zhao, Rong Zeng, Lisha Dai, Jianhao ZhaoAbstract:Abstract Bioinspired double-positively charged phosphodicholine (PdC)-chitosan conjugate was synthesized via Atherton-Todd Reaction, which can hydrolyze to zwitterionic phosphorylcholine (PC)-chitosan in basic solutions, confirmed by 1 H and 31 P NMR spectra. Thermal analysis revealed that there existed the freezing bound water due to the introduction of PdC and PC groups for both PdC-chitosan and PC-chitosan, implying that double-positively charged PdC-chitosan may exhibit excellent biocompatibility as zwitterionic PC-chitosan. Cytotoxicity, hemolysis and antibacterial activity evidenced that PdC-chitosan displayed high antibacterial activity against Escherichia coli and Staphylococcus aureus under physiological conditions, and very low cytotoxicity and hemolytic activity, owing to its highly selective lysis of bacterial membranes over mammalian cell membranes mainly resulting from the competition of electrostatic interactions and shielding effect of the restrained water of PdC, while biocompatible PC-chitosan showed no antibacterial activity due to its non-fouling property. The results indicated that biocompatible double-positively charged PdC-containing bioinspired polymers may provide a promising approach for developing safe and effective antibacterial agents.
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Self-assemblied nanocomplexes based on biomimetic amphiphilic chitosan derivatives for protein delivery
Carbohydrate polymers, 2015Co-Authors: Hongwei Dong, Rong Zeng, Kai Guo, Jianhao ZhaoAbstract:Abstract A bio-inspired nanocarrier was developed for protein delivery based on biodegradable amphiphilic chitosan derivative (DCA–PCCs) with hydrophilic cell membrane mimic phosphorylcholine (PC) and hydrophobic deoxycholic acid (DCA) moieties, which was synthesized via the combination of Atherton–Todd Reaction and carbodiimide coupling Reaction. Using bovine serum albumin (BSA) as model protein, it was found that DCA–PCCs with suitable degree of substitution of PC and DCA moieties can load proteins by forming nanocomplexes via a solvent evaporation method. The physicochemical characteristics of BSA/DCA–PCCs nanocomplexes were investigated by Zetasizer, atomic force microscopy (AFM) and Fourier-transform infrared (FT-IR) spectroscopy. In vitro biological evaluation revealed BSA/DCA–PCCs nanocomplexes as blank DCA–PCCs nanoparticles had excellent cytocompatibility and hemocompatibility mainly due to the presence of cell membrane mimic phosphorylcholine. BSA release results suggested BSA/DCA–PCCs nanocomplexes showed a sustained release behavior following first order exponential decay kinetics. The results indicated DCA–PCCs provided a promising approach for effectively delivering therapeutic proteins.
Kolio Troev - One of the best experts on this subject based on the ideXlab platform.
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Reactivity of P–H Group of Poly(alkylene H-phosphonate)s
Reactivity of P-H Group of Phosphorus Based Compounds, 2018Co-Authors: Kolio TroevAbstract:Methods for preparation of poly(alkylene H-phosphonate)s and characteristic Reactions of its P–H group are described. Oxidation (Atherton–Todd Reaction), nonoxidative chlorination, reduction (silylation), and polymer analogous Reactions—addition to carbon–carbon double bond, carbonyl compounds, Schiff bases—of P–H group of poly(alkylene H-phosphonate)s are included. Fundamental results obtained for the reactivity of P–H group of low molecular compounds, especially cross and dehydrogenative coupling, open attractive perspectives in the field of polymer modification of poly[(alkylene, or arylene) H-phosphonate]s. These polymer analogues Reactions have big potential for preparation of novel poly[aryl (alkylene, or arylene) phosphonate]s, poly(alkylene aminophosphonate)s.
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Reactivity of P–H Group of H-Phosphinic Acid and Its Derivatives
Reactivity of P-H Group of Phosphorus Based Compounds, 2018Co-Authors: Kolio TroevAbstract:Methods for preparation of H-phosphonic acid and its diesters are described. The following Reactions of H-phosphonic acid and its diesters are included in this chapter: Oxidation, reduction, addition to carbon–carbon multiple bonds and Schiff bases, Abramov Reaction, Atherton–Todd Reaction, Kabachnik–Fields Reaction, cross-coupling Reaction, cross-dehydrogenative Reaction. Mechanisms of the abovementioned Reaction are discussed. The potential of the cross-coupling and cross-dehydrogenative Reactions of P–H group of diesters of H-phosphonic acid for the synthesis of organophosphorus compounds such as arylphosphonates, α-aminophosphonates, P-stereogenic nucleosides is discussed in detail. The application of the electrochemical methods for the construction of C–P bond using palladium catalysts is included in this chapter. Cross-coupling and dehydrogenative coupling Reactions in the future will be key motif for scientists working in the field of phosphorus chemistry. Cross-coupling and dehydrogenative coupling Reactions will open new chemical routes for polymer modification and for preparation of new materials.
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Polyphosphoesters based - paclixatel complexes, synthesis and characterization
2014Co-Authors: Tatyana Hristova, Rumiana Cherkezova, Kolio TroevAbstract:Paclitaxel, a natural occurring diterpene alkaloid, is a relatively new antineoplastic agent for clinical treatment of breast, lung, ovarian, head and neck cancers. Anti-cancer agents in the cancer therapy cause a large number of toxic side effects which require a reduced dosage of chemotherapeutic agents or occasionally interruption of the therapy itself. Thus, invention of new effective agents preventing tumor cell growth without causing non-specific side effects is clinically important. Here below, we demonstrate a strategy for the preparation of new types of biodegradable, water-soluble polyphosphoester-based paclitaxel complexes. Object: Presentation of a new type of covalently bonded or physically immobilized paclitaxel. Materials: Used substances: Poly(ethylene glycol) with number-average molecular weight 600 g/mol (PEG 600); Paclitaxel (99%): distilled Dimethyl H-phosphonate. Methods: 1) Synthesis of poly(oxyethylene H-phosphonate); 2) Synthesis of poly(hydroxyoxyethylene phosphate); 3) Synthesis of Polyphosphoestes-Paclitaxel Conjugate; 4) Physical immobilization (hydrogen bonding) of paclitaxel onto of poly(hydroxyoxyethylene phosphate). Results: After the synthesis of the polyphosphoesters, their structure was proved by 1H, 13C{H} and 31 P NMR spectroscopy. Paclitaxel was immobilized onto poly(oxyethyle H-phosphonate)s with Mn = 5117 Da and Mn = 8822 Da via covalent bond using Atherton-Todd Reaction conditions. Different types of complexes were synthesized as a result of the physical immobilization of paclitaxel onto polyphosphoesters. Conclusion: We have developed new water-soluble paclitaxel-polyphosphoesters complexes. The synthesis of covalently bonded paclitaxel onto poly (oxyethylene H-phosphonate) was conducted at room temperature. Paclitaxel was physically
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A polyphosphoester conjugate of melphalan as antitumoral agent.
European Journal of Pharmaceutical Sciences, 2013Co-Authors: Anita Bogomilova, Kolio Troev, Miriam Höhn, Michael Günther, Annika Herrmann, Ernst Wagner, Laura SchreinerAbstract:Abstract The low molecular weight of many chemotherapeutics causes their untargeted distribution in the body and fast renal clearance, which leads to a loss of therapeutic activity and to unspecific toxic side effects. Therefore, there is a growing interest in conjugating anticancer drugs to water soluble polymers and thus, take advantage of the ‘enhanced permeability and retention’ (EPR) effect in tumors. In this study, water soluble polyphosphoesters were used as polymer carriers of melphalan hydrochloride (hydrochloride of p-bis(2-chloroethyl)amino- l -phenylalanine), which is a multifunctional alkylating agent. Melphalan was chemically immobilized by covalent bonding to poly(oxyethylene H-phosphonate) under Atherton-Todd Reaction conditions. Novel polymer-melphalan complexes with ionic and hydrogen bonds were designed as controls, basing on two other biodegradable polyphosphoesters: poly(hydroxyoxyethylene phosphate) and poly(methyloxyethylene phosphate). The structure of the formed products was elucidated by 1H, 13C, 31P NMR and FT-IR spectroscopy. The cytotoxic effect of the melphalan formulations was evaluated on different tumor cell lines. The novel polymer formulations showed a concentration dependent antitumoral activity, comparable to the effect of unmodified melphalan. The polymer-melphalan conjugate was also evaluated in vivo in the human hepatocellular carcinoma HuH7 xenograft mouse model. It improved the therapeutic efficacy of pure melphalan without causing side effects.
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On the design of polymeric 5′-O-ester prodrugs of 3′-azido-2′,3′-dideoxythymidine (AZT)
Tetrahedron Letters, 2010Co-Authors: Kolio Troev, Violeta Mitova, Ivan IvanovAbstract:Abstract A new 5′-O-AZT prodrug was synthesized by conjugating 3′-azido-2′,3′-dideoxythymidine (AZT) with poly(oxyethylene H-phosphonate) at room temperature under Atherton-Todd Reaction conditions. The acute toxicity of poly(5′-O-AZT-oxyethylene phosphate) was reduced significantly in comparison with non-immobilized AZT.
Renzhong Qiao - One of the best experts on this subject based on the ideXlab platform.
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Effect of bond linkage on in vitro drug release and anti-HIV activity of chitosan-stavudine conjugates
Macromolecular Research, 2012Co-Authors: Rong Zeng, Zehu Wang, Lin Yang, Hongran Wang, Liqiang Chen, Renzhong QiaoAbstract:Two kinds of chitosan-stavudine (d4T) conjugates, chitosan-O-isopropyl-5′-O-d4T monophosphate conjugate (Cs-P-d4T) with a phosphoramide linkage and chitosan-5′-O-succinyl-d4T conjugate (Cs-S-d4T) with a succinic spacer, were synthesized using an Atherton-Todd Reaction and carbodiimide coupling Reaction, respectively, and then structurally characterized. Their in vitro drug release behaviors and anti-human immunodeficiency virus (HIV) activity were investigated and compared. Both of the chitosan-d4T conjugates more strongly prefer to release corresponding d4T derivatives rather than free d4T in a prolonged manner but have different hydrolysis routes. The anti-HIV activity and cytotoxicity evaluated in the MT4 cell line revealed that the anti-HIV selectivity index was in the following order: Cs-P-d4T > d4T >> Cs-S-d4T since the released d4T-5′-(O-isopropyl) monophosphate from Cs-P-d4T can bypass the rate-limiting bottleneck of nucleoside phosphorylation, while the released 5′-O-succinyl-d4T from Cs-S-d4T has to be hydrolyzed to d4T and then successively phosphorylated to its active form to exert antiviral activity. The results suggested that constructing a chitosan-nucleoside reverse transcriptase inhibitor (NRTI) conjugate with a phosphoramide linkage may be an efficient approach for improving NRTI therapy efficacy in antiretroviral treatment. Open image in new window
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Synthesis, nanosizing and in vitro drug release of a novel anti-HIV polymeric prodrug: Chitosan-O-isopropyl-5′-O-d4T monophosphate conjugate
Bioorganic & medicinal chemistry, 2009Co-Authors: Lin Yang, Rong Zeng, Liqiang Chen, Renzhong QiaoAbstract:A novel approach to improve the antiviral efficacy of nucleoside reverse transcriptase inhibitors (NRTIs) and reduce their side effects was developed by constructing a nanosized NRTI monophosphate-polymer conjugate using d4T as a model NRTI. Firstly, a novel chitosan-O-isopropyl-5′-O-d4T monophosphate conjugate with a phosphoramidate linkage was efficiently synthesized through Atherton–Todd Reaction under mild conditions. The anti-HIV activity and cytotoxicity of the polymeric conjugate were evaluated in MT4 cell line. Then the conjugate nanoparticles were prepared by the process of ionotropic gelation between TPP and chitosan-d4T conjugate to improve their delivery to viral reservoirs, and their physicochemical properties were characterized by transmission electron microscopy (TEM), dynamic light scattering (DLS) techniques and X-ray diffraction (XRD). In vitro drug release studies in pH 1.1 and pH 7.4 suggested that both chitosan-d4T conjugate and its nanoparticles prefer to release d4T 5′-(O-isopropyl) monophosphate than free d4T for prolonged periods, which resulted in the enhancement of anti-HIV selectivity of the polymeric conjugate relative to free d4T due to bypassing the metabolic bottleneck of monophosphorylation. Additionally, the crosslinked conjugate nanoparticles can prevent the coupled drug from leaking out of the nanoparticles before entering the target viral reservoirs and provide a mild sustained release of d4T 5′-(O-isopropyl) monophosphate without the burst release. The results suggested that this kind of chitosan-O-isopropyl-5′-O-d4T monophosphate conjugate nano-prodrugs may be used as a targeting and sustained polymeric prodrugs for improving therapy efficacy and reducing side effects in antiretroviral treatment.
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Novel synthesis and in vitro drug release of polymeric prodrug: Chitosan-O-isopropyl-5'-O-d4T monophosphate conjugate.
Bioorganic & medicinal chemistry letters, 2009Co-Authors: Lin Yang, Rong Zeng, Renzhong QiaoAbstract:A novel approach to synthesize chitosan-O-isopropyl-5'-O-d4T monophosphate conjugate was developed. Chitosan-d4T monophosphate prodrug with a phosphoramidate linkage was efficiently synthesized through Atherton-Todd Reaction. In vitro drug release studies in pH 1.1 and 7.4 indicated that chitosan-O-isopropyl-5'-O-d4T monophosphate conjugate prefers to release the d4T 5'-(O-isopropyl)monophosphate than free d4T for a prolonged period. The results suggested that chitosan-O-isopropyl-5'-O-d4T monophosphate conjugate may be used as a sustained polymeric prodrug for improving therapy efficacy and reducing side effects in antiretroviral treatment.