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Synthesis and biological evaluation of C-28-modified pyrazole-fused betulinic acid derivatives as potent antiosteoporosis agents.

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Title: Synthesis and biological evaluation of C-28-modified pyrazole-fused betulinic acid derivatives as potent antiosteoporosis agents.
Authors: Zhao T; School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China., Li S; School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China., Qiu G; School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China., Xiao E; School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China., Chen Z; School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China., Liang Q; School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China., Yang F; Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, China., Tang J; Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, China., Wang B; School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China., Li NG; School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China., Qiu WW; Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, China., Chang L; School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China. Electronic address: changliang@njucm.edu.cn.
Source: European journal of medicinal chemistry [Eur J Med Chem] 2025 Dec 15; Vol. 300, pp. 118169. Date of Electronic Publication: 2025 Sep 15.
Publication Type: Journal Article
Language: English
Journal Info: Publisher: Editions Scientifiques Elsevier Country of Publication: France NLM ID: 0420510 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1768-3254 (Electronic) Linking ISSN: 02235234 NLM ISO Abbreviation: Eur J Med Chem Subsets: MEDLINE
Imprint Name(s): Publication: Paris : Editions Scientifiques Elsevier
Original Publication: Paris, S.E.C.T. [etc.]
MeSH Terms: Osteoporosis*/drug therapy , Osteoporosis*/metabolism , Pyrazoles*/chemistry , Pyrazoles*/pharmacology , Triterpenes*/chemistry , Triterpenes*/pharmacology , Triterpenes*/chemical synthesis, Animals ; Pentacyclic Triterpenes/pharmacology ; Pentacyclic Triterpenes/chemistry ; Mice ; Betulinic Acid ; RAW 264.7 Cells ; Structure-Activity Relationship ; Osteoclasts/drug effects ; Osteoclasts/cytology ; Molecular Structure ; Dose-Response Relationship, Drug ; Osteogenesis/drug effects ; Female ; RANK Ligand ; Cell Differentiation/drug effects
Abstract: Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Liang Chang reports financial support was provided by Nanjing University of Chinese Medicine. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
A series of novel C-28 amino acid/amide conjugates and oligo(ethylene glycol)-modified C-2, C-3 pyrazole-fused betulinic acid derivatives were designed, synthesized, and evaluated for their inhibitory effects on RANKL-induced osteoclastogenesis. Among these, compound 18, bearing a C-28 oligo(ethylene glycol) amino amide ester linkage, exhibited the most potent inhibitory activity. It demonstrated an IC 50 of 7.96 nM against RANKL-induced osteoclastogenesis in RAW264.7 cells, representing a 10-fold increase in potency compared to the XJ13 (IC 50  = 0.08 μM) and achieved >50 % inhibition at 0.01 μM. Importantly, the inhibitory effects of these compounds on RANKL-induced osteoclast differentiation were not attributed to cytotoxicity, as evidenced by the minimal cytotoxicity of compound 18 at 10 μM. Mechanistic studies showed that compound 18 could dose-dependently suppress the expression of osteoclast marker genes (TRAP, CTSK) and proteins (c-Fos, MMP-9). Furthermore, in an ovariectomized (OVX) mouse model, compound 18 (10 and 20 mg/kg, intraperitoneally, i.p.) dose - dependently prevented bone loss by improving key micro-CT parameters and decreasing serum bone resorption markers (CTx). Overall, compound 18 emerged as a highly promising candidate for the treatment of RANKL-driven osteoporosis.
(Copyright © 2025 Elsevier Masson SAS. All rights reserved.)
Substance Nomenclature: 0 (Pentacyclic Triterpenes)
4G6A18707N (Betulinic Acid)
0 (Pyrazoles)
0 (Triterpenes)
0 (RANK Ligand)
3QD5KJZ7ZJ (pyrazole)
Entry Date(s): Date Created: 20250921 Date Completed: 20251011 Latest Revision: 20251011
Update Code: 20251012
DOI: 10.1016/j.ejmech.2025.118169
PMID: 40975963
Database: MEDLINE
Description
Abstract:Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Liang Chang reports financial support was provided by Nanjing University of Chinese Medicine. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br />A series of novel C-28 amino acid/amide conjugates and oligo(ethylene glycol)-modified C-2, C-3 pyrazole-fused betulinic acid derivatives were designed, synthesized, and evaluated for their inhibitory effects on RANKL-induced osteoclastogenesis. Among these, compound 18, bearing a C-28 oligo(ethylene glycol) amino amide ester linkage, exhibited the most potent inhibitory activity. It demonstrated an IC <subscript>50</subscript> of 7.96 nM against RANKL-induced osteoclastogenesis in RAW264.7 cells, representing a 10-fold increase in potency compared to the XJ13 (IC <subscript>50</subscript>  = 0.08 μM) and achieved &gt;50 % inhibition at 0.01 μM. Importantly, the inhibitory effects of these compounds on RANKL-induced osteoclast differentiation were not attributed to cytotoxicity, as evidenced by the minimal cytotoxicity of compound 18 at 10 μM. Mechanistic studies showed that compound 18 could dose-dependently suppress the expression of osteoclast marker genes (TRAP, CTSK) and proteins (c-Fos, MMP-9). Furthermore, in an ovariectomized (OVX) mouse model, compound 18 (10 and 20 mg/kg, intraperitoneally, i.p.) dose - dependently prevented bone loss by improving key micro-CT parameters and decreasing serum bone resorption markers (CTx). Overall, compound 18 emerged as a highly promising candidate for the treatment of RANKL-driven osteoporosis.<br /> (Copyright © 2025 Elsevier Masson SAS. All rights reserved.)
ISSN:1768-3254
DOI:10.1016/j.ejmech.2025.118169