Bioorganic and Medicinal Chemistry Letters This is an RSS file. You can use it to subscribe to this data in your favourite RSS reader or to display this data on your own website or blog.

Identification of two novel chemical classes of Autotaxin (ATX) inhibitors using enalos asclepios KNIME nodes
In this study, we present an effort of identifying ATX inhibitors that bind to allosteric ATX binding sites using the Enalos Asclepios KNIME Node. All the available PDB crystal structures of ATX were collected, prepared, and aligned. Visual examination of these structures led to the identification of four crystal structures of human ATX co-crystallized with four known inhibitors. These inhibitors bind to five binding sites with five different binding modes. These five binding sites were thereafter used to virtually screen a compound library of 14,000 compounds to identify molecules that bind to allosteric sites. Based on t...
Source: Bioorganic and Medicinal Chemistry Letters - March 6, 2024 Category: Chemistry Authors: Elli-Anna Stylianaki Varnavas D Mouchlis Christiana Magkrioti Konstantinos D Papavasileiou Antreas Afantitis Alexios N Matralis Vassilis Aidinis Source Type: research

Self-assembly of amphiphilic helical-coiled peptide nanofibers and inhibition of fibril formation with curcumin
Bioorg Med Chem Lett. 2024 Mar 1:129682. doi: 10.1016/j.bmcl.2024.129682. Online ahead of print.ABSTRACTAmphiphilic peptide sequences are conducive to secondary structures that self-assemble into higher-ordered peptide nanostructures. A select set of amphiphilic polycationic peptides displayed stable helical-coiled structures that self-assembled into peptide nanofibers. The progression of peptide fibril formation revealed short protofibrils that extended into thin filaments and into an entangled network of nanofibers over an extended (5 days) incubation period. Ligand binding with 8-anilinonaphthalene-1-sulfonic acid (ANS)...
Source: Bioorganic and Medicinal Chemistry Letters - March 3, 2024 Category: Chemistry Authors: Grace Daniel George Hilan Lisa Ploeg David Sabatino Source Type: research

2-(3-Indolyl)acetamides and their oxazoline analogues: Anticancer SAR study
Bioorg Med Chem Lett. 2024 Mar 1;102:129681. doi: 10.1016/j.bmcl.2024.129681. Online ahead of print.ABSTRACTWe previously studied 2-aryl-2-(3-indolyl)acetohydroxamates as potential agents against melanoma. These compounds were ineffective in a mouse melanoma xenograft model, most likely due to unfavorable metabolic properties, specifically due to glucuronidation of the N-hydroxyl of the hydoxamic moiety. In the present work, we prepared a series of analogues, 2-aryl-2-(3-indolyl)acetamides and their oxazoline derivatives, which do not contain the N-hydroxyl group. We investigated the structure-activity relationship in both...
Source: Bioorganic and Medicinal Chemistry Letters - March 3, 2024 Category: Chemistry Authors: Dmitrii A Aksenov Jadyn L Smith Alexander V Aksenov Lidiya A Prityko Nicolai A Aksenov Iliya K Kuzminov Elena V Aleksandrova Puppala Sathish Nakya Mesa-Diaz Alexandra Vernaza Angela Zhang Liqin Du Alexander Kornienko Source Type: research

2-(3-Indolyl)acetamides and their oxazoline analogues: Anticancer SAR study
Bioorg Med Chem Lett. 2024 Mar 1:129681. doi: 10.1016/j.bmcl.2024.129681. Online ahead of print.ABSTRACTWe previously studied 2-aryl-2-(3-indolyl)acetohydroxamates as potential agents against melanoma. These compounds were ineffective in a mouse melanoma xenograft model, most likely due to unfavorable metabolic properties, specifically due to glucuronidation of the N-hydroxyl of the hydoxamic moiety. In the present work, we prepared a series of analogues, 2-aryl-2-(3-indolyl)acetamides and their oxazoline derivatives, which do not contain the N-hydroxyl group. We investigated the structure-activity relationship in both ser...
Source: Bioorganic and Medicinal Chemistry Letters - March 3, 2024 Category: Chemistry Authors: Dmitrii A Aksenov Jadyn L Smith Alexander V Aksenov Lidiya A Prityko Nicolai A Aksenov Iliya K Kuzminov Elena V Alexandrova Puppala Sathish Nakya Mesa-Diaz Alexandra Vernaza Angela Zhang Liqin Du Alexander Kornienko Source Type: research

"PROTAC" modified Dihydroquinolizinones (DHQs) that causes degradation of PAPD-5 and inhibition of hepatitis a virus and hepatitis B virus, in vitro
In this report, we describe RG7834-based Proteolysis Targeting Chimeras (PROTACs), such as compound 12b, (6S)-9-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-21-oxo-3,6,9,12,15,18-hexaoxa-22-azapentacosan-25-yl)oxy)-6-isopropyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid. The PROTAC DHQs described here inhibited an HAV reporter virus in vitro with an IC50 of 277 nM. Although the PROTAC DHQs were also inhibitory to HBV, their activities were substantially less potent against HBV in vitro, being in the 10 to 20 µM range, based on the reduction of HBsAg and HBV mRNA levels....
Source: Bioorganic and Medicinal Chemistry Letters - March 1, 2024 Category: Chemistry Authors: You Li Nicky Hwang Andrew Snedeker Stanley M Lemon Daisy Noe Liren Sun Jason A Clement Tianlun Zhou Liudi Tang Timothy Block Yanming Du Source Type: research

"PROTAC" modified Dihydroquinolizinones (DHQs) that causes degradation of PAPD-5 and inhibition of hepatitis a virus and hepatitis B virus, in vitro
In this report, we describe RG7834-based Proteolysis Targeting Chimeras (PROTACs), such as compound 12b, (6S)-9-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-21-oxo-3,6,9,12,15,18-hexaoxa-22-azapentacosan-25-yl)oxy)-6-isopropyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid. The PROTAC DHQs described here inhibited an HAV reporter virus in vitro with an IC50 of 277 nM. Although the PROTAC DHQs were also inhibitory to HBV, their activities were substantially less potent against HBV in vitro, being in the 10 to 20 µM range, based on the reduction of HBsAg and HBV mRNA levels....
Source: Bioorganic and Medicinal Chemistry Letters - March 1, 2024 Category: Chemistry Authors: You Li Nicky Hwang Andrew Snedeker Stanley Lemon Daisy Noe Liren Sun Jason A Clement Tianlun Zhou Liudi Tang Timothy Block Yanming Du Source Type: research

Synthesis, SARS-CoV-2 main protease inhibition, molecular docking and in silico ADME studies of furanochromene-quinoline hydrazone derivatives
Bioorg Med Chem Lett. 2024 Feb 27:129679. doi: 10.1016/j.bmcl.2024.129679. Online ahead of print.ABSTRACTSeven furanochromene-quinoline derivatives containing a hydrazone linker were synthesized by condensing a furanochromene hydrazide with 2-, 3-, 4-, 5-, 6-, and 8-quinoline carbaldehydes, including 8-hydroxyquinoline-2-carbaldehye. Structure-activity correlations were investigated to determine the influence of the location of the hydrazone linker on the quinoline unit on SARS-CoV-2 Mpro enzyme inhibition. The 3-, 5-, 6- and 8-substituted derivatives showed moderate inhibition of SARS-CoV-2 Mpro with IC50 values ranging f...
Source: Bioorganic and Medicinal Chemistry Letters - February 29, 2024 Category: Chemistry Authors: Blake M Shellenberger Olivia N Basile Joel Cassel Morgan R Olsen Joseph M Salvino Luis J Montaner Ian Tietjen Geneive E Henry Source Type: research

The discovery of novel and potent indazole NLRP3 inhibitors enabled by DNA-encoded library screening
Bioorg Med Chem Lett. 2024 Feb 28;102:129675. doi: 10.1016/j.bmcl.2024.129675. Online ahead of print.ABSTRACTNLRP3 is an intracellular sensor protein that detects a broad range of danger signals and environmental insults. Its activation results in a protective pro-inflammatory response designed to impair pathogens and repair tissue damage via the formation of the NLRP3 inflammasome. Assembly of the NLRP3 inflammasome leads to caspase 1-dependent secretory release of the pro-inflammatory cytokines IL-1β and IL-18 as well as to gasdermin d-mediated pyroptotic cell death. Herein, we describe the discovery of a novel indazole...
Source: Bioorganic and Medicinal Chemistry Letters - February 28, 2024 Category: Chemistry Authors: George Hartman Paul Humphries Robert Hughes Andrew Ho Rusty Montgomery Aditi Deshpande Maitriyee Mahanta Sarah Tronnes Samantha Cowdin Xu He Fangchao Liu Lifang Zhang Chuan Liu Dengfeng Dou Jin Li Aleksander Spasic Rebecca Coll Michael Marleaux Inga V Hoc Source Type: research

Development of STING degrader with double covalent ligands
In this study, we used a minimal covalent handle recently developed as the ligand portion of an E3 ligase. The engineered STING degrader with a low molecular weight compound covalently binds to STING and E3 ligase. Degrader 2 showed sustained STING degradation activity at lower concentrations (3 µM, 48 h, about 75 % degradation) compared to a reported STING PROTAC, SP23. This discovery holds significance for its potential in treating autoinflammatory and autoimmune diseases, offering promising avenues for developing more efficacious STING-targeted therapies.PMID:38408510 | DOI:10.1016/j.bmcl.2024.129677 (Source: Bioorgani...
Source: Bioorganic and Medicinal Chemistry Letters - February 26, 2024 Category: Chemistry Authors: Miki Nakamura Nobumichi Ohoka Norihito Shibata Takao Inoue Genichiro Tsuji Yosuke Demizu Source Type: research

Development of 1,5-diarylpyrazoles as EGFR/JNK-2 dual inhibitors: design, synthesis, moleecular docking, and bioactivity evaluation
Bioorg Med Chem Lett. 2024 Feb 24;102:129673. doi: 10.1016/j.bmcl.2024.129673. Online ahead of print.ABSTRACTThe eradication of multifactorial diseases, such as cancer, requires the design of drug candidates that attack multiple targets that contribute to the progression and proliferation of such diseases. Here, 1,5-diarylpyrazole derivatives bearing vanillin or sulfanilamide are developed as potential dual inhibitors of epidermal growth factor receptor (EGFR)/c-Jun N-terminal kinase 2 (JNK-2) for possible anticancer activity. These derivatives inhibited the growths of DLD-1, HeLa, K-562, SUIT-2 and HepG2 cancer cell lines...
Source: Bioorganic and Medicinal Chemistry Letters - February 26, 2024 Category: Chemistry Authors: Osama M Soltan Salah A Abdel-Aziz Montaser Sh Shaykoon Keima Osawa Atsushi Narumi Mohamed Abdel-Aziz Mai E Shoman Hiroyuki Konno Source Type: research

Exploration of bromodomain ligand-linker conjugation sites for efficient CBP/p300 heterobifunctional degrader activity
Bioorg Med Chem Lett. 2024 Feb 24:129676. doi: 10.1016/j.bmcl.2024.129676. Online ahead of print.ABSTRACTSynthesis of proteolysis targeting chimeras (PROTACs) involves conjugation of an E3 ligase binding ligand to a ligand targeting a protein of interest via a rigid or flexible chemical linker. The choice of linker conjugation site on these ligands can be informed by structural analysis of ligand-target binding modes, the feasibility of synthetic procedures to access specific sites, and computational modeling of predicted ternary complex formations. Small molecules that target bromodomains - epigenetic readers of lysine ac...
Source: Bioorganic and Medicinal Chemistry Letters - February 26, 2024 Category: Chemistry Authors: Praveen Kumar Tiwari Sai Reddy Doda Raghu Vannam Manish Hudlikar Drew Harrison Samuel Ojeda Sumit Rai Ann-Sophie Koglin Angelique Nguyen Gilbert Christopher J Ott Source Type: research