Synthesis, Biological Evaluation, and Docking Studies of a Novel Sulfonamido-Based Gallate as Pro-Chondrogenic Agent for the Treatment of Cartilage

Abstract

Gallic acid (GA) and its derivatives are anti-inflammatory agents and are reported to have potent effects on Osteoarthritis (OA) treatment. Nonetheless, it is generally accepted that the therapeutic effect and biocompatibility of GA is much weaker than its esters due to the high hydrophilicity. The therapeutic effect of GA on OA could be improved if certain structural modifications were made to increase its hydrophobicity. In this study, a novel sulfonamido-based gallate was synthesized by bonding sulfonamide with GA, and its biological evaluations on OA were investigated. Results show that 5-[4-(Pyrimidin-2-ylsulfamoylphenyl)]-carbamoyl-benzene-1,2,3-triyl triacetate (HAMDC) was able to reverse the effects induced by Interleukin-1 (IL-1) stimulation, and it also had a great effect on chondro-protection via promoting cell proliferation and maintaining the phenotype of articular chondrocytes, as well as enhancing synthesis of cartilage specific markers such as aggrecan, collagen II and Sox9. Furthermore, a docking study showed that HAMDC fits into the core of the active site of a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS-5), which provides an explanation for its activity and selectivity.

Butyrolactone‐I, an efficient α‐glucosidase inhibitor, improves type 2 diabetes with potent TNF‐α–lowering properties through modulating gut microbiota in db/db mice

“…Docking is a theoretical and powerful method used for the discovery of interactions between proteins and molecules (46). In our studies, a total of 100 random docking calculations were performed for A6 in the receptor hydrophobic cavity through molecular docking.…”

Special Issue: Sulfonamides

“…In the paper by Lin et al [ 47 ] sulfadiazine is again used as the main scaffold, to which gallic acid moieties were introduced in order to obtain agents with pro-chondrogenic effects for the treatment of cartilage diseases. Gallic acid was thus derivatized with the sulfonamide moiety present in the sulfa drug sulfadiazine in order to increase the hydrophobicity and the bioavailability of this agent.…”

“…Gallic acid was thus derivatized with the sulfonamide moiety present in the sulfa drug sulfadiazine in order to increase the hydrophobicity and the bioavailability of this agent. Although the mechanism of action of this agent is not clearly understood so far, it seems that it interferes with the activity of a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS-5) [ 47 ].…”

Icariin activates far upstream element binding protein 1 to regulate hypoxia-inducible factor-1α and hypoxia-inducible factor-2α signaling and benefits chondrocytes

“…Surgical treatment of cartilage injury includes drilling microfractures, chondrocyte transplantation, and joint replacement ( Ferreira et al, 2019 ), although surgical treatment is considered to be prone to recurrence and is associated with high cost and risk. Non-surgical treatment involves the administration of non-steroidal anti-inflammatory analgesics that can only delay disease progression but cannot fundamentally cure osteoarthritis ( Lin et al, 2016 ). Different from steroidal and non-steroidal drugs, Chinese medicinal monomers can inhibit chondrocyte apoptosis, cellular ECM degradation, and inflammatory factor expression, and promote chondrocyte proliferation through intracellular signaling pathways such as Akt/mammalian target of rapamycin (mTOR) ( Tang et al, 2021 ) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways ( Mi et al, 2018 ) to exert a comprehensive effect on cartilage.…”