Researchers at Jinan University and the Chinese Academy of Sciences, Shenzhen, reported on the discovery of a new category of phthalide compound in female ginseng (Angelica sinensis), one of which exhibited potent anti-osteoporotic activity in cell-based lab tests. The team also devised a method for synthesizing the compound—which they called falcarinphthalide A—in the lab at sufficient quantities to support in vitro testing. Their results showed that the compound exhibits a distinctive structure and mechanism that sets it apart from existing drugs used to treat osteoporosis. Tests found that the compound’s potent antiosteoporotic activity was linked with its ability to inhibit NF-κB and c-Fos signaling-mediated osteoclastogenesis.

Hao Gao, PhD, at Jinan University Institute of Traditional Chinese Medicine and Natural Products, and Xin-Luan Wang, PhD, at the Chinese Academy of Sciences Translational Medicine R&D Center, and colleagues suggest their discoveries could point to new possibilities for developing osteoporosis treatments that are based on the female ginseng compound, whether in its current form or used as a structural template for further drug development.

The team reported on its study in ACS Central Science, in a paper titled, “Discovery of a Potent Antiosteoporotic Drug Molecular Scaffold Derived from Angelica sinensis and its Bioinspired Total Synthesis,” in which they concluded, “The discovery of falcarinphthalide A (1) offers a groundbreaking molecular framework for potential therapeutic interventions targeting osteoporosis and other metabolic bone disorders.”

Osteoporosis is “a systemic metabolic bone disease characterized by loss of bone mass and strength, leading to increased bone fragility and susceptibility,” the authors explained, citing figures indicating that in the United States osteoporosis and low bone mass impact 54 million adults over the age of 50 years. The disorder can progress to significant disability, such as hip and spine fractures, and financial burdens, such as lost wages and hospitalization. “The high incidence, rate of disability, and economic burden of osteoporosis have rendered it as a major global public health concern, drawing the attention of the World Health Organization,” the investigators continued.

Several drugs have proven effective in either preventing bone loss or promoting bone formation, but each comes with potential side effects, including injury to jaw and leg bones. “The current available first-line drugs for osteoporosis include bisphosphonates, hormone, and antibody-based drugs,” the authors further noted. “Although these drugs have specific clinical efficacy for osteoporosis, their side effects, long-term safety, and high cost cannot be ignored.”

Searching for alternative treatments, the researchers turned to female ginseng, which has long been used in traditional Chinese medicine (TCM) to treat osteoporosis. “Angelica sinensis, commonly known as Dong Quai in Europe and America and as Dang-gui in China, is a medicinal plant widely utilized for the prevention and treatment of osteoporosis,” the authors further wrote.

For their study, the team performed chemical extraction on female ginseng, and identified two new compounds, calling them falcarinphthalide A and B, that were structurally unlike anything previously discovered in the plant. “We report the discovery of a new category of phthalide from Angelica sinensis, namely falcarinphthalides A and B (1 and 2), which contains two fragments, (3R,8S)-falcarindiol (3) and (Z)-ligustilide (4),” they wrote. “This discovery reveals an entirely new subclass of TCM chemical constituent, and these two compounds represent a new category of phthalide in natural products.”

The investigators then determined potential biosynthetic precursors and metabolic pathways that the plants use to form these compounds. Then, with these mechanisms as starting points, the team devised lab synthesis methods and produced the compounds at quantities sufficient for biological testing. Inspired by the traditional efficacy of female ginseng, the team tested the compounds for their impact on the formation of cells called osteoclasts, which facilitate bone loss.

They observed that only falcarinphthalide A and its precursors showed osteoclast inhibitory activity and an anti-osteoporotic effect. “The bioassays revealed that falcarinphthalide A (1) and its biosynthetic precursors (3 and 4) displayed potent antiosteoclastogenic activities, whereas falcarinphthalide B (2) was inactive,” they wrote. Further analysis showed that falcarinphthalide A blocked key molecular pathways involved in osteoclast generation. “Significantly, falcarinphthalide A (1) exerts a multifaceted mechanism of action by inhibiting RANKL-induced osteoclastogenesis through the suppression of both the NF-κB and c-Fos pathways.”

The team suggests that falcarinphthalide A exhibits a distinctive structure and mechanism that sets it apart from existing drugs such as bisphosphonates and estrogens. “These distinguishing features hold great potential for overcoming the adverse side effects commonly associated with current medications,” they wrote. Acknowledging that more research will be needed to identify the compound’s target receptors, study its in vivo efficacy, and look at potential structural modifications, the team nevertheless concluded, “Overall, these ground-breaking findings not only extend the natural product skeleton categories but also highlight the potential of natural products as a source of novel molecular scaffold for treating osteoporosis.”

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