Enhanced osteogenic activity of daidzein analogs on human mesenchymal stem cells
Inventors
STRONG, Amy • BOUE, Stephen • BUROW, Matthew • Bunnell, Bruce • Jiang, Quan • Zheng, Shilong • Wang, Guangdi
Assignees
Tulane University • US Department of Agriculture USDA • Xavier University of Louisiana
Publication Number
US-11098053-B2
Publication Date
2021-08-24
Expiration Date
2034-04-04
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Abstract
Disclosed are daidzein analogs having the formula (I). Also disclosed are compositions, include a disclosed daidzein analogs, methods of preventing or treating bone disease or bone injury and/or stimulating bone growth, in a subject that include administering to the subject an effective amount of disclosed daidzein analog. Disclosed are isolated mesenchymal stem cell that has been altered by treatment a disclosed daidzein analog, daidzein, glycinol, glyceollin I, or glyceollin II, to increase the osteogenic potential of the mesenchymal stem cells.
Core Innovation
The present invention discloses novel daidzein analogs designed to enhance osteogenesis in humans. These analogs have a defined chemical formula with variations in substituents denoted by R1 to R11 and X, creating compounds structurally distinct from daidzein, glycinol, glyceollin I, and glyceollin II. The invention also includes compositions comprising these daidzein analogs, methods to prevent or treat bone diseases or injuries such as osteoporosis and osteopenia, and methods to stimulate bone growth by administering effective amounts of these compounds. Additionally, mesenchymal stem cells treated with these compounds exhibit increased osteogenic potential, and the invention extends to biocompatible bone repair systems coated or seeded with these analogs or treated mesenchymal stem cells.
The problem addressed is osteoporosis and related bone diseases marked by low bone mass, compromised bone architecture, reduced bone strength, and increased fracture risk. Current treatments include anti-resorptive and anabolic drugs, with estrogen being an effective anabolic agent. However, estrogen therapy's risks include increased incidence of breast and endometrial cancers, and alternatives like raloxifene carry thromboembolic risks. There is a need for superior pharmacological therapies with enhanced bone regeneration capabilities and reduced side effects. The disclosed daidzein analogs meet this need by providing enhanced osteogenic activity and potential therapeutic alternatives to estrogen.
The disclosed daidzein analogs demonstrate increased osteogenic differentiation in human mesenchymal stem cells, including bone marrow-derived and adipose-derived stem cells, compared to daidzein and estrogen. The analogs promote the expression of key osteogenic transcription factors such as Sp7, alkaline phosphatase, osteopontin, and insulin-like growth factor 1, which regulate the maturation of osteoprogenitor cells into osteoblasts. Methods of treatment include administration of effective amounts of the compounds to subjects with bone defects to prevent or treat bone loss or stimulate bone growth. Biocompatible substrates may be coated or seeded with these analogs or treated stem cells for surgical implantation to repair bone defects.
Claims Coverage
The patent includes multiple independent claims covering compounds, compositions, and methods related to daidzein analogs.
Compound having a defined daidzein analog chemical structure
The invention claims compounds characterized by a specific formula featuring various substituents (R1 through R11) and a central moiety X that is carbon or nitrogen, with defined bonding conditions. These compounds exclude daidzein, glycinol, glyceollin I, and glyceollin II, with specific examples such as 3-(4-Hydroxyphenyl)-7-(2-(piperidin-1-yl)ethoxy)-4H-chromen-4-one.
Pharmaceutical composition comprising a daidzein analog and a pharmaceutically acceptable carrier
Compositions include at least one of the claimed compounds and a pharmaceutically acceptable carrier suitable for various administration routes such as oral, intravenous, intradermal, intramuscular, and subcutaneous. Compositions may further include mesenchymal stem cells, optionally pretreated with daidzein analogs or related compounds to enhance osteogenic potential.
Method of preventing or treating bone defects by administering the compound
Methods comprise administering an effective amount of the defined daidzein analog compound to a subject to prevent or treat bone diseases or injuries including osteoporosis and bone fractures.
Method of stimulating bone growth by administering the compound
Methods include administering the daidzein analog in effective amounts to a subject to stimulate bone growth, particularly in cases involving osteoporosis, osteopenia, or bone fractures.
The claims focus on specific daidzein analog compounds, their use in pharmaceutical compositions, and methods of treating bone diseases and stimulating bone growth by administering these compounds, optionally in combination with mesenchymal stem cells.
Stated Advantages
The daidzein analogs have enhanced osteogenic activity in human mesenchymal stem cells compared to estrogen and daidzein.
They promote increased expression of osteogenic transcription factors that regulate maturation of osteoprogenitor cells into mature osteoblasts.
The analogs exhibit reduced estrogenic side effects, providing a safer alternative to estrogen therapy for osteoporosis treatment.
The compounds can be combined with mesenchymal stem cells or used to coat biocompatible substrates for improved bone repair and regeneration.
Documented Applications
Preventing or treating bone diseases such as osteoporosis and osteopenia in subjects.
Treating bone injuries and fractures.
Stimulating bone growth in subjects with bone disease or injury.
Enhancing the osteogenic potential of mesenchymal stem cells either by direct treatment or pretreatment before application in regenerative therapies.
Use in biocompatible bone repair systems coated or seeded with daidzein analogs and/or treated mesenchymal stem cells for surgical implantation at bone defect sites.
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