Synthesis and Evaluation of Galloyl Conjugates of Flavanones as BMP-2 Upregulators with Promising Bone Anabolic and Fracture Healing Properties

Abstract

The molecular hybridization concept led us to design a series of galloyl conjugates of flavanones that have potent osteoblast differentiation ability in vitro and promote bone formation in vivo. An array of in vitro studies, especially gene expression of osteogenic markers, evinced compound 5e as the most potent bone anabolic agent, found to be active at 1 pM, which was then further assessed for its osteogenic potential in vivo. From in vivo studies on rat calvaria and a fracture defect model, we inferred that compound 5e, at an oral dose of 5 mg/(kg day), increased the expression of osteogenic genes (RUNX2, BMP-2, Col1, and OCN) and the bone formation rate and significantly promoted bone regeneration at the fracture site, as evidenced by the increased bone volume/tissue fraction compared with vehicle-treated rats. Furthermore, structure–activity relationship studies and pharmacokinetic studies suggest 5e as a potential bone anabolic lead for future osteoporosis drug development.

Using a two-step method of surface mechanical attrition treatment and calcium ion implantation to promote the osteogenic activity of mesenchymal stem cells as well as biomineralization on a β-titanium surface

“…9 BMP-2 and Type I collagen are of signicance for the development and maintenance of the phenotype of osteoblasts. 33,47,61 With the up-regulation of these osteo-related gene expressions (Fig. 9(a-f)), the respective protein contents in the cells were also observed to be promoted (Fig.…”

Crossing borders: On‐Water Synthesis of Flavanones

“…antibacterial [25,26] among others, they are considered privileged structures [3] . Some relevant examples of flavanones with biological activities are shown in Figure 1 [27–31] …”

Anticancer Activity of Natural and Synthetic Chalcones

“…Oskuei et al obtained imidazolechalcones (Tables S1 and S2, compounds [104][105][106][107][108][109][110][111][112][113][114][115][116][117][118][119][120][121] to evaluate their ability to inhibit tubulin. The antiproliferative activity of the compounds was evaluated on four different cancer cell lines (A549, MCF-7, MCF-7/MX (a mitoxatroneresistant human breast cancer cell line), and HepG2).…”

“…Isomerization of chalcones to corresponding flavanones in presence of acids or bases explains importance of these compounds as ligands (Figure 4) [115]. For example, Pandey et al obtained 5-nitro-flavanones by refluxing 2-hydroxychalcones in presence of concentrated sulfuric acid [116]. Due to their flexible structure, chalcones can effectively bind to many enzymes and receptors, which explains the many biological applications of these compounds [117].…”

“…Isomerization of chalcones to corresponding flavanones in presence of acids or bases explains importance of these compounds as ligands ( Figure 4 ) [ 115 ]. For example, Pandey et al obtained 5-nitro-flavanones by refluxing 2-hydroxychalcones in presence of concentrated sulfuric acid [ 116 ].…”