Synthesis and evaluation of 2-NMPA derivatives as potential agents for prevention of osteoporosis in vitro and in vivo.

Abnormal osteoclast differentiation causes various bone disorders such as osteoporosis. Targeting the formation and activation of osteoclasts has been recognized as an effective approach for preventing osteoporosis. Herein, we synthesized eleven 2-NMPA derivatives which are (2-(2-chlorophenoxy)-N-(4-alkoxy-2-morpholinophenyl) acetamides, and evaluated their suppression effects on osteoclastogenesis in vitro by using TRAP-staining assay. Among the synthesized eleven novel 2-NMPAs, 4-(2-(2-chlorophenoxy)acetamido)-3-morpholinophenyl trifluoromethanesulfonate (11b), 4-(2-(2-chlorophenoxy) acetamido)-3-morpholinophenyl-3-(N-(2-oxo-2-((2-(phenylthio) phenyl) amino) ethyl)methylsulfonamido)benzoate (11d), and 4-(2-(2-chlorophenoxy) acetamido)-3-morpholinophenyl 4-acetamidobenzenesulfonate (11h) displayed highly inhibitory bioactivity on the differentiation of primary osteoclasts. 11h was selected for further investigation of the inhibitory effects and potential mechanism involved in the suppression of osteoclastogenesis. In vitro analysis suggested that 11h inhibited osteoclastogenesis with an IC50 of 358.29 nM, decreased the formation of F-action belts and bone resorption, without interfering cell viability and osteoblast differentiation. Furthermore, the mRNA expressions of osteoclast-specific genes such as Acp5, Nfatc1, Dc-stamp, Atp6v0d2, Mmp9, and Ctsk significantly decreased following 11h treatment. RANKL-induced osteoclast-specific proteins analysis demonstrated that 11h suppressed osteoclast differentiation by downregulating of RANKL-mediated TRAF6 expression, followed by inactivation of PI3K/AKT and IκBα/NF-κB signaling pathways. Finally, 11h inhibited ovariectomy-induced bone loss in vivo. Therefore, the current work highlighted the therapeutic potential of 11h as an anti-osteoporosis lead compound.

Reaction of Amide and Sodium Azide for the Synthesis of Acyl Azide, Urea, and Iminophosphorane.

Amides reacted with NaN3 to give the acyl azides in DMF at 25 °C and produce the symmetrical ureas in THF/H2O at 80 °C via the sequential reaction of acyl substitution and Curtius rearrangement. All acyl azides were also obtained from the secondary amides via sequential reaction of p-toluenesulfonyl chloride and NaN3. In addition, keto-stabilized iminophosphoranes were prepared from a one-pot reaction of amides, NaN3, and phosphines.

Metal-free transamidation of benzoylpyrrolidin-2-one and amines under aqueous conditions.

N-Acyl lactam amides, such as benzoylpyrrolidin-2-one, benzoylpiperidin-2-one, and benzoylazepan-2-one reacted with amines in the presence of DTBP and TBAI to afford the transamidated products in good yields. The reactions were conducted under aqueous conditions and good functional group tolerance was achieved. Both aliphatic and aromatic primary amines displayed good activity under metal-free conditions. A radical reaction pathway is proposed.

Amide/Ester Cross-Coupling via C-N/C-H Bond Cleavage: Synthesis of ß-Ketoesters.

Activated primary, secondary, and tertiary amides were coupled with enolizable esters in the presence of LiHMDS to obtain good yields of ß-ketoesters at room temperature. Notably, this protocol provides an efficient, mild, and high chemoselectivity method to synthesis of ß-alkylketoesters using the cross-coupling between aliphatic amides and esters. Meanwhile, gram-scale secondary and primary amides reacted via in situ generated activated tertiary amides and exhibited good reactivity when coupled with esters.