Indole Inhibitors of MMP-13 for Arthritic Disorders

Taylor, Steven J.; Abeywardane, Asitha; Liang, Shuang; Xiong, Zhaoming; Proudfoot, John; Farmer, Bennett T.; Gao, Donghong A.; Heim-Riether, Alexander; Smith-Keenan, Lana L.; Muegge, Ingo; Yu, Yang; Zhang, Qiang; Souza, Donald; Panzenbeck, Mark; Goldberg, Daniel R.; Hill-Drzewi, Melissa; Margarit, Mariana; Collins, Brandon; Li, John Xiang; Zuvela-Jelaska, Ljiljana; Li, Jun; Farrow, Neil A.

doi:10.1021/acsomega.1c01320

Cited by 4 publications

(4 citation statements)

References 29 publications

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“…MMP-13 is considered the most important mediator in the pathogenesis of these diseases [ 52 , 53 ]. Indeed, treatment of RA mice with selective inhibitors of MMP-13 reduced the mean arthritic score in comparison to control mice [ 54 ], and MMP-13 knockout mice were protected from collagen antibody-induced arthritis [ 55 ], suggesting that MMP-13 inhibition could have a therapeutic value. In the present study, treatment of human chondrocyte cells with human serum containing compounds from Safr’Inside TM intake reduced the production of MMP-13 in inflammatory stress conditions.…”

Section: Discussionmentioning

confidence: 99%

Reduced Production of Pro-Inflammatory and Pro-Catabolic Factors by Human Serum Metabolites Derived from a Patented Saffron Extract Intake

Pourtau,

Wauquier,

Boutin-Wittrant

et al. 2024

Pharmaceutics

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Safe and anti-inflammatory plant-based natural products present an increasing focus in the treatment of chronic inflammatory diseases such as osteoarthritis or inflammatory bowel diseases. Among them, saffron, a spice derived from the stigma of Crocus sativus, could have anti-inflammatory properties and would be therefore a promising therapeutic agent for the treatment of such conditions. However, the anti-inflammatory molecular mechanisms of saffron in humans are still understudied and unclear. In this study, combining human serum metabolites and cell cultures, we evaluated the effect of circulating metabolites from the consumption of a patented saffron extract (Safr’InsideTM) on the chondrocytes and colon epithelial cell responses to inflammatory stress. Parametric or non-parametric Analysis of Variance with post hoc tests was performed. We demonstrated that human serum containing metabolites from saffron intake attenuated IL-1β-stimulated production of PGE2 and MMP-13 in chondrocyte cells and limited the increase in ICAM-1, MCP-1, iNOS, and MMP-3 in human epithelial cells following combined IL-1β and TNF-α inflammatory stimulation. Altogether, these data provide new findings into the mechanisms underlying the beneficial effects of saffron on chondrocytes and enterocyte cells at the cellular level and in the context of chronic inflammatory disorders.

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Section: Discussionmentioning

confidence: 99%

Reduced Production of Pro-Inflammatory and Pro-Catabolic Factors by Human Serum Metabolites Derived from a Patented Saffron Extract Intake

Pourtau,

Wauquier,

Boutin-Wittrant

et al. 2024

Pharmaceutics

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“…Considering the significantly decreased inhibition potency of C103 against MMP−13, the sandwiched π−π stacking and π−CH (Cβ) interactions with H222 and Y244 could be essential for the ligand binding to MMP−13. A recent X-ray co−crystal structure of MMP−13 in complex with a fragment, 4−(1,2,3-thiadiazole−4−yl)pyridine (ligand code: 9DY) shows that the pyridine ring of the fragment forms the offset π−π stacking interaction with H222 in the tunnel area (PDB code: 7JU8, Figure S4 ) [ 54 ]. Due to the presence of nitrogen on the pyridine of the fragment, its offset pattern is different from that of the phenyl ring of 1UA, and the pyridine ring is more shifted to the Zn−binding site, resulting in the offset π−CH (Cβ) interactions with Y244.…”

Section: Discussionmentioning

confidence: 99%

Molecular Dynamics Simulations of Matrix Metalloproteinase 13 and the Analysis of the Specificity Loop and the S1′−Site

Choi

Chung

2023

IJMS

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The specificity loop of Matrix Metalloproteinases (MMPs) is known to regulate recognition of their substrates, and the S1′−site surrounded by the loop is a unique place to address the selectivity of ligands toward each MMP. Molecular dynamics (MD) simulations of apo−MMP−13 and its complex forms with various ligands were conducted to identify the role of the specificity loop for the ligand binding to MMP−13. The MD simulations showed the dual role of T247 as a hydrogen bond donor to the ligand, as well as a contributor to the formation of the van der Waal surface area, with T245 and K249 on the S1′−site. The hydrophobic surface area mediated by T247 blocks the access of water molecules to the S1′−site of MMP−13 and stabilizes the ligand in the site. The F252 residue is flexible in order to search for the optimum location in the S1′−site of the apo−MMP−13, but once a ligand binds to the S1′−site, it can form offset π−π or edge−to−π stacking interactions with the ligand. Lastly, H222 and Y244 provide the offset π−π and π−CH(Cβ) interactions on each side of the phenyl ring of the ligand, and this sandwiched interaction could be critical for the ligand binding to MMP−13.

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“…[ 7 , 8 , 9 , 10 , 11 , 12 ]). The interesting feature of the 1,2,4-oxadiazole moiety from a medicinal chemistry viewpoint is its potential coverage of a broad spectrum of therapeutic areas, including oncology [ 13 , 14 , 15 ], immunology [ 16 ], neurology [ 17 , 18 , 19 , 20 ], infectious diseases [ 21 , 22 , 23 , 24 ], metabolism and endocrinology [ 25 , 26 , 27 , 28 ], urology [ 29 , 30 ], gastroenterology [ 31 ], cardiology [ 32 ], rheumatology [ 33 ], and respirology [ 34 ]. Such versatility of the 1,2,4-oxadiazole motif, in our opinion, is due to its recognition as the hydrolytically stable bioisostere of the amide and ester bonds [ 35 , 36 , 37 , 38 , 39 ].…”

Section: Introductionmentioning

confidence: 99%

Room Temperature Synthesis of Bioactive 1,2,4-Oxadiazoles

Baykov

Shetnev

Semenov

et al. 2023

IJMS

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1,2,4-Oxadiazole is an essential motif in drug discovery represented in many experimental, investigational, and marketed drugs. This review covers synthetic methods that allow the conversion of different types of organic compounds into 1,2,4-oxadiazole at ambient temperature and the practical application of the latter approaches for the preparation of pharmaceutically important molecules. The discussed methods are divided into three groups. The first combines two-stage protocols requiring the preliminary preparation of O-acylamidoximes followed by cyclization under the action of organic bases. The advantages of this route are its swiftness, high efficiency of the cyclization process, and uncomplicated work--up. However, it requires the preparation and isolation of O-acylamidoximes as a separate preliminary step. The second route is a one-pot synthesis of 1,2,4-oxadiazoles directly from amidoximes and various carboxyl derivatives or aldehydes in aprotic bipolar solvents (primarily DMSO) in the presence of inorganic bases. This recently proposed pathway proved to be highly efficient in the field of medicinal chemistry. The third group of methods consists of diverse oxidative cyclizations, and these reactions have found modest application in drug design thus far. It is noteworthy that the reviewed methods allow for obtaining 1,2,4-oxadiazoles with thermosensitive functions and expand the prospects of using the oxadiazole core as an amide- or ester-like linker in the design of bioactive compounds.

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Indole Inhibitors of MMP-13 for Arthritic Disorders

Cited by 4 publications

References 29 publications

Reduced Production of Pro-Inflammatory and Pro-Catabolic Factors by Human Serum Metabolites Derived from a Patented Saffron Extract Intake

Reduced Production of Pro-Inflammatory and Pro-Catabolic Factors by Human Serum Metabolites Derived from a Patented Saffron Extract Intake

Molecular Dynamics Simulations of Matrix Metalloproteinase 13 and the Analysis of the Specificity Loop and the S1′−Site

Room Temperature Synthesis of Bioactive 1,2,4-Oxadiazoles

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