title: Synthesis and biological evaluation of rhein amides as inhibitors of osteoclast differentiation and bone resorption.
abstract: Approaches of targeting excessive activation and differentiation of osteoclasts were considered as an effective treatment option for osteoporosis or osteopenia. In the present work, a series of rhein derivatives were synthesized and employed for their cytotoxicity screening against bone marrow-derived macrophages cells (BMMs) and their inhibition effects on osteoclasts activation and differentiation in vitro using an MTT assay and a TRAP activity assay respectively. Two rhein derivatives d6 and d11 inhibited BMMs activation and differentiation with 98% and 85% inhibitory activity respectively, without showing any cytotoxicity on BMMs. Subsequently, the most potent compound d6 was further validated for its inhibitory effects on the formation of TRAP-positive multinucleated cells and bone resorption as evaluated by TRAP staining and bone resorption assay. The regulation by d6 of osteoclast marker genes assay revealed that treatment of BMMs with M-CSF and RANKL resulted in the stimulation of mRNA expressions of NFATc1, c-fos, TRAP, MMP-9 and cathepsin K which were highly related with osteoclast activation and differentiation, while d6 decreased mRNA expressions of these genes. It was indicated that d6 might regulate osteoclasts activity through RANKL/RANK/NFATc1 pathway. Thus our current work is expected to provide a highly promising approach for the development of a new type of anti-osteoporosis agent.
authors.affiliation: Shanghai Key Laboratory for Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Shanghai Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 20025, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Drug Research, Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
authors.forename: Xueyu
authors.initials: X
authors.lastname: Qi
authors.affiliation: Shanghai Key Laboratory for Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Shanghai Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 20025, China.
authors.forename: Yufei
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Shanghai Key Laboratory for Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Shanghai Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 20025, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Qi
authors.affiliation: Shanghai Key Laboratory for Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Shanghai Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 20025, China.
authors.forename: Niandong
authors.initials: N
authors.lastname: Qian
authors.affiliation: Shanghai Key Laboratory for Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Shanghai Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 20025, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Guo
authors.affiliation: Shanghai Key Laboratory for Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Shanghai Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 20025, China.
authors.forename: Changwei
authors.initials: C
authors.lastname: Li
authors.affiliation: Shanghai Key Laboratory for Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Shanghai Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 20025, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Wang
authors.affiliation: Shanghai Key Laboratory for Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Shanghai Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 20025, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Huang
authors.affiliation: Shanghai Key Laboratory for Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Shanghai Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 20025, China.
authors.forename: Hanbing
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Shanghai Key Laboratory for Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Shanghai Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 20025, China.
authors.forename: Min
authors.initials: M
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Drug Research, Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China. Electronic address: chyang@simm.ac.cn.
authors.forename: Chunhao
authors.initials: C
authors.lastname: Yang
authors.affiliation: Shanghai Key Laboratory for Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Shanghai Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 20025, China.
authors.forename: Lianfu
authors.initials: L
authors.lastname: Deng
mesh_terms: D041721:3T3-L1 Cells; D000577:Amides / Q000737:chemistry*; D000818:Animals; D000880:Anthraquinones / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology; D001862:Bone Resorption / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects*; D060326:Chemistry Techniques, Synthetic; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D050778:NFATC Transcription Factors / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects*; D053245:RANK Ligand / Q000494:pharmacology
chemical_list: D000577:Amides; D000880:Anthraquinones; D015415:Biomarkers; D050778:NFATC Transcription Factors; D053245:RANK Ligand; C020491:rhein
keywords: Bone resorption; Inhibitor; Osteoclast; RANKL/RANK/NFATc1 pathway; Rhein derivatives