journal
https://read.qxmd.com/read/38394996/identification-of-benzothiazole-derived-monosaccharides-as-potent-selective-and-orally-bioavailable-inhibitors-of-human-and-mouse-galectin-3-a-rare-example-of-using-a-s%C3%A2-%C3%A2-%C3%A2-o-binding-interaction-for-drug-design
#1
JOURNAL ARTICLE
Chunjian Liu, Wei Wang, Jianxin Feng, Brett Beno, Thiruvenkadam Raja, Jacob Swidorski, Raju K V L P Manepalli, Muthalagu Vetrichelvan, Prasada Rao Jalagam, Satheesh K Nair, Anuradha Gupta, Manoranjan Panda, Kaushik Ghosh, Jinal Kaushikkumar Shukla, Harinath Sale, Devang Shah, Shashyendra Singh Gautam, Dipal Patel, Arvind Mathur, Bruce A Ellsworth, Dong Cheng, Alicia Regueiro-Ren
As a result of our continued efforts to pursue Gal-3 inhibitors that could be used to fully evaluate the potential of Gal-3 as a therapeutic target, two novel series of benzothiazole derived monosaccharides as potent (against both human and mouse Gal-3) and orally bioavailable Gal-3 inhibitors, represented by 4 and 5, respectively, were identified. These discoveries were made based on proposals that the benzothiazole sulfur atom could interact with the carbonyl oxygen of G182/G196 in h/mGal-3, and that the anomeric triazole moiety could be modified into an N-methyl carboxamide functionality...
February 11, 2024: Bioorganic & Medicinal Chemistry
https://read.qxmd.com/read/38368633/3-amino-5-6-7-8-tetrahydrothieno-2-3-b-quinoline-2-carbonitrile-a-fluorescent-molecule-that-induces-differentiation-in-pc12-cells
#2
JOURNAL ARTICLE
Kazuya Asao, Kento Sonoda, Shin-Ichi Kawaguchi, Yoshinori Kawazoe
Neural differentiation is triggered by the activation of multiple signaling pathways initiated by various neurotrophic factors. An elucidation of these mechanisms is anticipated to facilitate the prevention of diseases and the development of novel therapeutic approaches. Alternative small-molecule inducers for neuroscience studies are required instead of protein-based reagents for more efficient and convenient experiments. We demonstrated that small molecules of thieno[2,3-b]pyridine derivatives that induce neural differentiation, compounds 3a and 9a in particular, exhibited significant neuritogenic activity in rat pheochromocytoma (PC12) cells...
February 11, 2024: Bioorganic & Medicinal Chemistry
https://read.qxmd.com/read/38354458/iodoetherification-as-a-strategy-towards-sp-3-rich-scaffolds-for-drug-discovery
#3
JOURNAL ARTICLE
Lydia Barnes, Timothy N Birkinshaw, Aaron J Senior, Oscar Siles Brügge, William Lewis, Stephen P Argent, Christopher J Moody, Andrew Nortcliffe
Functionalised tetrahydropyran and spirooxepane scaffolds were prepared utilising an iodoetherification strategy and elaborated to demonstrate their potential use in library synthesis. The iodoetherification products could be readily transformed to the corresponding azides that could be further functionalised via copper-catalysed azide-alkyne cycloaddition or reduction to the amine. The lead-likeness and three-dimensionality of the scaffolds were examined and compared to commercial libraries.
February 10, 2024: Bioorganic & Medicinal Chemistry
https://read.qxmd.com/read/38359754/1-3-disubstituted-1-2-4-triazin-6-ones-with-potent-activity-against-androgen-receptor-dependent-prostate-cancer-cells
#4
JOURNAL ARTICLE
Shiting Zhao, Abdelsalam S Ali, Xiaomin Liu, Zhiwei Yu, Xinyu Kong, Yan Zhang, G Paul Savage, Yong Xu, Bin Lin, Donghai Wu, Craig L Francis
Synthesis and biological evaluation of a small, focused library of 1,3-disubstituted-1,2,4-triazin-6-ones for in vitro inhibitory activity against androgen-receptor-dependent (22Rv1) and androgen-receptor independent (PC3) castration-resistant prostate cancer (CRPC) cells led to highly active compounds with in vitro IC50 values against 22Rv1 cells of <200 nM, and with apparent selectivity for this cell type over PC3 cells. From metabolic/PK evaluations of these compounds, a 3-benzyl-1-(2,4-dichlorobenzyl) derivative had superior properties and showed considerably stronger activity, by nearly an order of magnitude, against AR-dependent LNCaP and C4-2B cells compared to AR-independent DU145 cells...
February 7, 2024: Bioorganic & Medicinal Chemistry
https://read.qxmd.com/read/38340641/cationic-lipids-from-multi-component-passerini-reaction-for-non-viral-gene-delivery-a-structure-activity-relationship-study
#5
JOURNAL ARTICLE
Jia-Jia Chen, Yu Guo, Rong Wang, Hui-Zhen Yang, Xiao-Qi Yu, Ji Zhang
Although many types of cationic lipids have been developed as efficient gene vectors, the construction of lipid molecules with simple procedures remains challenging. Passerini reaction, as a classic multicomponent reaction, could directly give the α-acyloxycarboxamide products with biodegradable ester and amide bonds. Herein, two series of novel cationic lipids with heterocyclic pyrrolidine and piperidine as headgroups were synthesized through Passerini reaction (P-series) and amide condensation (A-series), and relevant structure-activity relationships on their gene delivery capability was studied...
February 7, 2024: Bioorganic & Medicinal Chemistry
https://read.qxmd.com/read/38342078/discovery-of-novel-mat2a-inhibitors-by-an-allosteric-site-compatible-fragment-growing-approach
#6
JOURNAL ARTICLE
Feng Gao, Xiaoyu Ding, Zhongying Cao, Wei Zhu, Yaya Fan, Barbara Steurer, Hailong Wang, Xin Cai, Man Zhang, Alex Aliper, Feng Ren, Xiao Ding, Alex Zhavoronkov
The methionine adenosyltransferase MAT2A catalyzes the synthesis ofthe methyl donor S-adenosylmethionine (SAM) and thereby regulates critical aspects of metabolism and transcription. Aberrant MAT2A function can lead to metabolic and transcriptional reprogramming of cancer cells, and MAT2A has been shown to promote survival of MTAP-deficient tumors, a genetic alteration that occurs in ∼ 13 % of all tumors. Thus, MAT2A holds great promise as a novel anticancer target. Here, we report a novel series of MAT2A inhibitors generated by a fragment growing approach from AZ-28, a low-molecular weight MAT2A inhibitor with promising pre-clinical properties...
February 5, 2024: Bioorganic & Medicinal Chemistry
https://read.qxmd.com/read/38340642/design-synthesis-and-biological-evaluation-of-phenylcyclopropylamine-entinostat-conjugates-that-selectively-target-cancer-cells
#7
JOURNAL ARTICLE
Yosuke Ota, Yukihiro Itoh, Yuri Takada, Yasunobu Yamashita, Chenliang Hu, Mano Horinaka, Yoshihiro Sowa, Mitsuharu Masuda, Toshiyuki Sakai, Takayoshi Suzuki
Small molecule-based selective cancer cell-targeting can be a desirable anticancer therapeutic strategy. Aiming to discover such small molecules, we previously developed phenylcyclopropylamine (PCPA)-drug conjugates (PDCs) that selectively release anticancer agents in cancer cells where lysine-specific demethylase 1 (LSD1) is overexpressed. In this work, we designed PCPA-entinostat conjugates for selective cancer cell targeting. PCPA-entinostat conjugate 12 with a 4-oxybenzyl group linker released entinostat in the presence of LSD1 in in vitro assays and selectively inhibited the growth of cancer cells in preference to normal cells, suggesting the potential of PCPA-entinostat conjugates as novel anticancer drug delivery small molecules...
February 5, 2024: Bioorganic & Medicinal Chemistry
https://read.qxmd.com/read/38340640/structure-based-design-and-optimization-of-a-new-class-of-small-molecule-inhibitors-targeting-the-p-stalk-binding-pocket-of-ricin
#8
JOURNAL ARTICLE
Michael J Rudolph, Arkajyoti Dutta, Anastasiia M Tsymbal, John E McLaughlin, Yang Chen, Simon A Davis, Sophia A Theodorous, Michael Pierce, Benjamin Algava, Xiaoyu Zhang, Zoltan Szekely, Jacques Y Roberge, Xiao-Ping Li, Nilgun E Tumer
Ricin, a category-B agent for bioterrorism, and Shiga toxins (Stxs), which cause food poisoning bind to the ribosomal P-stalk to depurinate the sarcin/ricin loop. No effective therapy exists for ricin or Stx intoxication. Ribosome binding sites of the toxins have not been targeted by small molecules. We previously identified CC10501, which inhibits toxin activity by binding the P-stalk pocket of ricin toxin A subunit (RTA) remote from the catalytic site. Here, we developed a fluorescence polarization assay and identified a new class of compounds, which bind P-stalk pocket of RTA with higher affinity and inhibit catalytic activity with submicromolar potency...
February 5, 2024: Bioorganic & Medicinal Chemistry
https://read.qxmd.com/read/38342079/chemoenzymatic-synthesis-and-immunological-evaluation-of-sialyl-thomsen-friedenreich-stf-antigen-conjugate-to-crm197
#9
JOURNAL ARTICLE
Weizhao Weng, Sumei Ren, Changcai Teng, Jia Guo, Qiuyu Guo, Wei Zhang, Chengli Zong, Ning Ding
sTF (sialyl-Thomsen-Friedenreich) is a type of tumor-associated carbohydrate antigens (TACAs) and is highly expressed in various human malignancies. To validate if sTF could be a valuable molecular target for future cancer vaccine development, in this work the sTF antigen was prepared by adopting a strategy combining chemical and enzymatic methods, and then was covalently conjugated to a carrier protein, CRM197. The preliminary immunological evaluation, performed on BALB/c mice, revealed that the sTF-CRM197 conjugate elicited high titers of specific IgG antibodies...
February 3, 2024: Bioorganic & Medicinal Chemistry
https://read.qxmd.com/read/38330849/design-of-a-novel-long-acting-dual-glp-1-gip-receptor-agonist
#10
JOURNAL ARTICLE
Yuanzhen Dong, Jinhua Zhang, Hongjiang Xu, Hengqiao Shen, Qin Lu, Jun Feng, Zhengyan Cai
Tirzepatide, 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 obese (DIO) mice...
February 3, 2024: Bioorganic & Medicinal Chemistry
https://read.qxmd.com/read/38330848/design-and-synthesis-1h-pyrrolo-2-3-b-pyridine-derivatives-as-flt3-inhibitors-for-the-treatment-of-acute-myeloid-leukemia
#11
JOURNAL ARTICLE
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
Acute 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]pyridine derivatives CM1-CM24, as FLT3 inhibitors based on F14, which we previously reported, that can target the hydrophobic FLT3 back pocket...
February 2, 2024: Bioorganic & Medicinal Chemistry
https://read.qxmd.com/read/38330850/colony-stimulating-factor-1-receptor-an-emerging-target-for-neuroinflammation-pet-imaging-and-ad-therapy
#12
REVIEW
Anupriya Adhikari, Kanchan Chauhan, Manish Adhikari, Anjani K Tiwari
Although 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 (CSF-1R) PET imaging is a novel method for the quantification of neuroinflammation...
February 1, 2024: Bioorganic & Medicinal Chemistry
https://read.qxmd.com/read/38324946/the-prognostic-values-of-plasma-desmosines-crosslinking-molecules-of-elastic-fibers-in-the-disease-progression-of-moyamoya-disease
#13
JOURNAL ARTICLE
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
Moyamoya disease (MMD) is a cerebrovascular disease which is characterized by the chronic progression of steno-occlusive changes at the terminal portion of internal carotid arteries and the development of "moyamoya vessels." Dysregulation of the extracellular matrix is regarded as a key pathophysiology underlying unique vascular remodeling. Here, we measured the concentration of elastin crosslinkers desmosine and isodesmosine in the plasma of MMD patients. We aimed to reveal its diagnostic values of desmosines in the progression of steno-occlusive lesions...
February 1, 2024: Bioorganic & Medicinal Chemistry
https://read.qxmd.com/read/38320389/synthesis-and-biological-evaluation-of-1h-pyrrolo-3-2-g-isoquinolines
#14
JOURNAL ARTICLE
Mathilde Defois, Béatrice Josselin, Pierre Brindeau, Andreas Krämer, Stefan Knapp, Fabrice Anizon, Francis Giraud, Sandrine Ruchaud, Pascale Moreau
A 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 haspin was determined by X-ray crystallography...
February 1, 2024: Bioorganic & Medicinal Chemistry
https://read.qxmd.com/read/38310752/research-progress-on-small-molecule-inhibitors-targeting-kras-g12c-with-acrylamide-structure-and-the-strategies-for-solving-kras-inhibitor-resistance
#15
REVIEW
Zhiyan Jiang, Yan Li, Xin Zhou, Jie Wen, Pengwu Zheng, Wufu Zhu
KRAS (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 considered an undruggable target...
February 1, 2024: Bioorganic & Medicinal Chemistry
https://read.qxmd.com/read/38309200/discovery-of-novel-biaryl-benzoxazepinones-as-dual-mode-receptor-interacting-protein-kinase-1-ripk1-inhibitors
#16
JOURNAL ARTICLE
YuFeng Xin, Pengcheng Dai, Hongming Shao, Chunlin Zhuang, Jiao Li
Systemic inflammatory response syndrome (SIRS), an exaggerated defense response of the organism to a noxious stressor, involves a massive inflammatory cascade that ultimately leads to reversible or irreversible end-organ dysfunction and even death. Suppressing RIPK1, a key protein in necroptosis pathway, has been proven to be an effective therapeutic strategy for inflammation and SIRS. 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...
February 1, 2024: Bioorganic & Medicinal Chemistry
https://read.qxmd.com/read/38309201/exploration-of-the-p1-residue-in-3cl-protease-inhibitors-leading-to-the-discovery-of-a-2-tetrahydrofuran-p1-replacement
#17
JOURNAL ARTICLE
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 Padrón-Barthe, Jaclyn R Patterson, Neil D Pearson, Jeffrey J Pouliot, Alan R Rendina, Alexander Buitrago Santanilla, Jessica L Schneck, Olalla Sanz, Reema K Thalji, Paris Ward, Shawn P Williams, Bryan W King
The 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 suitable P1 replacement that is a potent enzymatic inhibitor of 3CLpro in SARS-CoV-2 virus is described herein...
January 29, 2024: Bioorganic & Medicinal Chemistry
https://read.qxmd.com/read/38330847/discovery-of-small-molecule-benzothiazole-and-indole-derivatives-tackling-tau-2n4r-and-%C3%AE-synuclein-fibrils
#18
JOURNAL ARTICLE
Ahmed A Elbatrawy, Taiwo A Ademoye, Heba Alnakhala, Arati Tripathi, Ashique Zami, Raluca Ostafe, Ulf Dettmer, Jessica S Fortin
Tau and α-synuclein aggregates are the main histopathological hallmarks present in Alzheimer's disease (AD), Parkinson's disease (PD), and other neurodegenerative disorders. Intraneuronal hyperphosphorylated tau accumulation is significantly connected to the degree of cognitive impairment in AD patients. In particular, the longest 2N4R tau isoform has a propensity to rapidly form oligomers and mature fibrils. On the other hand, misfolding of α-synuclein (α-syn) is the characteristic feature in PD and dementia with Lewy bodies (DLB)...
January 28, 2024: Bioorganic & Medicinal Chemistry
https://read.qxmd.com/read/38306881/semisynthesis-of-segmentally-isotope-labeled-and-site-specifically-palmitoylated-cd44-cytoplasmic-tail
#19
JOURNAL ARTICLE
Dominik P Vogl, Borja Mateos, Mario Migotti, Manuel Felkl, Anne C Conibear, Robert Konrat, Christian F W Becker
CD44, 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 a semisynthetic approach combining solid-phase peptide synthesis, recombinant expression, and native chemical ligation to investigate the impact of palmitoylation on the cytoplasmic domain (residues 669-742) of CD44 (CD44ct) by NMR spectroscopy...
January 28, 2024: Bioorganic & Medicinal Chemistry
https://read.qxmd.com/read/38295488/n-3-methyluridine-and-2-o-alkyl-2-fluoro-n-3-methyluridine-functionalized-nucleic-acids-improve-nuclease-resistance-while-maintaining-duplex-geometry
#20
JOURNAL ARTICLE
Avijit Sahoo, Gourav Das, Atanu Ghosh, Siddharam Shivappa Bagale, Nishant Kumar Choudhary, S Harikrishna, Surajit Sinha, Kiran R Gore
Herein, we report the synthesis of 2'-O-alkyl/2'-fluoro-N3 -methyluridine (2'-O-alkyl/2'-F-m3 U) 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-m3 U modifications significantly decreased the thermal stability and base-pairing discrimination ability. Serum stability study of dT20 with 2'-O-alkyl-m3 U modification exhibited excellent nuclease resistance when incubated with 3'-exonucleases (SVPD) or 5'-exonucleases (PDE-II) as compared to m3 U, 2'-F, 2'-OMe modified oligonucleotides...
January 28, 2024: Bioorganic & Medicinal Chemistry
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