Synthesis of substituted triazolyl curcumin mimics that inhibit RANKL-induced osteoclastogenesis

doi:10.1016/j.bmcl.2011.04.106

Bioorganic & Medicinal Chemistry Letters

Volume 21, Issue 12, 15 June 2011, Pages 3573-3577

https://doi.org/10.1016/j.bmcl.2011.04.106 Get rights and content

Abstract

Some promising new antiresorptive agents of potential utility for treating osteoporosis were uncovered in a curcumin mimics library possessing a substituted triazole moiety, which is synthesized by the Cu(I)-catalyzed Huisgen 1,3-cycloaddition reaction between two azido intermediates (9 and 10) and various alkynes (a–k). A tartarate-resistant acid phosphatase (TRAP) activity assay was carried out with RANKL-induced osteoclastogenesis of mouse monocyte/macrophage RAW264.7 cells; the results indicated that the curcumin mimics derived from intermediate 10 exhibited stronger inhibitory activity than 9. In particular, curcumin mimics 12h, 13c, and 13e strongly inhibited osteoclast differentiation.

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Synthesis of alkylsulfonyl and substituted benzenesulfonyl curcumin mimics as dual antagonist of L-type Ca<sup>2+</sup> channel and endothelin A/B<inf>2</inf> receptor
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Newly synthesized compounds created for a more detailed structure–activity relationship included ethyl (11b), trifluoromethyl (11e), p-toluyl (11g), p-chlorophenyl (11h), and 2′,6′-dichlorophenyl (11s) sulfonylamide curcumin mimic derivatives. The double bond in the feruloyl structure was confirmed to the trans configuration because of a large coupling constant (approximately J = 15 Hz) between its two protons.11 The structure of synthetic intermediate (10) and all sulfonylamide linked curcumin compounds (11a–11u) were identified by 1H and 13C NMR spectroscopy, and GC/MS analysis and were evaluated for vasodilation effect on rabbit basilar artery contracted with depolarization (50 mM K+) and ET-1.
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Similar results were found in osteoblast-like cells in culture obtained from SCI rats (Jiang et al., 2007). It was reported that curcumin and its mimics inhibited osteoclastogenesis by decreasing RANKL expression in bone marrow stromal cells and RAW264.7 cells (Park et al., 2011; Oh et al., 2008). In this work, curcumin treatment reduced RANKL expression and enhanced OPG expression in distal femurs of SCI rats.
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^†: These authors are equally contributed on this work.

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Synthesis of substituted triazolyl curcumin mimics that inhibit RANKL-induced osteoclastogenesis

Abstract

Graphical abstract

Joint Bone Spine

Bone Miner.

Bone

Bone

Bioorg. Med. Chem. Lett.

Biochem. Biophys. Res. Commun.

Bioorg. Med. Chem.

Bioorg. Med. Chem. Lett.

Biochem. Pharmacol.

Phytomedicine

Curr. Opin. Rheumatol.

Curr. Osteoporos. Rep.

J. Clin. Invest.