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Synthesis and evaluation of andrographolide derivatives as potent anti-osteoporosis agents in vitro and in vivo. 2021

Songxuan Zhang, and Yuting Zhang, and Yuying Fang, and Hao Chen, and Mengjiao Hao, and Qingyun Tan, and Chen Hu, and Huihao Zhou, and Jun Xu, and Qiong Gu
Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China.

In this work, we found that 14-deoxy-11,12-didehydroandrographolide (2), a derivative of andrographolide (AP, 1), had greatly reduced cytotoxicity compared with AP and exhibited moderate anti-osteoclastogenesis activity. Thirty compounds were synthesized by introducing anti-osteoporosis chemotypes at C-19 of 2. Six of them exhibited stronger inhibition of osteoclastogenesis than AP. Of note, compound 12g displayed the most potent activity with IC50 value of 0.35 μM. The expression levels of osteoclast-specific genes such as TRAcP, CTSK, NFATc1, and MMP-9 were also decreased by 12g treatment. Furthermore, Western blot and immunofluorescence analyses demonstrated that compound 12g inhibited osteoclast differentiation through downregulation of RANKL-induced NF-κB signaling pathway. In an ovariectomized (OVX) female mice model, compound 12g significantly ameliorated bone loss. Therefore, compound 12g exhibited promising in vivo efficacy and low toxicity, indicating its therapeutic potential for the treatment of osteoporosis.

UI MeSH Term Description Entries
D008810 Mice, Inbred C57BL One of the first INBRED MOUSE STRAINS to be sequenced. This strain is commonly used as genetic background for transgenic mouse models. Refractory to many tumors, this strain is also preferred model for studying role of genetic variations in development of diseases. Mice, C57BL,Mouse, C57BL,Mouse, Inbred C57BL,C57BL Mice,C57BL Mice, Inbred,C57BL Mouse,C57BL Mouse, Inbred,Inbred C57BL Mice,Inbred C57BL Mouse
D010010 Osteoclasts A large multinuclear cell associated with the BONE RESORPTION. An odontoclast, also called cementoclast, is cytomorphologically the same as an osteoclast and is involved in CEMENTUM resorption. Odontoclasts,Cementoclast,Cementoclasts,Odontoclast,Osteoclast
D010012 Osteogenesis The process of bone formation. Histogenesis of bone including ossification. Bone Formation,Ossification, Physiologic,Endochondral Ossification,Ossification,Ossification, Physiological,Osteoclastogenesis,Physiologic Ossification,Endochondral Ossifications,Ossification, Endochondral,Ossifications,Ossifications, Endochondral,Osteoclastogeneses,Physiological Ossification
D010024 Osteoporosis Reduction of bone mass without alteration in the composition of bone, leading to fractures. Primary osteoporosis can be of two major types: postmenopausal osteoporosis (OSTEOPOROSIS, POSTMENOPAUSAL) and age-related or senile osteoporosis. Age-Related Osteoporosis,Bone Loss, Age-Related,Osteoporosis, Age-Related,Osteoporosis, Post-Traumatic,Osteoporosis, Senile,Senile Osteoporosis,Osteoporosis, Involutional,Age Related Osteoporosis,Age-Related Bone Loss,Age-Related Bone Losses,Age-Related Osteoporoses,Bone Loss, Age Related,Bone Losses, Age-Related,Osteoporoses,Osteoporoses, Age-Related,Osteoporoses, Senile,Osteoporosis, Age Related,Osteoporosis, Post Traumatic,Post-Traumatic Osteoporoses,Post-Traumatic Osteoporosis,Senile Osteoporoses
D001862 Bone Resorption Bone loss due to osteoclastic activity. Bone Loss, Osteoclastic,Osteoclastic Bone Loss,Bone Losses, Osteoclastic,Bone Resorptions,Loss, Osteoclastic Bone,Losses, Osteoclastic Bone,Osteoclastic Bone Losses,Resorption, Bone,Resorptions, Bone
D002454 Cell Differentiation Progressive restriction of the developmental potential and increasing specialization of function that leads to the formation of specialized cells, tissues, and organs. Differentiation, Cell,Cell Differentiations,Differentiations, Cell
D004195 Disease Models, Animal Naturally-occurring or experimentally-induced animal diseases with pathological processes analogous to human diseases. Animal Disease Model,Animal Disease Models,Disease Model, Animal
D004224 Diterpenes Twenty-carbon compounds derived from MEVALONIC ACID or deoxyxylulose phosphate. Diterpene,Diterpenes, Cembrane,Diterpenes, Labdane,Diterpenoid,Labdane Diterpene,Norditerpene,Norditerpenes,Norditerpenoid,Cembranes,Diterpenoids,Labdanes,Norditerpenoids,Cembrane Diterpenes,Diterpene, Labdane,Labdane Diterpenes
D004305 Dose-Response Relationship, Drug The relationship between the dose of an administered drug and the response of the organism to the drug. Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D005260 Female Females

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