Nuruddin Mahadik, Gemma A. Barron, Paul Kong Thoo Lin, Colin J. Thompson
{"title":"合成和评估聚合物-药物共轭物作为神经退行性疾病的潜在抗氧化剂和胆碱酯酶抑制剂","authors":"Nuruddin Mahadik, Gemma A. Barron, Paul Kong Thoo Lin, Colin J. Thompson","doi":"10.1021/acs.chemmater.4c01767","DOIUrl":null,"url":null,"abstract":"Polymer-drug conjugates (PDCs) may offer improved water-solubility and <i>in vitro</i> activity of potential antioxidant and cholinesterase (ChE) inhibitor drugs compared to the drugs alone. Conjugation of these potential drugs to water-soluble polymers could increase their therapeutic efficacy. Vanillin was conjugated to poly(allylamine hydrochloride) (NM10 and NM15) and naphthalimidohexylamine (HEXNAP) was conjugated to poly(acrylic acid) (N5 and N10). The antioxidant and cholinesterase inhibitory activities of these novel PDCs were evaluated and compared with those of their respective starting materials. Additionally, <i>in silico</i> molecular modeling studies were conducted to explore the potential cholinesterase inhibitory mechanisms of these conjugates. NM15 (unadjusted and adjusted value) showed significantly enhanced <i>in vitro</i> antioxidant activity (<i>p</i> ≤ 0.0001) compared to vanillin. The adjusted value of N5 compared to HEXNAP showed significantly enhanced <i>in vitro</i> cholinesterase inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) (<i>p</i> ≤ 0.0001). Kinetic and molecular modeling studies revealed that N5 was a competitive inhibitor of butyrylcholinesterase and interacted with the active sites of human acetylcholinesterase and human butyrylcholinesterase enzymes. NM15 and N5 were identified as lead PDCs based on their enhanced antioxidant and cholinesterase inhibitory activity, respectively. Overall, this work demonstrates the potential use of PDCs as treatment options for neurodegenerative diseases.","PeriodicalId":33,"journal":{"name":"Chemistry of Materials","volume":"23 1","pages":""},"PeriodicalIF":7.2000,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Synthesis and Evaluation of Polymer-Drug Conjugates as Potential Antioxidants and Cholinesterase Inhibitors for Neurodegenerative Diseases\",\"authors\":\"Nuruddin Mahadik, Gemma A. Barron, Paul Kong Thoo Lin, Colin J. Thompson\",\"doi\":\"10.1021/acs.chemmater.4c01767\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Polymer-drug conjugates (PDCs) may offer improved water-solubility and <i>in vitro</i> activity of potential antioxidant and cholinesterase (ChE) inhibitor drugs compared to the drugs alone. Conjugation of these potential drugs to water-soluble polymers could increase their therapeutic efficacy. Vanillin was conjugated to poly(allylamine hydrochloride) (NM10 and NM15) and naphthalimidohexylamine (HEXNAP) was conjugated to poly(acrylic acid) (N5 and N10). The antioxidant and cholinesterase inhibitory activities of these novel PDCs were evaluated and compared with those of their respective starting materials. Additionally, <i>in silico</i> molecular modeling studies were conducted to explore the potential cholinesterase inhibitory mechanisms of these conjugates. NM15 (unadjusted and adjusted value) showed significantly enhanced <i>in vitro</i> antioxidant activity (<i>p</i> ≤ 0.0001) compared to vanillin. The adjusted value of N5 compared to HEXNAP showed significantly enhanced <i>in vitro</i> cholinesterase inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) (<i>p</i> ≤ 0.0001). Kinetic and molecular modeling studies revealed that N5 was a competitive inhibitor of butyrylcholinesterase and interacted with the active sites of human acetylcholinesterase and human butyrylcholinesterase enzymes. NM15 and N5 were identified as lead PDCs based on their enhanced antioxidant and cholinesterase inhibitory activity, respectively. 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Synthesis and Evaluation of Polymer-Drug Conjugates as Potential Antioxidants and Cholinesterase Inhibitors for Neurodegenerative Diseases
Polymer-drug conjugates (PDCs) may offer improved water-solubility and in vitro activity of potential antioxidant and cholinesterase (ChE) inhibitor drugs compared to the drugs alone. Conjugation of these potential drugs to water-soluble polymers could increase their therapeutic efficacy. Vanillin was conjugated to poly(allylamine hydrochloride) (NM10 and NM15) and naphthalimidohexylamine (HEXNAP) was conjugated to poly(acrylic acid) (N5 and N10). The antioxidant and cholinesterase inhibitory activities of these novel PDCs were evaluated and compared with those of their respective starting materials. Additionally, in silico molecular modeling studies were conducted to explore the potential cholinesterase inhibitory mechanisms of these conjugates. NM15 (unadjusted and adjusted value) showed significantly enhanced in vitro antioxidant activity (p ≤ 0.0001) compared to vanillin. The adjusted value of N5 compared to HEXNAP showed significantly enhanced in vitro cholinesterase inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) (p ≤ 0.0001). Kinetic and molecular modeling studies revealed that N5 was a competitive inhibitor of butyrylcholinesterase and interacted with the active sites of human acetylcholinesterase and human butyrylcholinesterase enzymes. NM15 and N5 were identified as lead PDCs based on their enhanced antioxidant and cholinesterase inhibitory activity, respectively. Overall, this work demonstrates the potential use of PDCs as treatment options for neurodegenerative diseases.
期刊介绍:
The journal Chemistry of Materials focuses on publishing original research at the intersection of materials science and chemistry. The studies published in the journal involve chemistry as a prominent component and explore topics such as the design, synthesis, characterization, processing, understanding, and application of functional or potentially functional materials. The journal covers various areas of interest, including inorganic and organic solid-state chemistry, nanomaterials, biomaterials, thin films and polymers, and composite/hybrid materials. The journal particularly seeks papers that highlight the creation or development of innovative materials with novel optical, electrical, magnetic, catalytic, or mechanical properties. It is essential that manuscripts on these topics have a primary focus on the chemistry of materials and represent a significant advancement compared to prior research. Before external reviews are sought, submitted manuscripts undergo a review process by a minimum of two editors to ensure their appropriateness for the journal and the presence of sufficient evidence of a significant advance that will be of broad interest to the materials chemistry community.