Panaxadiol carbamate derivatives: Synthesis and biological evaluation as potential multifunctional anti-Alzheimer agents.

It is reported that panaxadiol has neuroprotective effects. Previous studies have found that compound with carbamate structure introduced at the 3-OH position of 20 (R) -panaxadiol showed the most effective neuroprotective activity with an EC50 of 13.17 µM. Therefore, we designed and synthesized a series of ginseng diol carbamate derivatives with ginseng diol as the lead compound, and tested their anti-AD activity. It was found that the protective effect of compound Q4 on adrenal pheochromocytoma was 80.6 ±â€¯10.85 % (15 µM), and the EC50 was 4.32 µM. According to the ELISA results, Q4 reduced the expression of Aß25-35 by decreasing ß-secretase production. Molecular docking studies revealed that the binding affinity of Q4 to ß-secretase was -49.67 kcal/mol, indicating a strong binding affinity of Q4 to ß-secretase. Western blotting showed that compound Q4 decreased IL-1ß levels, which may contribute to its anti-inflammatory effect. Furthermore, compound Q4 exhibits anti-AD activities by reducing abnormal phosphorylation of tau protein and activation of the mitogen activated protein kinase pathway. The learning and memory deficits in mice treated with Q4in vivo were significantly alleviated. Therefore, Q4 may be a promising multifunctional drug for the treatment of AD, providing a new way for anti-AD drugs.

Design, synthesis fusidic acid derivatives alleviate acute lung injury via inhibiting MAPK/NF-κB/NLRP3 pathway.

Acute lung injury (ALI) refers to a series of lung lesions resulting from multiple lung injuries, even leading to morbidity and death, abundant previous reports have showed that anti-inflammatory as a key to treatment of ALI. Fusidic acid (FA) as an antibiotic has significant anti-bacterial activity and anti-inflammatory effects. In this study, we designed and synthesized 34 FA derivatives to identify new anti-inflammatory drugs. The anti-inflammatory activities of the derivatives were screened using lipopolysaccharide (LPS)-induced RAW264.7 cells to evaluate the anti-inflammatory activity of the compounds, we measured nitric oxide (NO) and interleukin-6 (IL-6). Most of compounds showed inhibitory effects on inflammatory NO and IL-6 in LPS-induced RAW264.7 cells. Based on the screening results, compound a1 showed the strongest anti-inflammatory activity. Compared with FA, the inhibition rate NO and IL-6 of compound a1 increased 3.08 and 2.09 times at 10 µM, respectively. We further measured a1 inhibited inflammatory factor NO (IC50 = 3.26 ± 0.42 µM), IL-6 (IC50 = 1.85 ± 0.21 µM) and TNF-α (IC50 = 3.88 ± 0.55 µM). We also demonstrated that a1 markedly inhibits the expression of certain immune-related cytotoxic factors, including cyclooxygenase-2 (COX-2) and inducible nitric-oxide synthase (iNOS). In vivo results indicate that a1 can reduce lung inflammation and NO, IL-6, TNF-α, COX-2 and iNOS in LPS-induced ALI mice. On the one hand, we demonstrated a1 inhibits the mitogen-activated protein kinase (MAPK) signaling pathway by down-regulating the phosphorylation of p38 MAPK, c-Jun N-terminal kinase (c-JNK) and extracellular signal-regulated kinase (ERK). Moreover, a1 also suppressing the phosphorylation of inhibitory NF-κB inhibitor α (IκBα) inhibits the activation of the nuclear factor-κB (NF-κB) signaling pathway. On the other hand, we demonstrated a1 also role in anti-inflammatory by inhibits nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome and further inhibits Caspase-1 and inflammatory factor interleukin-1ß (IL-1ß). In conclusion, our study demonstrates that a1 has an anti-inflammatory effect and alleviates ALI by regulating inflammatory mediators and suppressing the MAPK, NF-κB and NLRP3 inflammasome signaling pathways.

In vitro and in vivo biological evaluation of newly synthesized multi-target 20(R)-panaxadiol derivatives for treating Alzheimer's disease.

An extensive study was performed to discover a series of novel 20(R)-panaxadiol derivatives with various substituents at the 3-OH position as nontoxic, brain-permeable, multi-target leads for treating Alzheimer's disease. In vitro analysis revealed that a compound bearing benzyl-substituted carbamate, which we denoted compound 14a, exhibited the most potent neuroprotective activity, with an EC50 of 13.17 µM. The neuroprotective effect of compound 14a was slightly more potent than that of donepezil and much more potent than that of 20(R)-panaxadiol. Compound 14a at 7.5-120 µM exhibited low toxicity in various cell lines. In addition, compound 14a exhibited a wide range of biological activities, including inhibiting apoptosis; inducing tau hyperphosphorylation; affecting beta-amyloid (Aß), ß-secretase, reactive oxygen species, tumor necrosis factor-α, cyclooxygenase-2, and interleukin-1ß production; and promoting Aß25-35 disaggregation. The effective permeability of compound 14a across the blood-brain barrier was 26.13 × 10-6 cm/s, indicating that it can provide adequate exposure in the central nervous system. Further, compound 14a improved learning, memory, and novel object recognition in mice, and in vivo toxicity experiments confirmed a good therapeutic safety range. Thus, compound 14a is a promising multifunctional lead for treating Alzheimer's disease and offers new avenues for natural product-derived anti-Alzheimer's disease drugs.

Potential α-glucosidase inhibitor from Hylotelephium erythrostictum.

In light of the adequate sources for Hylotelephium erythrostictum, its active components have aroused research interest. 2-(3',4'-dihydroxyphenyl)-2,3-dihydro-4,6-dihydroxy-2-(methoxy)- 3-benzofuranone(1), apigenin(2), diosmetin(3), kaempferol(4), kaempferide(5), rhamnocitrin(6), quercetin(7), and gallic acid(8) were isolated from H. erythrostictum. Rarely occurring naturally, 1 is 2-methoxybenzofuranone type compound against α-glucosidase and exhibits a potential inhibitory effect on α-glucosidase(IC50 = 1.8 µM), with a Ki value of 709 nM. In silico molecular docking was performed for the investigation of the inhibition mechanism. H. erythrostictum is a potential source of antidiabetic agent. This information is useful in finding more potent antidiabetic candidates from medicinal plants for the clinical development of therapeutics.