[1,2,4]Triazolo[3,4-<i>b</i>]benzothiazole Scaffold as Versatile Nicotinamide Mimic Allowing Nanomolar Inhibition of Different PARP Enzymes

Murthy, Sudarshan; Nizi, Maria Giulia; Maksimainen, Mirko M.; Massari, Serena; Alaviuhkola, Juho; Lippok, Barbara E.; Vagaggini, Chiara; Sowa, Sven T.; Galera‐Prat, Albert; Ashok, Yashwanth; Venkannagari, Harikanth; Prunskaite‐Hyyryläinen, Renata; Dreassi, Elena; Lüscher, Bernhard; Korn, Patricia; Tabarrini, Oriana; Lehtiö, L.

doi:10.1021/acs.jmedchem.2c01460

Cited by 8 publications

(5 citation statements)

References 92 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The human poly(ADP-ribose)polymerase ( h PARP) family consists of at least 18 members that share a conserved catalytic domain that catalyzes the transfer of adenosine diphosphate ribose (ADP-ribose) units to target proteins . These enzymes, especially h PARP-1 and h PARP-2, which are prominent members of this protein family, play an important role in various cellular processes, including chromatin structure regulation, transcription, replication, recombination, and DNA repair . Considering that certain tumors defective in homologous recombination mechanisms may rely on PARP-mediated DNA repair for survival and be sensitive to its control, it increases the importance of the role of h PARP proteins in DNA repair .…”

Section: Resultsmentioning

confidence: 99%

Practical Three-Component Regioselective Synthesis of Drug-Like 3-Aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnolines as Potential Non-Covalent Multi-Targeting Inhibitors To Combat Neurodegenerative Diseases

Mousavi,

Rimaz,

Zeynizadeh

2024

ACS Chem. Neurosci.

View full text Add to dashboard Cite

Neurodegenerative diseases (NDs) are one of the prominent health challenges facing contemporary society, and many efforts have been made to overcome and (or) control it. In this research paper, we described a practical one-pot two-step three-component reaction between 3,4-dihydronaphthalen-1(2H)one (1), aryl(or heteroaryl)glyoxal monohydrates (2a−h), and hydrazine monohydrate (NH 2 NH 2 •H 2 O) for the regioselective preparation of some 3-aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnoline derivatives (3a−h). After synthesis and characterization of the mentioned cinnolines (3a−h), the in silico multi-targeting inhibitory properties of these heterocyclic scaffolds have been investigated upon various Homo sapiens-type enzymes, including

show abstract

Section: Resultsmentioning

confidence: 99%

Practical Three-Component Regioselective Synthesis of Drug-Like 3-Aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnolines as Potential Non-Covalent Multi-Targeting Inhibitors To Combat Neurodegenerative Diseases

Mousavi,

Rimaz,

Zeynizadeh

2024

ACS Chem. Neurosci.

View full text Add to dashboard Cite

show abstract

“…Parp14 is subject of an active drug development campaign. Compounds that target the NAD+ binding pocket with subsequent ART activity inhibition, e.g., 14,29 , or that target the NAD+ binding pocket with subsequent Parp14 proteolysis (proteolysis targeting chimera) 30 have been reported. Also, one line of research has focused on compounds that target the Parp14 macrodomains, e.g., 31–33 , involved in the binding of Parp14 to ADP-ribose conjugates and removal of them 5,6 .…”

Section: Discussionmentioning

confidence: 99%

Body-wide genetic deficiency of poly(ADP-ribose) polymerase 14 sensitizes mice to colitis

Vedantham,

Polari,

Poosakkannu

et al. 2024

Preprint

View full text Add to dashboard Cite

Inflammatory bowel disease (IBD) is a debilitating and relapsing chronic disease of the gastrointestinal tract affecting millions of people. Here, we investigated the expression and functions of poly (ADP-ribose) polymerase 14 (Parp14), an important regulatory protein in immune cells, using a biobank IBD patient cohort as well as two mouse models of colitis, i.e., the IBD-mimicking oral dextran sulfate sodium (DSS) exposure model, and the oral Salmonella exposure model. Parp14 was expressed in the human colon, by cells in the lamina propria, but, in particular, by the epithelial cells with a typical granular staining pattern in the cytosol. The same Parp14 staining pattern was evidenced in both colitis models. Body-wide genetic deficiency of Parp14 in C57BL/6N background sensitized mice to DSS colitis. The Parp14-deficient mice displayed increased rectal bleeding as well as stronger epithelial erosion, Goblet cell loss and immune cell infiltration. The absence of Parp14 did not affect the mouse colon bacterial microbiota based on PacBio long read sequencing. Also, the colon leukocyte populations of Parp14-deficient mice were normal based on flow cytometry. In contrast, we witnessed an altered transcriptional signature in Parp14-deficient mice with bulk tissue RNA-Seq. Gene Ontology (GO)-based classification of differentially expressed genes demonstrated that the colon transcriptional signature of Parp14-deficient mice was dominated by abnormalities in inflammation and infection responses both prior and after the 1-week DSS exposure. Overall, the data indicate that Parp14 has an important role in the maintenance of colon epithelial barrier integrity. The prognostic and predictive biomarker potential of Parp14 in IBD merits further investigation.

show abstract

“…7,8,15 Parp14 is the subject of an active drug development campaign. Compounds that target the NAD+ binding pocket with subsequent ART activity inhibition, for example, 14,42 or that target the NAD+ binding pocket with subsequent Parp14 proteolysis (proteolysis targeting chimera) 43 have been reported. Also, one line of research has focused on compounds that target the Parp14 macrodomains, for example, [44][45][46] involved in the binding of Parp14 to ADPribose conjugates and removal of them.…”

Section: Discussionmentioning

confidence: 99%

Body‐wide genetic deficiency of poly(ADP‐ribose) polymerase 14 sensitizes mice to colitis

Vedantham,

Polari,

Poosakkannu

et al. 2024

The FASEB Journal

View full text Add to dashboard Cite

Inflammatory bowel disease (IBD) is a chronic disease of the gastrointestinal tract affecting millions of people. Here, we investigated the expression and functions of poly(ADP‐ribose) polymerase 14 (Parp14), an important regulatory protein in immune cells, with an IBD patient cohort as well as two mouse colitis models, that is, IBD‐mimicking oral dextran sulfate sodium (DSS) exposure and oral Salmonella infection. Parp14 was expressed in the human colon by cells in the lamina propria, but, in particular, by the epithelial cells with a granular staining pattern in the cytosol. The same expression pattern was evidenced in both mouse models. Parp14‐deficiency caused increased rectal bleeding as well as stronger epithelial erosion, Goblet cell loss, and immune cell infiltration in DSS‐exposed mice. The absence of Parp14 did not affect the mouse colon bacterial microbiota. Also, the colon leukocyte populations of Parp14‐deficient mice were normal. In contrast, bulk tissue RNA‐Seq demonstrated that the colon transcriptomes of Parp14‐deficient mice were dominated by abnormalities in inflammation and infection responses both prior and after the DSS exposure. Overall, the data indicate that Parp14 has an important role in the maintenance of colon epithelial barrier integrity. The prognostic and predictive biomarker potential of Parp14 in IBD merits further investigation.

show abstract

[1,2,4]Triazolo[3,4-b]benzothiazole Scaffold as Versatile Nicotinamide Mimic Allowing Nanomolar Inhibition of Different PARP Enzymes

Cited by 8 publications

References 92 publications

Practical Three-Component Regioselective Synthesis of Drug-Like 3-Aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnolines as Potential Non-Covalent Multi-Targeting Inhibitors To Combat Neurodegenerative Diseases

Practical Three-Component Regioselective Synthesis of Drug-Like 3-Aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnolines as Potential Non-Covalent Multi-Targeting Inhibitors To Combat Neurodegenerative Diseases

Body-wide genetic deficiency of poly(ADP-ribose) polymerase 14 sensitizes mice to colitis

Body‐wide genetic deficiency of poly(ADP‐ribose) polymerase 14 sensitizes mice to colitis

Contact Info

Product

Resources

About