Design, synthesis, and biological evaluation of aralkyl piperazine and piperidine derivatives targeting SSRI/5-HT < sub > 1A < /sub > /5-HT < sub > 7 < /sub >
Bioorg Med Chem. 2024 Mar 26;104:117698. doi: 10.1016/j.bmc.2024.117698. Online ahead of print.ABSTRACTSerotonin reuptake inhibition combined with the action targeting 5-hydroxytryptamine receptor subtypes can serve as a potential target for the development of antidepressant drugs. Herein a series of new aralkyl piperazines and piperidines were designed and synthesized by the structural modifications of the previously discovered aralkyl piperidine compound 1, targeting SSRI/5-HT1A/5-HT7. The results exhibited that compound 5a showed strong binding to 5-HT1A and 5-HT7 (Ki of 0.46 nM, 2.7 nM, respectively) and a high level o...
Source: Bioorganic and Medicinal Chemistry - March 29, 2024 Category: Chemistry Authors: Jianwei Wu Zixue Zhang Qingwei Zhang Jianqi Li Source Type: research
Rational design of prodrug-type apoB-targeted siRNA for nuclease resistance improvement without compromising gene silencing potency
In this study, we developed a nuclease-resistant prodrug-type 2'-O-MDTM siRNA for deployment in future animal experiments. To rationally design siRNA modified with a minimal number of 2'-O-MDTM nucleotide residues, we identified the sites susceptible to nuclease digestion and tolerant to 2'-O-methyl (2'-OMe) modification in the antisense strand of apolipoprotein B-targeted siRNA. Subsequently, we optimized the positions where the 2'-OMe and 2'-O-MDTM groups should be incorporated. siRNA bearing the 2'-O-MDTM and 2'-OMe groups at their respective optimized positions exhibited efficient knockdown potency in vitro and enhance...
Source: Bioorganic and Medicinal Chemistry - March 29, 2024 Category: Chemistry Authors: Junsuke Hayashi Yosuke Ochi Kota Senpuku Shun-Ichi Wada Fumito Wada Mariko Harada-Shiba Hidehito Urata Source Type: research
Crbn-based molecular Glues: Breakthroughs and perspectives
Bioorg Med Chem. 2024 Mar 18;104:117683. doi: 10.1016/j.bmc.2024.117683. Online ahead of print.ABSTRACTCRBN is a substrate receptor for the Cullin Ring E3 ubiquitin ligase 4 (CRL4) complex. It has been observed that CRBN can be exploited by small molecules to facilitate the recruitment and ubiquitination of non-natural CRL4 substrates, resulting in the degradation of neosubstrate through the ubiquitin-proteasome system. This phenomenon, known as molecular glue-induced protein degradation, has emerged as an innovative therapeutic approach in contrast to traditional small-molecule drugs. One key advantage of molecular glues,...
Source: Bioorganic and Medicinal Chemistry - March 29, 2024 Category: Chemistry Authors: Juzeng An Xiaojun Zhang Source Type: research
Design, synthesis, and biological evaluation of aralkyl piperazine and piperidine derivatives targeting SSRI/5-HT < sub > 1A < /sub > /5-HT < sub > 7 < /sub >
Bioorg Med Chem. 2024 Mar 26;104:117698. doi: 10.1016/j.bmc.2024.117698. Online ahead of print.ABSTRACTSerotonin reuptake inhibition combined with the action targeting 5-hydroxytryptamine receptor subtypes can serve as a potential target for the development of antidepressant drugs. Herein a series of new aralkyl piperazines and piperidines were designed and synthesized by the structural modifications of the previously discovered aralkyl piperidine compound 1, targeting SSRI/5-HT1A/5-HT7. The results exhibited that compound 5a showed strong binding to 5-HT1A and 5-HT7 (Ki of 0.46 nM, 2.7 nM, respectively) and a high level o...
Source: Bioorganic and Medicinal Chemistry - March 29, 2024 Category: Chemistry Authors: Jianwei Wu Zixue Zhang Qingwei Zhang Jianqi Li Source Type: research
Rational design of prodrug-type apoB-targeted siRNA for nuclease resistance improvement without compromising gene silencing potency
In this study, we developed a nuclease-resistant prodrug-type 2'-O-MDTM siRNA for deployment in future animal experiments. To rationally design siRNA modified with a minimal number of 2'-O-MDTM nucleotide residues, we identified the sites susceptible to nuclease digestion and tolerant to 2'-O-methyl (2'-OMe) modification in the antisense strand of apolipoprotein B-targeted siRNA. Subsequently, we optimized the positions where the 2'-OMe and 2'-O-MDTM groups should be incorporated. siRNA bearing the 2'-O-MDTM and 2'-OMe groups at their respective optimized positions exhibited efficient knockdown potency in vitro and enhance...
Source: Bioorganic and Medicinal Chemistry - March 29, 2024 Category: Chemistry Authors: Junsuke Hayashi Yosuke Ochi Kota Senpuku Shun-Ichi Wada Fumito Wada Mariko Harada-Shiba Hidehito Urata Source Type: research
Crbn-based molecular Glues: Breakthroughs and perspectives
Bioorg Med Chem. 2024 Mar 18;104:117683. doi: 10.1016/j.bmc.2024.117683. Online ahead of print.ABSTRACTCRBN is a substrate receptor for the Cullin Ring E3 ubiquitin ligase 4 (CRL4) complex. It has been observed that CRBN can be exploited by small molecules to facilitate the recruitment and ubiquitination of non-natural CRL4 substrates, resulting in the degradation of neosubstrate through the ubiquitin-proteasome system. This phenomenon, known as molecular glue-induced protein degradation, has emerged as an innovative therapeutic approach in contrast to traditional small-molecule drugs. One key advantage of molecular glues,...
Source: Bioorganic and Medicinal Chemistry - March 29, 2024 Category: Chemistry Authors: Juzeng An Xiaojun Zhang Source Type: research
Design, synthesis, and biological evaluation of aralkyl piperazine and piperidine derivatives targeting SSRI/5-HT < sub > 1A < /sub > /5-HT < sub > 7 < /sub >
Bioorg Med Chem. 2024 Mar 26;104:117698. doi: 10.1016/j.bmc.2024.117698. Online ahead of print.ABSTRACTSerotonin reuptake inhibition combined with the action targeting 5-hydroxytryptamine receptor subtypes can serve as a potential target for the development of antidepressant drugs. Herein a series of new aralkyl piperazines and piperidines were designed and synthesized by the structural modifications of the previously discovered aralkyl piperidine compound 1, targeting SSRI/5-HT1A/5-HT7. The results exhibited that compound 5a showed strong binding to 5-HT1A and 5-HT7 (Ki of 0.46 nM, 2.7 nM, respectively) and a high level o...
Source: Bioorganic and Medicinal Chemistry - March 29, 2024 Category: Chemistry Authors: Jianwei Wu Zixue Zhang Qingwei Zhang Jianqi Li Source Type: research
Rational design of prodrug-type apoB-targeted siRNA for nuclease resistance improvement without compromising gene silencing potency
In this study, we developed a nuclease-resistant prodrug-type 2'-O-MDTM siRNA for deployment in future animal experiments. To rationally design siRNA modified with a minimal number of 2'-O-MDTM nucleotide residues, we identified the sites susceptible to nuclease digestion and tolerant to 2'-O-methyl (2'-OMe) modification in the antisense strand of apolipoprotein B-targeted siRNA. Subsequently, we optimized the positions where the 2'-OMe and 2'-O-MDTM groups should be incorporated. siRNA bearing the 2'-O-MDTM and 2'-OMe groups at their respective optimized positions exhibited efficient knockdown potency in vitro and enhance...
Source: Bioorganic and Medicinal Chemistry - March 29, 2024 Category: Chemistry Authors: Junsuke Hayashi Yosuke Ochi Kota Senpuku Shun-Ichi Wada Fumito Wada Mariko Harada-Shiba Hidehito Urata Source Type: research
Crbn-based molecular Glues: Breakthroughs and perspectives
Bioorg Med Chem. 2024 Mar 18;104:117683. doi: 10.1016/j.bmc.2024.117683. Online ahead of print.ABSTRACTCRBN is a substrate receptor for the Cullin Ring E3 ubiquitin ligase 4 (CRL4) complex. It has been observed that CRBN can be exploited by small molecules to facilitate the recruitment and ubiquitination of non-natural CRL4 substrates, resulting in the degradation of neosubstrate through the ubiquitin-proteasome system. This phenomenon, known as molecular glue-induced protein degradation, has emerged as an innovative therapeutic approach in contrast to traditional small-molecule drugs. One key advantage of molecular glues,...
Source: Bioorganic and Medicinal Chemistry - March 29, 2024 Category: Chemistry Authors: Juzeng An Xiaojun Zhang Source Type: research
Design, synthesis, and biological evaluation of aralkyl piperazine and piperidine derivatives targeting SSRI/5-HT < sub > 1A < /sub > /5-HT < sub > 7 < /sub >
Bioorg Med Chem. 2024 Mar 26;104:117698. doi: 10.1016/j.bmc.2024.117698. Online ahead of print.ABSTRACTSerotonin reuptake inhibition combined with the action targeting 5-hydroxytryptamine receptor subtypes can serve as a potential target for the development of antidepressant drugs. Herein a series of new aralkyl piperazines and piperidines were designed and synthesized by the structural modifications of the previously discovered aralkyl piperidine compound 1, targeting SSRI/5-HT1A/5-HT7. The results exhibited that compound 5a showed strong binding to 5-HT1A and 5-HT7 (Ki of 0.46 nM, 2.7 nM, respectively) and a high level o...
Source: Bioorganic and Medicinal Chemistry - March 29, 2024 Category: Chemistry Authors: Jianwei Wu Zixue Zhang Qingwei Zhang Jianqi Li Source Type: research
Rational design of prodrug-type apoB-targeted siRNA for nuclease resistance improvement without compromising gene silencing potency
In this study, we developed a nuclease-resistant prodrug-type 2'-O-MDTM siRNA for deployment in future animal experiments. To rationally design siRNA modified with a minimal number of 2'-O-MDTM nucleotide residues, we identified the sites susceptible to nuclease digestion and tolerant to 2'-O-methyl (2'-OMe) modification in the antisense strand of apolipoprotein B-targeted siRNA. Subsequently, we optimized the positions where the 2'-OMe and 2'-O-MDTM groups should be incorporated. siRNA bearing the 2'-O-MDTM and 2'-OMe groups at their respective optimized positions exhibited efficient knockdown potency in vitro and enhance...
Source: Bioorganic and Medicinal Chemistry - March 29, 2024 Category: Chemistry Authors: Junsuke Hayashi Yosuke Ochi Kota Senpuku Shun-Ichi Wada Fumito Wada Mariko Harada-Shiba Hidehito Urata Source Type: research
Crbn-based molecular Glues: Breakthroughs and perspectives
Bioorg Med Chem. 2024 Mar 18;104:117683. doi: 10.1016/j.bmc.2024.117683. Online ahead of print.ABSTRACTCRBN is a substrate receptor for the Cullin Ring E3 ubiquitin ligase 4 (CRL4) complex. It has been observed that CRBN can be exploited by small molecules to facilitate the recruitment and ubiquitination of non-natural CRL4 substrates, resulting in the degradation of neosubstrate through the ubiquitin-proteasome system. This phenomenon, known as molecular glue-induced protein degradation, has emerged as an innovative therapeutic approach in contrast to traditional small-molecule drugs. One key advantage of molecular glues,...
Source: Bioorganic and Medicinal Chemistry - March 29, 2024 Category: Chemistry Authors: Juzeng An Xiaojun Zhang Source Type: research
Design, synthesis, and biological evaluation of aralkyl piperazine and piperidine derivatives targeting SSRI/5-HT < sub > 1A < /sub > /5-HT < sub > 7 < /sub >
Bioorg Med Chem. 2024 Mar 26;104:117698. doi: 10.1016/j.bmc.2024.117698. Online ahead of print.ABSTRACTSerotonin reuptake inhibition combined with the action targeting 5-hydroxytryptamine receptor subtypes can serve as a potential target for the development of antidepressant drugs. Herein a series of new aralkyl piperazines and piperidines were designed and synthesized by the structural modifications of the previously discovered aralkyl piperidine compound 1, targeting SSRI/5-HT1A/5-HT7. The results exhibited that compound 5a showed strong binding to 5-HT1A and 5-HT7 (Ki of 0.46 nM, 2.7 nM, respectively) and a high level o...
Source: Bioorganic and Medicinal Chemistry - March 29, 2024 Category: Chemistry Authors: Jianwei Wu Zixue Zhang Qingwei Zhang Jianqi Li Source Type: research
Rational design of prodrug-type apoB-targeted siRNA for nuclease resistance improvement without compromising gene silencing potency
In this study, we developed a nuclease-resistant prodrug-type 2'-O-MDTM siRNA for deployment in future animal experiments. To rationally design siRNA modified with a minimal number of 2'-O-MDTM nucleotide residues, we identified the sites susceptible to nuclease digestion and tolerant to 2'-O-methyl (2'-OMe) modification in the antisense strand of apolipoprotein B-targeted siRNA. Subsequently, we optimized the positions where the 2'-OMe and 2'-O-MDTM groups should be incorporated. siRNA bearing the 2'-O-MDTM and 2'-OMe groups at their respective optimized positions exhibited efficient knockdown potency in vitro and enhance...
Source: Bioorganic and Medicinal Chemistry - March 29, 2024 Category: Chemistry Authors: Junsuke Hayashi Yosuke Ochi Kota Senpuku Shun-Ichi Wada Fumito Wada Mariko Harada-Shiba Hidehito Urata Source Type: research
Design, synthesis and biological evaluation of aryloxy thiophosphoramidate triesters of anticancer nucleoside analogues
Bioorg Med Chem. 2024 Mar 25;103:117696. doi: 10.1016/j.bmc.2024.117696. Online ahead of print.ABSTRACTAryloxy phosphoroamidate triesters, known as ProTides, are a class of prodrugs developed to enhance the physicochemical and pharmacological properties of therapeutic nucleosides. This approach has been extensively investigated in the antiviral and anticancer areas leading to three prodrugs on the market and several others in clinical stage. In this article we have prepared the PS analogues of three ProTides that have reached the clinic as anticancer agents. These novel PS ProTides were tested for their capacity in enzymat...
Source: Bioorganic and Medicinal Chemistry - March 28, 2024 Category: Chemistry Authors: Michaela Serpi Samule di Ciano Fabrizio Pertusati Source Type: research
