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| Main Authors: | , , , , , , |
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| Format: | Artículo científico |
| Language: | en |
| Published: |
Bioorganic chemistry
2026
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| Subjects: | |
| Online Access: | https://pubmed.ncbi.nlm.nih.gov/41865565/ |
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Table of Contents:
- Discovery of novel ten-membered lactones as osteoblastogenesis agents targeting Wnt/β-catenin signaling pathway. Zhai, Yi-Jie Zhang, Jing-Wen Yang, Jia-Xuan Wang, Tingting Gao, Jin-Ming Wang, Weiyi Han, Wen-Bo Lactones Animals Wnt Signaling Pathway Zebrafish Mice Structure-Activity Relationship Molecular Structure Osteogenesis Osteoblasts Drug Discovery Dose-Response Relationship, Drug Cell Differentiation beta Catenin Hypocreales Twelve novel ten-membered lactones crispatumines A - L (1-12), along with two known analogs decarestrictine I (13) and botryolide B (14), were isolated from the moss-associated fungus Trichocladium crispatum SQ11-20. Their structures were elucidated by means of spectroscopic data, J-based configuration analysis, C NMR calculations with DP4+ probability analysis, modified Mosher's method, calculated ECD, and single crystal X-ray diffraction. Crispatumines A and B (1 and 2) represent the first examples of oxygen-bridged homodimers of two monomeric ten-membered lactone units, crispatumines C - F (3-6) are the distinctive ten-membered lactone monomers decorated with various appendages, crispatumines G - K (7-11) are the rare pyran-containing ten-membered lactone dimers featuring a 9/5/6/10/3 and 9/5/6/6 ring systems, and crispatumine L (12) is an oxidative cleavage product from the monomeric ten-membered lactone. Moreover, these compounds were tested for their osteoblastogenic activity in vitro and in vivo. Alkaline phosphatase (ALP) and Alizarin red S (ARS) staining experiments showed that compounds 1, 3-9, 11, 13 and 14 significantly enhanced the osteoblastogenesis in dexamethasone-induced MC3T3-E1 cells. Importantly, compounds 4 and 8 were demonstrated to be potent osteoblastogenesis agents by activating the Wnt/β-catenin signaling pathway. In addition, compound 8 could alleviate dexamethasone-induced osteoporotic zebrafish in vivo. These findings not only expanded the chemical diversity of the ten-membered lactones, but also shed new light on the development of lead compounds for the treatment of osteoporosis.