Assessing the rigidity of cubanes and bicyclo(1.1.1)pentanes as benzene bioisosteres
Bioorg Med Chem. 2024 Feb 23;102:117652. doi: 10.1016/j.bmc.2024.117652. Online ahead of print.ABSTRACTAromatic rings are critical core substructures in the majority of pharmaceutical compounds. There is much recent interest in replacing aromatic structures with saturated bioisosteres of benzene, which are generally fused or bridged ring systems. These bioisosteres often show improved solubility properties compared to benzene, and may also undergo fewer unwanted metabolic processes. One key reason why aromatic rings have proven so successful in drug design is their rigidity. This paper uses molecular dynamics simulations s...
Source: Bioorganic and Medicinal Chemistry - March 5, 2024 Category: Chemistry Authors: Graham Pattison Source Type: research
Design, synthesis and antitumor activity of 2-substituted quinazoline-4-amine derivatives
In this study, a series of new N-arylquinazoline-4-amine analogs were designed and synthesized based on structure optimization of quinazoline. The structures of the thirty-two newly synthesized compounds were confirmed by 1H NMR, 13C NMR and ESI-MS. The anticancer activity in vitro against chronic myeloid leukemia cells (K562), non-small cell lung cancer cells (A549), human prostate cancer cells (PC3), and cervical cancer cells (HeLa) of the target compounds was evaluated. Among them, the inhibition ratio of compounds 17d, 18a, 18b, 11 and 23a against four cancer cells at 5 μM concentration were more than 50 %. The IC50 v...
Source: Bioorganic and Medicinal Chemistry - March 5, 2024 Category: Chemistry Authors: Menghan Wang Jia Yu Xinyi Huang Gang Yu Qi Liang Sha Cheng Xueling Meng Guangcan Xu Huimin Li Heng Luo Bixue Xu Source Type: research
Design, synthesis and anti-necroptosis activity of fused heterocyclic MLKL inhibitors
In this study, with the covalent motif maintained, we aim to improve the activity by introducing the terminal fused heterocycles and meanwhile revealing the SAR on the part. As a result, compounds 9 and 14 showed the best activity (EC50 = 148.4 and 595.9 nM) against necroptosis among the analogues by covalently binding to MLKL. The SAR was also concluded to guide further structural optimization in this field.PMID:38442525 | DOI:10.1016/j.bmc.2024.117659 (Source: Bioorganic and Medicinal Chemistry)
Source: Bioorganic and Medicinal Chemistry - March 5, 2024 Category: Chemistry Authors: Yining Tang Chunlin Zhuang Source Type: research
Assessing the rigidity of cubanes and bicyclo(1.1.1)pentanes as benzene bioisosteres
Bioorg Med Chem. 2024 Feb 23;102:117652. doi: 10.1016/j.bmc.2024.117652. Online ahead of print.ABSTRACTAromatic rings are critical core substructures in the majority of pharmaceutical compounds. There is much recent interest in replacing aromatic structures with saturated bioisosteres of benzene, which are generally fused or bridged ring systems. These bioisosteres often show improved solubility properties compared to benzene, and may also undergo fewer unwanted metabolic processes. One key reason why aromatic rings have proven so successful in drug design is their rigidity. This paper uses molecular dynamics simulations s...
Source: Bioorganic and Medicinal Chemistry - March 5, 2024 Category: Chemistry Authors: Graham Pattison Source Type: research
Design, synthesis and antitumor activity of 2-substituted quinazoline-4-amine derivatives
In this study, a series of new N-arylquinazoline-4-amine analogs were designed and synthesized based on structure optimization of quinazoline. The structures of the thirty-two newly synthesized compounds were confirmed by 1H NMR, 13C NMR and ESI-MS. The anticancer activity in vitro against chronic myeloid leukemia cells (K562), non-small cell lung cancer cells (A549), human prostate cancer cells (PC3), and cervical cancer cells (HeLa) of the target compounds was evaluated. Among them, the inhibition ratio of compounds 17d, 18a, 18b, 11 and 23a against four cancer cells at 5 μM concentration were more than 50 %. The IC50 v...
Source: Bioorganic and Medicinal Chemistry - March 5, 2024 Category: Chemistry Authors: Menghan Wang Jia Yu Xinyi Huang Gang Yu Qi Liang Sha Cheng Xueling Meng Guangcan Xu Huimin Li Heng Luo Bixue Xu Source Type: research
Design, synthesis and anti-necroptosis activity of fused heterocyclic MLKL inhibitors
In this study, with the covalent motif maintained, we aim to improve the activity by introducing the terminal fused heterocycles and meanwhile revealing the SAR on the part. As a result, compounds 9 and 14 showed the best activity (EC50 = 148.4 and 595.9 nM) against necroptosis among the analogues by covalently binding to MLKL. The SAR was also concluded to guide further structural optimization in this field.PMID:38442525 | DOI:10.1016/j.bmc.2024.117659 (Source: Bioorganic and Medicinal Chemistry)
Source: Bioorganic and Medicinal Chemistry - March 5, 2024 Category: Chemistry Authors: Yining Tang Chunlin Zhuang Source Type: research
AGCM-22, a novel cetuximab-based EGFR-targeting antibody-drug-conjugate with highly selective anti-glioblastoma efficacy
In this study, we synthesized AGCM-22, an EGFR-targeted ADC derived from cetuximab, by conjugating it with the tubulin inhibitor monomethyl auristatin E (MMAE) using our Valine-Alanine Cathepsin B cleavable linker. In vitro experiments demonstrated that AGCM-22 effectively inhibited GBM cell proliferation through increased levels of apoptosis and autophagy-related cell death, whereas cetuximab alone had no anti-GBM effects. Additionally, both mouse and human orthotopic tumor models exhibited the selective tumor-targeting efficacy of AGCM-22, along with favorable metabolic properties and superior anti-GBM activity compared ...
Source: Bioorganic and Medicinal Chemistry - March 1, 2024 Category: Chemistry Authors: Dapeng Li Xianyan Sun Yiquan Li Chao Shang Yuchao Dong Renshuang Zhao Hang Zhang Zihao Wang Shiyong Fan Chengyuan Ma Xiao Li Source Type: research
AGCM-22, a novel cetuximab-based EGFR-targeting antibody-drug-conjugate with highly selective anti-glioblastoma efficacy
In this study, we synthesized AGCM-22, an EGFR-targeted ADC derived from cetuximab, by conjugating it with the tubulin inhibitor monomethyl auristatin E (MMAE) using our Valine-Alanine Cathepsin B cleavable linker. In vitro experiments demonstrated that AGCM-22 effectively inhibited GBM cell proliferation through increased levels of apoptosis and autophagy-related cell death, whereas cetuximab alone had no anti-GBM effects. Additionally, both mouse and human orthotopic tumor models exhibited the selective tumor-targeting efficacy of AGCM-22, along with favorable metabolic properties and superior anti-GBM activity compared ...
Source: Bioorganic and Medicinal Chemistry - March 1, 2024 Category: Chemistry Authors: Dapeng Li Xianyan Sun Yiquan Li Chao Shang Yuchao Dong Renshuang Zhao Hang Zhang Zihao Wang Shiyong Fan Chengyuan Ma Xiao Li Source Type: research
AGCM-22, a novel cetuximab-based EGFR-targeting antibody-drug-conjugate with highly selective anti-glioblastoma efficacy
In this study, we synthesized AGCM-22, an EGFR-targeted ADC derived from cetuximab, by conjugating it with the tubulin inhibitor monomethyl auristatin E (MMAE) using our Valine-Alanine Cathepsin B cleavable linker. In vitro experiments demonstrated that AGCM-22 effectively inhibited GBM cell proliferation through increased levels of apoptosis and autophagy-related cell death, whereas cetuximab alone had no anti-GBM effects. Additionally, both mouse and human orthotopic tumor models exhibited the selective tumor-targeting efficacy of AGCM-22, along with favorable metabolic properties and superior anti-GBM activity compared ...
Source: Bioorganic and Medicinal Chemistry - March 1, 2024 Category: Chemistry Authors: Dapeng Li Xianyan Sun Yiquan Li Chao Shang Yuchao Dong Renshuang Zhao Hang Zhang Zihao Wang Shiyong Fan Chengyuan Ma Xiao Li Source Type: research
AGCM-22, a novel cetuximab-based EGFR-targeting antibody-drug-conjugate with highly selective anti-glioblastoma efficacy
In this study, we synthesized AGCM-22, an EGFR-targeted ADC derived from cetuximab, by conjugating it with the tubulin inhibitor monomethyl auristatin E (MMAE) using our Valine-Alanine Cathepsin B cleavable linker. In vitro experiments demonstrated that AGCM-22 effectively inhibited GBM cell proliferation through increased levels of apoptosis and autophagy-related cell death, whereas cetuximab alone had no anti-GBM effects. Additionally, both mouse and human orthotopic tumor models exhibited the selective tumor-targeting efficacy of AGCM-22, along with favorable metabolic properties and superior anti-GBM activity compared ...
Source: Bioorganic and Medicinal Chemistry - March 1, 2024 Category: Chemistry Authors: Dapeng Li Xianyan Sun Yiquan Li Chao Shang Yuchao Dong Renshuang Zhao Hang Zhang Zihao Wang Shiyong Fan Chengyuan Ma Xiao Li Source Type: research
Synthesis and biological evaluation of triazolones/oxadiazolones as novel urease inhibitors
Bioorg Med Chem. 2024 Feb 25;102:117656. doi: 10.1016/j.bmc.2024.117656. Online ahead of print.ABSTRACTUrease is the main virulence factor of infectious gastritis and gastric ulcers. Urease inhibitors are regarded as the first choice for the treatment of such diseases. Based on the triazolone/oxadiazolone skeleton, a urea-like fragment being able to specifically bind the urease activity pocket and prevent urea from hydrolysis, we designed and synthesized 45 triazolones/oxadiazolones as urease inhibitors. Eight compounds were proved to show excellent inhibitory activity against Helicobacter pylori urease, being more potency...
Source: Bioorganic and Medicinal Chemistry - February 29, 2024 Category: Chemistry Authors: Yi-Ning Wang Su-Ya Li Liang-Chao Yuan Shu-Fang Bu Yao Zeng Zhu-Ping Xiao Hai-Liang Zhu Source Type: research
Synthesis and biological evaluation of triazolones/oxadiazolones as novel urease inhibitors
Bioorg Med Chem. 2024 Feb 25;102:117656. doi: 10.1016/j.bmc.2024.117656. Online ahead of print.ABSTRACTUrease is the main virulence factor of infectious gastritis and gastric ulcers. Urease inhibitors are regarded as the first choice for the treatment of such diseases. Based on the triazolone/oxadiazolone skeleton, a urea-like fragment being able to specifically bind the urease activity pocket and prevent urea from hydrolysis, we designed and synthesized 45 triazolones/oxadiazolones as urease inhibitors. Eight compounds were proved to show excellent inhibitory activity against Helicobacter pylori urease, being more potency...
Source: Bioorganic and Medicinal Chemistry - February 29, 2024 Category: Chemistry Authors: Yi-Ning Wang Su-Ya Li Liang-Chao Yuan Shu-Fang Bu Yao Zeng Zhu-Ping Xiao Hai-Liang Zhu Source Type: research
Synthesis, biological evaluation, and stability studies of raloxifene mono- and bis-sulfamates as dual-targeting agents
Bioorg Med Chem. 2024 Feb 16;101:117645. doi: 10.1016/j.bmc.2024.117645. Online ahead of print.ABSTRACTAll three possible sulfamate derivatives of the selective estrogen receptor modulator Raloxifene (bis-sulfamate 7 and two mono-sulfamates 8-9) were synthesized and evaluated as inhibitors of the clinical drug target steroid sulfatase (STS), both in cell-free and in cell-based assays, and also as estrogen receptor (ER) modulators. Bis-sulfamate 7 was the most potent STS inhibitor with an IC50 of 12.2 nM in a whole JEG3 cell-based assay, with the two mono-sulfamates significantly weaker. The estrogen receptor-modulating act...
Source: Bioorganic and Medicinal Chemistry - February 24, 2024 Category: Chemistry Authors: Seyed-Omar Zaraei Wolfgang Dohle Hanan S Anbar Randa El-Gamal Bertrand Leblond Paul A Foster Taleb H Al-Tel Barry V L Potter Mohammed I El-Gamal Source Type: research
Research progress of LSD1-based dual-target agents for cancer therapy
Bioorg Med Chem. 2024 Feb 21;101:117651. doi: 10.1016/j.bmc.2024.117651. Online ahead of print.ABSTRACTLysine-specific demethylase 1 (LSD1) is a histone lysine demethylase that is significantly overexpressed or dysregulated in different cancers and plays important roles in cell growth, invasion, migration, immune escape, angiogenesis, gene regulation, and transcription. Therefore, it is a superb target for the discovery of novel antitumor agents. However, because of their innate and acquired resistance and low selectivity, LSD1 inhibitors are associated with limited therapeutic efficacy and high toxicity. Furthermore, LSD1...
Source: Bioorganic and Medicinal Chemistry - February 24, 2024 Category: Chemistry Authors: Xiaojuan Yang Source Type: research
Multi-target potential of newly designed tacrine-derived cholinesterase inhibitors: Synthesis, computational and pharmacological study
Bioorg Med Chem. 2024 Feb 18;101:117649. doi: 10.1016/j.bmc.2024.117649. Online ahead of print.ABSTRACTSimple and scalable synthetic approach was used for the preparation of thirteen novel tacrine derivatives consisting of tacrine and N-aryl-piperidine-4-carboxamide moiety connected by a five-methylene group linker. An anti-Alzheimer disease (AD) potential of newly designed tacrine derivatives was evaluated against two important AD targets, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). In vitro pharmacological evaluation showed strong ChE inhibitory activity of all compounds, with IC50 values ranging from ...
Source: Bioorganic and Medicinal Chemistry - February 24, 2024 Category: Chemistry Authors: Ivana I Jevti ć Relja V Suru čić Gordana Tovilovi ć-Kovačević Nevena Zogovi ć Sla đana V Kostić-Rajačić Deana B Andri ć Jelena Z Penji šević Source Type: research
