Ring Opening of N-Acyl Lactams Using Nickel-Catalyzed Transamidation.

We successfully developed a nickel-catalyzed transamidation method for the ring opening of N-acyl lactams. The method involves a reaction between N-benzoylpyrrolidin-2-one derivatives and aniline derivatives, with Ni(PPh3)2Cl2 serving as the catalyst, 2,2'-bipyridine as the ligand, and manganese as the reducing agent. This reaction led to the formation of ring-opening-amidated products in good yields. Notably, the method exhibited excellent efficiency for producing the corresponding ring-opening transamidation products for various ring sizes, including four-, five-, six-, seven-, and eight-membered ring lactams.

Discovery of PMSA Derivative 11 as a Novel Lead Compound for Therapeutic Treatment of Osteoporosis In Vitro and In Vivo.

To discover a potent candidate for suppressing mature osteoclasts formation in vitro using a TRAP staining assay. A series of PMSA derivatives were synthesized and evaluated for their bioactivity in our current study. Our results showed that PMSA derivative 11 exhibited the most promising bioactivity, with an IC50 value of 322.9 nM, which was ∼15-fold better than PMSA-3-Ac in suppressing osteoclastogenesis in vitro. Additionally, 11 blocked the formation of F-action belts and bone resorption in a concentration-dependent manner. Mechanistically, 11 decreased the expression of genes required for osteoclastogenesis by blocking NFATc1 translocation from the cytoplasm to nucleus. Furthermore, 11 demonstrated a therapeutic inhibitory effect on the differentiation of human iPSC-derived primary osteoclasts. In vivo investigation showed that 11 prevented excessive osteoclastogenesis-mediated bone loss in ovariectomized osteoporosis mimic mice. These findings highlighted the therapeutic potential of 11 as a lead compound for anti-osteoporosis by targeting NFATc1 translocation.