Target discovery of bioactive natural products with native-compound-coupled CNBr-activated Sepharose 4B beads (NCCB): Applications, mechanisms and outlooks
Bioorg Med Chem. 2023 Sep 26;96:117483. doi: 10.1016/j.bmc.2023.117483. Online ahead of print.ABSTRACTNatural products (NPs) represent a treasure trove for drug discovery and development due to their chemical structural diversity and a broad spectrum of biological activities. Uncovering the biological targets and understanding their molecular mechanism of actions are crucial steps in the development of clinical therapeutics. However, the structural complexity of NPs and intricate nature of biological system present formidable challenges in target identification of NPs. Although significant advances have been made in the de...
Source: Bioorganic and Medicinal Chemistry - November 11, 2023 Category: Chemistry Authors: Yueteng Zhang Junjie Zhang Menglong Li Yan Qiao Wei Wang Lu Ma Kangdong Liu Source Type: research
Structure-guided design and synthesis of ATP-competitive N-acyl-substituted sulfamide d-alanine-d-alanine ligase inhibitors
Bioorg Med Chem. 2023 Oct 26;96:117509. doi: 10.1016/j.bmc.2023.117509. Online ahead of print.ABSTRACTd-Alanine-d-alanine ligase (Ddl) catalyses the ATP-dependent formation of d-Ala-d-Ala, a critical component in bacterial cell wall biosynthesis and is a validated target for new antimicrobial agents. Here, we describe the structure-guided design, synthesis, and evaluation of ATP-competitive N-acyl-substituted sulfamides 27-36, 42, 46, 47 as inhibitors of Staphylococcus aureus Ddl (SaDdl). A crystal structure of SaDdl complexed with ATP and d-Ala-d-Ala (PDB: 7U9K) identified ATP-mimetic 8 as an initial scaffold for further ...
Source: Bioorganic and Medicinal Chemistry - November 10, 2023 Category: Chemistry Authors: Rouven Becker Jordan L Pederick Edward G Dawes John B Bruning Andrew D Abell Source Type: research
Discovery of a new dihydroeugenol-chalcone hybrid with cytotoxic and anti-migratory potential: A dual-action hit for cancer therapeutics
Bioorg Med Chem. 2023 Nov 3;96:117516. doi: 10.1016/j.bmc.2023.117516. Online ahead of print.ABSTRACTCancer still represents a serious public health problem and one of the main problems related to the worsening of this disease is the ability of some tumors to develop metastasis. In this work, we synthesized a new series of chalcones and isoxazoles derived from eugenol and analogues as molecular hybrids and these compounds were evaluated against different tumor cell lines. This structural pattern was designed considering the cytotoxic potential already known for eugenol, chalcones and isoxazoles. Notably, chalcones 7, 9, 10...
Source: Bioorganic and Medicinal Chemistry - November 9, 2023 Category: Chemistry Authors: Izadora Amaral Nakao Tamires Cunha Almeida Adriana Cotta Cardoso Reis Gabrielly Guimar ães Coutinho Aline Mol Hermenegildo Cleydson Finotti Cordeiro Glenda Nicioli da Silva Danielle Ferreira Dias Geraldo C élio Brandão Saulo Fehelberg Pinto Braga Thiag Source Type: research
Discovery of novel dual Bruton's tyrosine kinase (BTK) and Janus kinase 3 (JAK3) inhibitors as a promising strategy for rheumatoid arthritis
We reported the discovery of dual BTK/JAK3 inhibitors which are based on the structure of BTK inhibitor ibrutinib via the method of bioisosterism and computer-aided drug design) Most of the target compounds exhibited moderate to strong inhibitory activities against BTK and JAK3. Among them, compound XL-12 stood out as the most promising candidate targeting BTK and JAK3 with potent inhibitory activities (IC50 = 2.0 nM and IC50 = 14.0 nM respectively). In the in vivo studies, compound XL-12 (40 mg/kg) exhibited more potent antiarthritic activity than ibrutinib (10 mg/kg) in adjuvant arthritis (AA) rat model. Furthermore, com...
Source: Bioorganic and Medicinal Chemistry - November 9, 2023 Category: Chemistry Authors: Tingting Liang Lifang Cen Junjie Wang Ming Cheng Weibo Guo Wenjie Wang Chunqiu Yu Haifeng Zhang Yuan Wang Zhongyan Hao Jiaming Jin Yaoyao Wu Teng Jiang Qihua Zhu Yungen Xu Source Type: research
Discovery of a new dihydroeugenol-chalcone hybrid with cytotoxic and anti-migratory potential: A dual-action hit for cancer therapeutics
Bioorg Med Chem. 2023 Nov 3;96:117516. doi: 10.1016/j.bmc.2023.117516. Online ahead of print.ABSTRACTCancer still represents a serious public health problem and one of the main problems related to the worsening of this disease is the ability of some tumors to develop metastasis. In this work, we synthesized a new series of chalcones and isoxazoles derived from eugenol and analogues as molecular hybrids and these compounds were evaluated against different tumor cell lines. This structural pattern was designed considering the cytotoxic potential already known for eugenol, chalcones and isoxazoles. Notably, chalcones 7, 9, 10...
Source: Bioorganic and Medicinal Chemistry - November 9, 2023 Category: Chemistry Authors: Izadora Amaral Nakao Tamires Cunha Almeida Adriana Cotta Cardoso Reis Gabrielly Guimar ães Coutinho Aline Mol Hermenegildo Cleydson Finotti Cordeiro Glenda Nicioli da Silva Danielle Ferreira Dias Geraldo C élio Brandão Saulo Fehelberg Pinto Braga Thiag Source Type: research
Discovery of novel dual Bruton's tyrosine kinase (BTK) and Janus kinase 3 (JAK3) inhibitors as a promising strategy for rheumatoid arthritis
We reported the discovery of dual BTK/JAK3 inhibitors which are based on the structure of BTK inhibitor ibrutinib via the method of bioisosterism and computer-aided drug design) Most of the target compounds exhibited moderate to strong inhibitory activities against BTK and JAK3. Among them, compound XL-12 stood out as the most promising candidate targeting BTK and JAK3 with potent inhibitory activities (IC50 = 2.0 nM and IC50 = 14.0 nM respectively). In the in vivo studies, compound XL-12 (40 mg/kg) exhibited more potent antiarthritic activity than ibrutinib (10 mg/kg) in adjuvant arthritis (AA) rat model. Furthermore, com...
Source: Bioorganic and Medicinal Chemistry - November 9, 2023 Category: Chemistry Authors: Tingting Liang Lifang Cen Junjie Wang Ming Cheng Weibo Guo Wenjie Wang Chunqiu Yu Haifeng Zhang Yuan Wang Zhongyan Hao Jiaming Jin Yaoyao Wu Teng Jiang Qihua Zhu Yungen Xu Source Type: research
Biocompatible conjugated polymer nanoparticles labeled with < sup > 225 < /sup > Ac for tumor endoradiotherapy
Bioorg Med Chem. 2023 Nov 4;96:117517. doi: 10.1016/j.bmc.2023.117517. Online ahead of print.ABSTRACTRecently, endoradiotherapy based on actinium-225 (225Ac) has attracted increasing attention, which is due to its α particles can generate maximal damage to cancer cells while minimizing unnecessary radiation effects on healthy tissues. Herein, 111In/225Ac-radiolabeled conjugated polymer nanoparticles (CPNs) coated with amphiphilic polymer DSPE-PEG-DOTA have been developed as a new injectable nano-radiopharmaceuticals for cancer endoradiotherapy under the guidance of nuclear imaging. Single photon emission computed tomograp...
Source: Bioorganic and Medicinal Chemistry - November 8, 2023 Category: Chemistry Authors: Xijian Chen Ranxi Liang Weihao Liu Huan Ma Chiyao Bai Yao Xiong Tu Lan Jiali Liao Yuanyou Yang Jijun Yang Feize Li Ning Liu Source Type: research
Harvesting phosphorus-containing moieties for their antibacterial effects
Bioorg Med Chem. 2023 Nov 2;96:117512. doi: 10.1016/j.bmc.2023.117512. Online ahead of print.ABSTRACTClinically manifested resistance of bacteria to antibiotics has emerged as a global threat to society and there is an urgent need for the development of novel classes of antibacterial agents. Recently, the use of phosphorus in antibacterial agents has been explored in quite an unprecedent manner. In this comprehensive review, we summarize the use of phosphorus-containing moieties (phosphonates, phosphonamidates, phosphonopeptides, phosphates, phosphoramidates, phosphinates, phosphine oxides, and phosphoniums) in compounds w...
Source: Bioorganic and Medicinal Chemistry - November 8, 2023 Category: Chemistry Authors: Manuela Vor áčová Matej Zore Jari Yli-Kauhaluoma Paula Kiuru Source Type: research
Biocompatible conjugated polymer nanoparticles labeled with < sup > 225 < /sup > Ac for tumor endoradiotherapy
Bioorg Med Chem. 2023 Nov 4;96:117517. doi: 10.1016/j.bmc.2023.117517. Online ahead of print.ABSTRACTRecently, endoradiotherapy based on actinium-225 (225Ac) has attracted increasing attention, which is due to its α particles can generate maximal damage to cancer cells while minimizing unnecessary radiation effects on healthy tissues. Herein, 111In/225Ac-radiolabeled conjugated polymer nanoparticles (CPNs) coated with amphiphilic polymer DSPE-PEG-DOTA have been developed as a new injectable nano-radiopharmaceuticals for cancer endoradiotherapy under the guidance of nuclear imaging. Single photon emission computed tomograp...
Source: Bioorganic and Medicinal Chemistry - November 8, 2023 Category: Chemistry Authors: Xijian Chen Ranxi Liang Weihao Liu Huan Ma Chiyao Bai Yao Xiong Tu Lan Jiali Liao Yuanyou Yang Jijun Yang Feize Li Ning Liu Source Type: research
Harvesting phosphorus-containing moieties for their antibacterial effects
Bioorg Med Chem. 2023 Nov 2;96:117512. doi: 10.1016/j.bmc.2023.117512. Online ahead of print.ABSTRACTClinically manifested resistance of bacteria to antibiotics has emerged as a global threat to society and there is an urgent need for the development of novel classes of antibacterial agents. Recently, the use of phosphorus in antibacterial agents has been explored in quite an unprecedent manner. In this comprehensive review, we summarize the use of phosphorus-containing moieties (phosphonates, phosphonamidates, phosphonopeptides, phosphates, phosphoramidates, phosphinates, phosphine oxides, and phosphoniums) in compounds w...
Source: Bioorganic and Medicinal Chemistry - November 8, 2023 Category: Chemistry Authors: Manuela Vor áčová Matej Zore Jari Yli-Kauhaluoma Paula Kiuru Source Type: research
Synthesis and biological evaluation of indane-based fluorescent probes for detection of amyloid- β aggregates in Alzheimer's disease
Bioorg Med Chem. 2023 Nov 3;95:117513. doi: 10.1016/j.bmc.2023.117513. Online ahead of print.ABSTRACTIn this article, the development of fluorescent imaging probes for the detection of Alzheimer's disease (AD)-associated protein aggregates is described. Indane derivatives with a donor-π-acceptor (D-π-A) structure were designed and synthesized. The probes were evaluated for their ability to bind to β-amyloid (Aβ) protein aggregates, which are a key pathological hallmark of AD. The results showed that several probes exhibited significant changes in fluorescence intensity at wavelengths greater than 600 nm when they were ...
Source: Bioorganic and Medicinal Chemistry - November 6, 2023 Category: Chemistry Authors: Hyunseung Lee Yihoon Kim Hira Aziz Dong-Min Kang Jaewoon Lee Sujin Lee Sunhwa Jung Suyeon Hyeon Hyunah Choo Ghilsoo Nam Yun Kyung Kim Sungsu Lim Sun-Joon Min Source Type: research
Discovery of a potent and selective human AC2 inhibitor based on 7-deazapurine analogues of adefovir
Bioorg Med Chem. 2023 Oct 26;95:117508. doi: 10.1016/j.bmc.2023.117508. Online ahead of print.ABSTRACTAdefovir based acyclic nucleoside phosphonates were previously shown to modulate bacterial and, to a certain extent, human adenylate cyclases (mACs). In this work, a series of 24 novel 7-substituted 7-deazaadefovir analogues were synthesized in the form of prodrugs. Twelve analogues were single-digit micromolar inhibitors of Bordetella pertussis adenylate cyclase toxin with no cytotoxicity to J774A.1 macrophages. In HEK293 cell-based assays, compound 14 was identified as a potent (IC50 = 4.45 μM), non-toxic, and selective...
Source: Bioorganic and Medicinal Chemistry - November 6, 2023 Category: Chemistry Authors: Pavel Kraina Michal Česnek Eva Tlou šťová Helena Mertl íková-Kaiserová Camryn J Fulton Emily K Davidson Brenton P Smith Val J Watts Zlatko Janeba Source Type: research
Synthesis and biological evaluation of indane-based fluorescent probes for detection of amyloid- β aggregates in Alzheimer's disease
Bioorg Med Chem. 2023 Nov 3;95:117513. doi: 10.1016/j.bmc.2023.117513. Online ahead of print.ABSTRACTIn this article, the development of fluorescent imaging probes for the detection of Alzheimer's disease (AD)-associated protein aggregates is described. Indane derivatives with a donor-π-acceptor (D-π-A) structure were designed and synthesized. The probes were evaluated for their ability to bind to β-amyloid (Aβ) protein aggregates, which are a key pathological hallmark of AD. The results showed that several probes exhibited significant changes in fluorescence intensity at wavelengths greater than 600 nm when they were ...
Source: Bioorganic and Medicinal Chemistry - November 6, 2023 Category: Chemistry Authors: Hyunseung Lee Yihoon Kim Hira Aziz Dong-Min Kang Jaewoon Lee Sujin Lee Sunhwa Jung Suyeon Hyeon Hyunah Choo Ghilsoo Nam Yun Kyung Kim Sungsu Lim Sun-Joon Min Source Type: research
Discovery of a potent and selective human AC2 inhibitor based on 7-deazapurine analogues of adefovir
Bioorg Med Chem. 2023 Oct 26;95:117508. doi: 10.1016/j.bmc.2023.117508. Online ahead of print.ABSTRACTAdefovir based acyclic nucleoside phosphonates were previously shown to modulate bacterial and, to a certain extent, human adenylate cyclases (mACs). In this work, a series of 24 novel 7-substituted 7-deazaadefovir analogues were synthesized in the form of prodrugs. Twelve analogues were single-digit micromolar inhibitors of Bordetella pertussis adenylate cyclase toxin with no cytotoxicity to J774A.1 macrophages. In HEK293 cell-based assays, compound 14 was identified as a potent (IC50 = 4.45 μM), non-toxic, and selective...
Source: Bioorganic and Medicinal Chemistry - November 6, 2023 Category: Chemistry Authors: Pavel Kraina Michal Česnek Eva Tlou šťová Helena Mertl íková-Kaiserová Camryn J Fulton Emily K Davidson Brenton P Smith Val J Watts Zlatko Janeba Source Type: research
Synthesis, anti-inflammatory activity, inverse molecular docking, and acid dissociation constants of new naphthoquinone-thiazole hybrids
Bioorg Med Chem. 2023 Oct 31;95:117510. doi: 10.1016/j.bmc.2023.117510. Online ahead of print.ABSTRACTChronic Inflammation is associated with various types of diseases that involves pro-inflammatory cytokines like IL-6 and TNF-α. High costs and serious side effects of available anti-inflammatory/immunomodulatory drugs led us to design new compounds with promising anti-inflammatory activities. Many drugs and biologically important compounds involve naphthoquinone and thiazole moieties in their core structures. Thereby, here we report the synthesis, characterization and anti-inflammatory activities of new naphthoquinone thi...
Source: Bioorganic and Medicinal Chemistry - November 5, 2023 Category: Chemistry Authors: Cagla Efeoglu Sena Taskin Ozge Selcuk Begum Celik Ece Tumkaya Abdulilah Ece Hayati Sari Zeynel Seferoglu Furkan Ayaz Yahya Nural Source Type: research