Design and synthesis 1H-Pyrrolo[2,3-b]pyridine derivatives as FLT3 inhibitors for the treatment of Acute myeloid Leukemia
Bioorg Med Chem. 2024 Feb 2;100:117631. doi: 10.1016/j.bmc.2024.117631. Online ahead of print.ABSTRACTAcute myeloid leukemia (AML) is the most common type of blood cancer and has been strongly correlated with the overexpression of Fms-like tyrosine kinase 3 (FLT3), a member of the class III receptor tyrosine kinase family. With the emergence of FLT3 internal tandem duplication alteration (ITD) and tyrosine kinase domain (TKD) mutations, the development of FLT3 small molecule inhibitors has become an effective medicinal chemistry strategy for AML. Herein, we have designed and synthesized two series of 1H-pyrrolo[2,3-b]pyrid...
Source: Bioorganic and Medicinal Chemistry - February 8, 2024 Category: Chemistry Authors: Tian-Hua Wei Yun Zhou Jin Yang Meng-Yuan Zhang Jing-Jing Wang Zhen-Jiang Tong Jia-Zhen Wu Yi-Bo Wang Jiu-Kai Sha Min Chen Ning Ding Yan-Cheng Yu Wei-Chen Dai Xue-Jiao Leng Xin Xue Shan-Liang Sun Xiao-Long Wang Nian-Guang Li Zhi-Hao Shi Source Type: research
Design of a novel long-acting dual GLP-1/GIP receptor agonist
Bioorg Med Chem. 2024 Feb 3;100:117630. doi: 10.1016/j.bmc.2024.117630. Online ahead of print.ABSTRACTTirzepatide, the first approved dual GLP-1/GIP receptor agonist (RA), has achieved better clinical outcomes than other GLP-1RAs. However, it is an imbalanced dual GIP/GLP-1 RA, and it remains unclear whether the degree of imbalance is optimal. Here, we present a novel long-acting dual GLP-1/GIP RA that exhibits better activity than tirzepatide toward GLP-1R. A candidate conjugate, D314, identified via peptide design, synthesis, conjugation, and experimentation, was evaluated using chronic studies in db/db and diet induced ...
Source: Bioorganic and Medicinal Chemistry - February 8, 2024 Category: Chemistry Authors: Yuanzhen Dong Jinhua Zhang Hongjiang Xu Hengqiao Shen Qin Lu Jun Feng Zhengyan Cai Source Type: research
Colony Stimulating Factor-1 Receptor: An emerging target for neuroinflammation PET imaging and AD therapy
Bioorg Med Chem. 2024 Feb 1;100:117628. doi: 10.1016/j.bmc.2024.117628. Online ahead of print.ABSTRACTAlthough neuroinflammation is a significant pathogenic feature of many neurologic disorders, its precise function in-vivo is still not completely known. PET imaging enables the longitudinal examination, quantification, and tracking of different neuroinflammation biomarkers in living subjects. Particularly, PET imaging of Microglia, specialised dynamic immune cells crucial for maintaining brain homeostasis in central nervous system (CNS), is crucial for staging the neuroinflammation. Colony Stimulating Factor- 1 Receptor (C...
Source: Bioorganic and Medicinal Chemistry - February 8, 2024 Category: Chemistry Authors: Anupriya Adhikari Kanchan Chauhan Manish Adhikari Anjani K Tiwari Source Type: research
The prognostic values of plasma desmosines, crosslinking molecules of elastic fibers, in the disease progression of Moyamoya disease
In conclusion, plasma desmosines could be potential biomarkers to predict the progression of steno-occlusive changes in MMD patients.PMID:38324946 | DOI:10.1016/j.bmc.2024.117602 (Source: Bioorganic and Medicinal Chemistry)
Source: Bioorganic and Medicinal Chemistry - February 7, 2024 Category: Chemistry Authors: Ryosuke Tashiro Riki Anzawa Tomoo Inoue Ayame Mikagi Dan Ozaki Keita Tominaga Takashi Inoue Tomohisa Ishida Miki Fujimura Toyonobu Usuki Hidenori Endo Kuniyasu Niizuma Teiji Tominaga Source Type: research
Synthesis and biological evaluation of 1H-pyrrolo[3,2-g]isoquinolines
Bioorg Med Chem. 2024 Feb 1;100:117619. doi: 10.1016/j.bmc.2024.117619. Online ahead of print.ABSTRACTA structure-activity relationship study performed on 1H-pyrrolo[3,2-g]isoquinoline scaffold identified new haspin inhibitors with nanomolar potencies and selectivity indices (SI) over 6 (inhibitory potency evaluated against 8 protein kinases). Compound 22 was the most active of the series (haspin IC50 = 76 nM). Cellular evaluation of 22 confirmed its activity for endogenous haspin in U-2 OS cells and its anti-proliferative activity against various cell lines. In addition, the binding mode of analog 22 in complex with haspi...
Source: Bioorganic and Medicinal Chemistry - February 6, 2024 Category: Chemistry Authors: Mathilde Defois B éatrice Josselin Pierre Brindeau Andreas Kr ämer Stefan Knapp Fabrice Anizon Francis Giraud Sandrine Ruchaud Pascale Moreau Source Type: research
Research progress on small molecule inhibitors targeting KRAS G12C with acrylamide structure and the strategies for solving KRAS inhibitor resistance
Bioorg Med Chem. 2024 Feb 1;100:117627. doi: 10.1016/j.bmc.2024.117627. Online ahead of print.ABSTRACTKRAS (Kirsten-RAS) is a highly mutated gene in the RAS (rat sarcoma) gene family that acts as a critical switch in intracellular signaling pathways, regulating cell proliferation, differentiation, and survival. The continuous activation of KRAS protein resulting from mutations leads to the activation of multiple downstream signaling pathways, inducing the development of malignant tumors. Despite the significant role of KRAS in tumorigenesis, targeted drugs against KRAS gene mutations have failed, and KRAS was once consider...
Source: Bioorganic and Medicinal Chemistry - February 4, 2024 Category: Chemistry Authors: Zhiyan Jiang Yan Li Xin Zhou Jie Wen Pengwu Zheng Wufu Zhu Source Type: research
Discovery of novel biaryl benzoxazepinones as dual-mode receptor-interacting protein kinase-1 (RIPK1) inhibitors
In this study, a series of novel biaryl benzoxazepinone RIPK1 inhibitors were designed and synthesized by introducing different aryl substituents at the C7 position of benzoxazepinone. As a result, p-cyanophenyl substituted analog 19 exhibited the most potent in vitro anti-necroptotic effect in HT-29 cells (EC50 = 1.7 nM) and superior protection against temperature loss and death in mice in the TZ-induced SIRS model compared to GSK'772. What's more, in vivo analysis of the levels of inflammatory factors in mice also revealed that compound 19 had better anti-inflammatory activity than GSK'772.PMID:38309200 | DOI:10.1016/j.b...
Source: Bioorganic and Medicinal Chemistry - February 3, 2024 Category: Chemistry Authors: YuFeng Xin Pengcheng Dai Hongming Shao Chunlin Zhuang Jiao Li Source Type: research
Exploration of the P1 residue in 3CL protease inhibitors leading to the discovery of a 2-tetrahydrofuran P1 replacement
Bioorg Med Chem. 2024 Jan 29;100:117618. doi: 10.1016/j.bmc.2024.117618. Online ahead of print.ABSTRACTThe virally encoded 3C-like protease (3CLpro) is a well-validated drug target for the inhibition of coronaviruses including Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). Most inhibitors of 3CLpro are peptidomimetic, with a γ-lactam in place of Gln at the P1 position of the pseudopeptide chain. An effort was pursued to identify a viable alternative to the γ-lactam P1 mimetic which would improve physicochemical properties while retaining affinity for the target. Discovery of a 2-tetrahydrofuran as a suitab...
Source: Bioorganic and Medicinal Chemistry - February 3, 2024 Category: Chemistry Authors: Linda S Barton James F Callahan Juan Cantizani Nestor O Concha Ignacio Cotillo Torrejon Nicole C Goodwin Amruta Joshi-Pangu Terry J Kiesow Jeff J McAtee Mark Mellinger Christopher J Nixon Laura Padr ón-Barthe Jaclyn R Patterson Neil D Pearson Jeffrey J P Source Type: research
Semisynthesis of segmentally isotope-labeled and site-specifically palmitoylated CD44 cytoplasmic tail
Bioorg Med Chem. 2024 Jan 28;100:117617. doi: 10.1016/j.bmc.2024.117617. Online ahead of print.ABSTRACTCD44, a ubiquitously expressed transmembrane receptor, plays a crucial role in cell growth, migration, and tumor progression. Dimerization of CD44 is a key event in signal transduction and has emerged as a potential target for anti-tumor therapies. Palmitoylation, a posttranslational modification, disrupts CD44 dimerization and promotes CD44 accumulation in ordered membrane domains. However, the effects of palmitoylation on the structure and dynamics of CD44 at atomic resolution remain poorly understood. Here, we present ...
Source: Bioorganic and Medicinal Chemistry - February 2, 2024 Category: Chemistry Authors: Dominik P Vogl Borja Mateos Mario Migotti Manuel Felkl Anne C Conibear Robert Konrat Christian F W Becker Source Type: research
SAR study of N'-(Salicylidene)heteroarenecarbohydrazides as promising antifungal agents
Bioorg Med Chem. 2024 Jan 24;100:117610. doi: 10.1016/j.bmc.2024.117610. Online ahead of print.ABSTRACTClinically available antifungal drugs have therapeutic limitations due to toxicity, narrow spectrum of activity, and intrinsic or acquired drug resistance. Thus, there is an urgent need for new broad-spectrum antifungal agents with low toxicity and a novel mechanism of action. In this context, we have successfully identified several highly promising lead compounds, i.e., aromatic N'-(salicylidene)carbohydrazides, exhibiting excellent antifungal activities against Cryptococcus neoformans, Candida albicans, Aspergillus fumi...
Source: Bioorganic and Medicinal Chemistry - February 2, 2024 Category: Chemistry Authors: Yi Sun Saerom Kim SeungYoun Shin Kathryn Takemura Gabriel S Matos Cristina Lazzarini Krupanandan Haranahalli Julia Zambito Ashna Garg Maurizio Del Poeta Iwao Ojima Source Type: research
Discovery of thiophen-2-ylmethylene bis-dimedone derivatives as novel WRN inhibitors for treating cancers with microsatellite instability
This study provides a new pharmacophore for WRN inhibitors, emphasizing their therapeutic potential for MSI cancers.PMID:38295487 | DOI:10.1016/j.bmc.2024.117588 (Source: Bioorganic and Medicinal Chemistry)
Source: Bioorganic and Medicinal Chemistry - January 31, 2024 Category: Chemistry Authors: Hwasun Yang Miso Kang Seonyeong Jang Soo Yeon Baek Jiwon Kim Gyeong Un Kim Dongwoo Kim Junsu Ha Jong Seung Kim Cheulhee Jung Nam-Jung Kim Sung-Yup Cho Woong-Hee Shin Juyong Lee Junsu Ko Ansoo Lee Gyochang Keum Sanghee Lee Taek Kang Source Type: research
N < sup > 3 < /sup > -Methyluridine and 2'-O-Alkyl/2'-Fluoro-N < sup > 3 < /sup > -methyluridine functionalized nucleic acids improve nuclease resistance while maintaining duplex geometry
Bioorg Med Chem. 2024 Jan 28;100:117616. doi: 10.1016/j.bmc.2024.117616. Online ahead of print.ABSTRACTHerein, we report the synthesis of 2'-O-alkyl/2'-fluoro-N3-methyluridine (2'-O-alkyl/2'-F-m3U) phosphoramidites and their incorporation in DNA and RNA oligonucleotides. The duplex binding affinity and base discrimination studies showed that all 2'-O-alkyl/2'-F-m3U modifications significantly decreased the thermal stability and base-pairing discrimination ability. Serum stability study of dT20 with 2'-O-alkyl-m3U modification exhibited excellent nuclease resistance when incubated with 3'-exonucleases (SVPD) or 5'-exonuclea...
Source: Bioorganic and Medicinal Chemistry - January 31, 2024 Category: Chemistry Authors: Avijit Sahoo Gourav Das Atanu Ghosh Siddharam Shivappa Bagale Nishant Kumar Choudhary S Harikrishna Surajit Sinha Kiran R Gore Source Type: research
Synergistic effect of tryptamine-urea derivatives to overcome the chromosomally-mediated colistin resistance in Klebsiella pneumoniae
In this study, the synthesis of a small library of tryptamine urea derivatives was carried out. In addition, antibiotic susceptibility, antibiotic adjuvant screening and checkerboard assays were used to investigate the antibacterial activity of these synthesized compounds and the potential synergistic activity of their combination with colistin. Conformational analysis of the docked binding modes of the active compound in the predicted binding pocket of bacterial response regulator PhoP were carried out, to see if the active compound inhibits PhoP which is involved in colistin resistance. Finally, hemolytic activity studie...
Source: Bioorganic and Medicinal Chemistry - January 30, 2024 Category: Chemistry Authors: Chaimae Majdi Jean Dessolin David B énimélis Catherine Dunyach-R émy Alix Pantel Patrick Meffre Zohra Benfodda Source Type: research
Synthesis of a fluorescent probe for measuring the activity of endo- β-N-acetylglucosaminidases recognizing hybrid-type N-glycans
Bioorg Med Chem. 2024 Jan 27;100:117612. doi: 10.1016/j.bmc.2024.117612. Online ahead of print.ABSTRACTA fluorescence-quenching-based assay system was constructed to determine the hydrolytic activity of endo-β-N-acetylglucosaminidases (ENGases) interacting with hybrid-type N-glycans. This was achieved using a dual-labeled fluorescent probe with a nonasaccharide structure. We produced the nonasaccharide skeleton by the stepwise glycosylation of the galactose residue on a galactosyl chitobiose derivative. Next, we introduced azido and acetoxy groups into the nonasaccharide derivative in a stepwise manner, which led to stere...
Source: Bioorganic and Medicinal Chemistry - January 30, 2024 Category: Chemistry Authors: Nozomi Ishii Shusei Inoue Kanae Sano Satoshi Takahashi Ichiro Matsuo Source Type: research
Synthesis and antimicrobial studies of cadasides analogues via on-resin esterification
Bioorg Med Chem. 2024 Feb 1;99:117601. doi: 10.1016/j.bmc.2024.117601. Epub 2024 Jan 14.ABSTRACTA series of cadasides analogues have been prepared via a combination of solid-phase peptide synthesis and solution-phase cyclization. Primary structure-activity relationship studies of cadasides have also been established and revealed the critical roles of unnatural amino acid residues, which will facilitate the further development of cadasides analogues with improved antimicrobial activities.PMID:38278098 | DOI:10.1016/j.bmc.2024.117601 (Source: Bioorganic and Medicinal Chemistry)
Source: Bioorganic and Medicinal Chemistry - January 26, 2024 Category: Chemistry Authors: Xiangzhen Yan Chengshuo He Zhuang Li Kang Jin Source Type: research
