Caprospinol

In order to produce an effective and multi-targeted clinical drug that could prevent progressive neurodegeneration, a series of diosgenin carbamate derivatives were designed, synthesized and tested for their anti-inflammatory, antioxidant and anti-Aβ activities. The results demonstrated that compound M15 was the most promising derivative against inflammatory (NO inhibition 22.7 ± 2.2%,10 μM) and cellular damage induced by H₂O₂ (SH-SY5Y cell protection = 75.3 ± 3.4%, 10 μM) or Aβ (astrocytes protection = 70.2 ± 6.5%, 10 μM). Molecular docking studies revealed the strong binding affinity of M15 to the active site of nNOS, Aβ₄₂ and pro-inflammatory proteins. Western blot demonstrated that M15 decreased IL-1β, IL-6 and TNF-α level, which may contribute to its anti-inflammatory effects. In addition, M15 maintained mitochondrial function as well as cell viability through reducing H₂O₂-induced ROS production. The results indicated that oral administration of M15 attenuated memory deficits and played a neuroprotective effect on subcutaneous (s.c.) D-gal aging mice. In summary, M15 could be considered as a potential multifunctional neuroprotective agent due to the effects of anti-inflammatory, antioxidant and anti-Aβ activities.

A series of multifunctional 3-piperazinecarboxylate sarsasapogenin derivatives were designed and synthesized against Alzheimer's disease (AD). The protection against H₂O₂-triggered oxidative stress in PC12 cells, and inhibition on LPS-induced NO production in RAW264.7 cell lines in vitro by these derivatives were firstly evaluated. Most of the compounds showed better antioxidant and antiinflammatory activities compared with sarsasapogenin, especially AA34 and AA36. Structure-activity relationships revealed that benzyl group, electron-donating group and intramolecular hydrogen bond might be beneficial to enhancing their neuroprotective activities. Moreover, Aβ42 was the optimum predicted target based on the high 3D molecular similarity between compound AA36 and caprospinol. In the following experiments, AA36 significantly protected PC12 cells from Aβ-induced damage and improved learning and memory impairments in Aβ-injected mice. Thus AA36 is regarded as a potent anti-AD agent and N-substituted piperazinecarboxylate can be served as a promising structural unit for anti-AD drug design.