The new N < sup > 2 < /sup > , N < sup > 4 < /sup > -diphenylpyridine-2,4-diamine deuterated derivatives as EGFR inhibitors to overcome C797S-mediated resistance
Bioorg Chem. 2024 Mar 26;146:107313. doi: 10.1016/j.bioorg.2024.107313. Online ahead of print.ABSTRACTA series of new deuterated and non-deuterated N2, N4-diphenylpyridine - 2,4-diamine derivatives were synthesized and evaluated as EGFR C797S-mediated resistance inhibitors. Most of these compounds exhibited potent antiproliferative activity against Baf3-EGFR L858R/T790M/C797S and Baf3-EGFR Del19/T790M/C797S cancel cell lines, with IC50 values in the nanomolar concentration range. Among them, compound 14l represented the most active compound with IC50 values of 8-11 nM. Interestingly, metabolic stability assay with rat live...
Source: Bioorganic Chemistry - March 30, 2024 Category: Chemistry Authors: Jiadai Liu Wenyan Nie Haoran Nie Han Yao Yuanyuan Ren Longcai Cao Jiaqi Qiu Mengxuan Wang Xingshu Li Baijiao An Xian Jia Source Type: research
The new N < sup > 2 < /sup > , N < sup > 4 < /sup > -diphenylpyridine-2,4-diamine deuterated derivatives as EGFR inhibitors to overcome C797S-mediated resistance
Bioorg Chem. 2024 Mar 26;146:107313. doi: 10.1016/j.bioorg.2024.107313. Online ahead of print.ABSTRACTA series of new deuterated and non-deuterated N2, N4-diphenylpyridine - 2,4-diamine derivatives were synthesized and evaluated as EGFR C797S-mediated resistance inhibitors. Most of these compounds exhibited potent antiproliferative activity against Baf3-EGFR L858R/T790M/C797S and Baf3-EGFR Del19/T790M/C797S cancel cell lines, with IC50 values in the nanomolar concentration range. Among them, compound 14l represented the most active compound with IC50 values of 8-11 nM. Interestingly, metabolic stability assay with rat live...
Source: Bioorganic Chemistry - March 30, 2024 Category: Chemistry Authors: Jiadai Liu Wenyan Nie Haoran Nie Han Yao Yuanyuan Ren Longcai Cao Jiaqi Qiu Mengxuan Wang Xingshu Li Baijiao An Xian Jia Source Type: research
Structure-activity relationship and biofilm formation-related gene targets of oleanolic acid-type saponins from Pulsatilla chinensis against Candida albicans
Bioorg Chem. 2024 Mar 25;146:107311. doi: 10.1016/j.bioorg.2024.107311. Online ahead of print.ABSTRACTIn the course of our investigations of antifungal natural products, the structure-activity relationship and antifungal activities of oleanolic acid-type saponins (1-28) from Pulsatilla chinensis against human and plant pathogenic fungi were elucidated. The analysis of structure-activity relationship of oleanolic acid-type saponins showed that the free carboxyl at C-28 was essential for their antifungal activities; the free hydroxyl group at the C-23 site of oleanolic acid-type saponins played a crucial role in their antifu...
Source: Bioorganic Chemistry - March 28, 2024 Category: Chemistry Authors: Junfeng Tan Zengguang Zhang Dan Zheng Yu Mu Bixuan Cao Junwei Yang Li Han Xueshi Huang Source Type: research
Discovery of macrocyclic CDK2/4/6 inhibitors with improved potency and DMPK properties through a highly efficient macrocyclic drug design platform
Bioorg Chem. 2024 Mar 15;146:107285. doi: 10.1016/j.bioorg.2024.107285. Online ahead of print.ABSTRACTCyclin-dependent kinases (CDKs) are critical cell cycle regulators that are often overexpressed in tumors, making them promising targets for anti-cancer therapies. Despite substantial advancements in optimizing the selectivity and drug-like properties of CDK inhibitors, safety of multi-target inhibitors remains a significant challenge. Macrocyclization is a promising drug discovery strategy to improve the pharmacological properties of existing compounds. Here we report the development of a macrocyclization platform that en...
Source: Bioorganic Chemistry - March 28, 2024 Category: Chemistry Authors: Fanye Meng Jinxin Liu Zhongying Cao Jiaojiao Yu Barbara Steurer Yilin Yang Yazhou Wang Xin Cai Man Zhang Feng Ren Alex Aliper Xiao Ding Alex Zhavoronkov Source Type: research
Design, synthesis and biological evaluation of new 2,6-difluorinated phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates as new antimicrotubule agents
In this study, we evaluated the effect of the difluorination of the aromatic ring bearing the imidazolidin-2-one moiety (ring A) at positions 3, 5 and 2, 6 on their antiproliferative activity on four cancer cell lines, their ability to disrupt the microtubules and their toxicity toward chick embryos. We thus synthesized, characterized and biologically evaluated 24 new difluorinated PIB-SO derivatives designated as phenyl 3,5-difluoro-4-(2-oxoimidazolidin-1-yl)benzenesulfonates (3,5-PFB-SOs, 4-15) and phenyl 2,6-difluoro-4-(2-oxoimidazolidin-1-yl)benzenesulfonates (2,6-PFB-SOs, 16-27). The concentration of the drug required...
Source: Bioorganic Chemistry - March 28, 2024 Category: Chemistry Authors: Chahrazed Bouzriba Mathieu Gagn é-Boulet Atziri Corin Chavez Alvarez Vincent Ouellette Isabelle Laverdi ère S ébastien Fortin Source Type: research
Structure-activity relationship and biofilm formation-related gene targets of oleanolic acid-type saponins from Pulsatilla chinensis against Candida albicans
Bioorg Chem. 2024 Mar 25;146:107311. doi: 10.1016/j.bioorg.2024.107311. Online ahead of print.ABSTRACTIn the course of our investigations of antifungal natural products, the structure-activity relationship and antifungal activities of oleanolic acid-type saponins (1-28) from Pulsatilla chinensis against human and plant pathogenic fungi were elucidated. The analysis of structure-activity relationship of oleanolic acid-type saponins showed that the free carboxyl at C-28 was essential for their antifungal activities; the free hydroxyl group at the C-23 site of oleanolic acid-type saponins played a crucial role in their antifu...
Source: Bioorganic Chemistry - March 28, 2024 Category: Chemistry Authors: Junfeng Tan Zengguang Zhang Dan Zheng Yu Mu Bixuan Cao Junwei Yang Li Han Xueshi Huang Source Type: research
Discovery of macrocyclic CDK2/4/6 inhibitors with improved potency and DMPK properties through a highly efficient macrocyclic drug design platform
Bioorg Chem. 2024 Mar 15;146:107285. doi: 10.1016/j.bioorg.2024.107285. Online ahead of print.ABSTRACTCyclin-dependent kinases (CDKs) are critical cell cycle regulators that are often overexpressed in tumors, making them promising targets for anti-cancer therapies. Despite substantial advancements in optimizing the selectivity and drug-like properties of CDK inhibitors, safety of multi-target inhibitors remains a significant challenge. Macrocyclization is a promising drug discovery strategy to improve the pharmacological properties of existing compounds. Here we report the development of a macrocyclization platform that en...
Source: Bioorganic Chemistry - March 28, 2024 Category: Chemistry Authors: Fanye Meng Jinxin Liu Zhongying Cao Jiaojiao Yu Barbara Steurer Yilin Yang Yazhou Wang Xin Cai Man Zhang Feng Ren Alex Aliper Xiao Ding Alex Zhavoronkov Source Type: research
Design, synthesis and biological evaluation of new 2,6-difluorinated phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates as new antimicrotubule agents
In this study, we evaluated the effect of the difluorination of the aromatic ring bearing the imidazolidin-2-one moiety (ring A) at positions 3, 5 and 2, 6 on their antiproliferative activity on four cancer cell lines, their ability to disrupt the microtubules and their toxicity toward chick embryos. We thus synthesized, characterized and biologically evaluated 24 new difluorinated PIB-SO derivatives designated as phenyl 3,5-difluoro-4-(2-oxoimidazolidin-1-yl)benzenesulfonates (3,5-PFB-SOs, 4-15) and phenyl 2,6-difluoro-4-(2-oxoimidazolidin-1-yl)benzenesulfonates (2,6-PFB-SOs, 16-27). The concentration of the drug required...
Source: Bioorganic Chemistry - March 28, 2024 Category: Chemistry Authors: Chahrazed Bouzriba Mathieu Gagn é-Boulet Atziri Corin Chavez Alvarez Vincent Ouellette Isabelle Laverdi ère S ébastien Fortin Source Type: research
Synthesis of narrow-spectrum anti-mycobacterial molecules without effect on the diversity of gut microbiota in mice based on the structure of rifampicin
Bioorg Chem. 2024 Mar 13;146:107282. doi: 10.1016/j.bioorg.2024.107282. Online ahead of print.ABSTRACTRifampicin (RIF) is a broad-spectrum antimicrobial agent that is also a first-line drug for treating tuberculosis (TB). Based on the naphthyl ring structure of RIF this study synthesized 16 narrow-spectrum antimicrobial molecules that were specifically anti-Mycobacterium tuberculosis (Mtb). The most potent candidate was 2-((6-hydroxynaphthalen-2-yl) methylene) hydrazine-1-carbothioamide (compound 3c) with minimum inhibitory concentration (MIC) of 1 μg/mL against Mtb. Synergistic anti-Mtb test indicated that none of the co...
Source: Bioorganic Chemistry - March 27, 2024 Category: Chemistry Authors: Jun-Xian Chen Hong-Mei Dong Yu-Xiang Cai Li-Xia Tian Zai-Chang Yang Source Type: research
Design and application of a novel "turn-on" fluorescent probe for imaging sulfite in living cells and inflammation models
Bioorg Chem. 2024 Mar 24;146:107305. doi: 10.1016/j.bioorg.2024.107305. Online ahead of print.ABSTRACTSulfite is one of the main existing forms of sulfur dioxide (SO2) in living system, which has been recognized as an endogenous mediator in inflammation. Evidence has accumulated to show that abnormal level of sulfite is associated with many inflammatory diseases, including neurological diseases and cancers. Herein, a novel fluorescent probe named QX-OA was designed and synthesized to detect sulfite. QX-OA was constructed by choosing quinolinium-xanthene as the fluorophore and levulinate as the specific and relatively stead...
Source: Bioorganic Chemistry - March 27, 2024 Category: Chemistry Authors: Kun Yao Hua Liu Binbin Fang Congyang Xia Lingmin Gu Lin Fang Haohao Zhu Jie Pan Guofu Zhang Source Type: research
Qingkailing granule alleviates pulmonary fibrosis by inhibiting PI3K/AKT and SRC/STAT3 signaling pathways
Bioorg Chem. 2024 Mar 13;146:107286. doi: 10.1016/j.bioorg.2024.107286. Online ahead of print.ABSTRACTPulmonary fibrosis (PF) poses a significant challenge with limited treatment options and a high mortality rate of approximately 45 %. Qingkailing Granule (QKL), derived from the Angong Niuhuang Pill, shows promise in addressing pulmonary conditions. Using a comprehensive approach, combining network pharmacology analysis with experimental validation, this study explores the therapeutic effects and mechanisms of QKL against PF for the first time. In vivo, QKL reduced collagen deposition and suppressed proinflammatory cytokin...
Source: Bioorganic Chemistry - March 27, 2024 Category: Chemistry Authors: Hong Li Guang Xin Qilong Zhou Xiuxian Yu Chengyu Wan Yilan Wang Ao Wen Kun Zhang Boli Zhang Yu Cao Wen Huang Source Type: research
Design, synthesis and Anti-Plasmodial activity of Mortiamide-Lugdunin conjugates
In this study, two linear and corresponding cyclic heptapeptide versions of mortiamide A-lugdunin hybrids were designed and synthesized by integrating an anti-malarial peptide epitope derived from Mortiamide A, combined with four residues known for their membrane interactions. Using this synthetic strategy, the sequence of mortiamide A was partly re-engineered with an epitope sequence of lugdunin along with an amino acid replacement using all-L and D/L configurations. Importantly, the re-engineered cyclic mortiamides with all-L (3) and D/L (4) configurations exhibited promising anti-malarial activities against the P. falci...
Source: Bioorganic Chemistry - March 27, 2024 Category: Chemistry Authors: Nattamon Trirattanaporn Roonglawan Rattanajak Kanchana Dokladda Sumalee Kamchonwongpaisan Panumart Thongyoo Source Type: research
The design, synthesis and bioactivity evaluation of novel androgen receptor degraders based on hydrophobic tagging
In conclusion, the present study lays the foundation for the development of a completely new class of therapeutic agents for the treatment of mCRPC, and further design and synthesis of AR-targeting degraders are currently in progress for better degradation rate.PMID:38537338 | DOI:10.1016/j.bioorg.2024.107309 (Source: Bioorganic Chemistry)
Source: Bioorganic Chemistry - March 27, 2024 Category: Chemistry Authors: Ying Sun Huating Wang Yaru Li Zhaoxiang Li Zhihui Mao Mengyao Zhang Yixian Shao Jiaqi Ye Dan Li Lihong Shan Source Type: research
Synthesis of narrow-spectrum anti-mycobacterial molecules without effect on the diversity of gut microbiota in mice based on the structure of rifampicin
Bioorg Chem. 2024 Mar 13;146:107282. doi: 10.1016/j.bioorg.2024.107282. Online ahead of print.ABSTRACTRifampicin (RIF) is a broad-spectrum antimicrobial agent that is also a first-line drug for treating tuberculosis (TB). Based on the naphthyl ring structure of RIF this study synthesized 16 narrow-spectrum antimicrobial molecules that were specifically anti-Mycobacterium tuberculosis (Mtb). The most potent candidate was 2-((6-hydroxynaphthalen-2-yl) methylene) hydrazine-1-carbothioamide (compound 3c) with minimum inhibitory concentration (MIC) of 1 μg/mL against Mtb. Synergistic anti-Mtb test indicated that none of the co...
Source: Bioorganic Chemistry - March 27, 2024 Category: Chemistry Authors: Jun-Xian Chen Hong-Mei Dong Yu-Xiang Cai Li-Xia Tian Zai-Chang Yang Source Type: research
Design and application of a novel "turn-on" fluorescent probe for imaging sulfite in living cells and inflammation models
Bioorg Chem. 2024 Mar 24;146:107305. doi: 10.1016/j.bioorg.2024.107305. Online ahead of print.ABSTRACTSulfite is one of the main existing forms of sulfur dioxide (SO2) in living system, which has been recognized as an endogenous mediator in inflammation. Evidence has accumulated to show that abnormal level of sulfite is associated with many inflammatory diseases, including neurological diseases and cancers. Herein, a novel fluorescent probe named QX-OA was designed and synthesized to detect sulfite. QX-OA was constructed by choosing quinolinium-xanthene as the fluorophore and levulinate as the specific and relatively stead...
Source: Bioorganic Chemistry - March 27, 2024 Category: Chemistry Authors: Kun Yao Hua Liu Binbin Fang Congyang Xia Lingmin Gu Lin Fang Haohao Zhu Jie Pan Guofu Zhang Source Type: research
