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Synthesis of novel 5,6-dehydrokawain analogs as osteogenic inducers and their action mechanisms.

Abstract：

:An imbalance between bone resorption by osteoclasts and bone formation by osteoblasts can cause bone loss and bone-related disease. In a previous search for natural products that increase osteogenic activity, we found that 5,6-dehydrokawain (1) from Alpinia zerumbet promotes osteoblastogenesis. In this study, we synthesized and evaluated series of 5,6-dehydrokawain analogs. Our structure-activity relationships revealed that alkylation of para or meta position of aromatic ring of 1 promote osteogenic activity. Among the potential analogs we synthesized, (E)-6-(4-Ethylstyryl)-4-methoxy-2H-pyran-2-one (14) and (E)-6-(4-Butylstyryl)-4-methoxy-2H-pyran-2-one (21) both significantly up-regulated Runx2 and Osterix mRNA expression at 10µM. These osteogenic activities could be mediated by bone morphogenetic protein (BMP) and activation of p38 MAPK signaling pathways. Compounds 14 and 21 also inhibited RANKL-induced osteoclast differentiation of RAW264 cells. These results indicated that novel 5,6-dehydrokawain analogs not only increase osteogenic activity but also inhibit osteoclast differentiation, and could be potential lead compounds for the development of anti-osteoporosis agents.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Kumagai M,Nishikawa K,Mishima T,Yoshida I,Ide M,Koizumi K,Nakamura M,Morimoto Y

doi

10.1016/j.bmcl.2017.04.016

subject

Has Abstract

pub_date

2017-06-01 00:00:00

pages

2401-2406

issue

11

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(17)30380-3

journal_volume

27

pub_type

杂志文章

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