Design, synthesis, and biological evaluation of diosgenin-indole derivatives as dual-functional agents for the treatment of Alzheimer's disease.

The complex pathogenesis of Alzheimer's disease (AD) has become a major obstacle in its treatment. An effective approach is to develop multifunctional agents that simultaneously target multiple pathological processes. Here, a series of diosgenin-indole compounds were designed, synthesized and evaluated for their neuroprotective effects against H2O2 (hydrogen peroxide), 6-OHDA (6-hydroxydopamine) and Aß (beta amyloid) damages. Preliminary structure-activities relationship revealed that the introduction of indole fragment and electron-donating group at C-5 on ring indole could be beneficial for neuroprotective activities. Results indicated that compound 5b was the most promising candidate against cellular damage induced by H2O2 (52.9 ± 1.9%), 6-OHDA (38.4 ± 2.4%) and Aß1-42 (54.4 ± 2.7%). Molecular docking study suggested the affinity for 5b bound to Aß1-42 was -40.59 kcal/mol, which revealed the strong binding affinity of 5b to Aß1-42. The predicted values of brain/blood partition coefficient (-0.733) and polar surface area (85.118 Å2) indicated the favorable abilities of BBB permeation and absorption of 5b. In addition, 5b significantly decreased ROS (reactive oxygen species) production induced by H2O2. In the following in vivo experiment, 5b obviously attenuated memory and learning impairments of Aß-injected mice. In summary, compound 5b could be considered as a promising dual-functional neuroprotective agent against AD.

Design, synthesis, molecular modeling, and biological evaluation of acrylamide derivatives as potent inhibitors of human dihydroorotate dehydrogenase for the treatment of rheumatoid arthritis.

Human dihydroorotate dehydrogenase (DHODH) is a viable target for the development of therapeutics to treat cancer and immunological diseases, such as rheumatoid arthritis (RA), psoriasis and multiple sclerosis (MS). Herein, a series of acrylamide-based novel DHODH inhibitors as potential RA treatment agents were designed and synthesized. 2-Acrylamidobenzoic acid analog 11 was identified as the lead compound for structure-activity relationship (SAR) studies. The replacement of the phenyl group with naphthyl moieties improved inhibitory activity significantly to double-digit nanomolar range. Further structure optimization revealed that an acrylamide with small hydrophobic groups (Me, Cl or Br) at the 2-position was preferred. Moreover, adding a fluoro atom at the 5-position of the benzoic acid enhanced the potency. The optimization efforts led to potent compounds 42 and 53‒55 with IC50 values of 41, 44, 32, and 42 nmol/L, respectively. The most potent compound 54 also displayed favorable pharmacokinetic (PK) profiles and encouraging in vivo anti-arthritic effects in a dose-dependent manner.

The immunosuppressant fingolimod ameliorates experimental autoimmune myasthenia gravis by regulating T-cell balance and cytokine secretion.

Myasthenia gravis is an autoimmune disease that affects skeletal muscle strength by impeding communication within the neuromuscular junction (NMJ). Research has shown that sphingosine-1-phosphate (S1P)/S1P receptor signaling may be involved in the process of neuromuscular diseases. Fingolimod is structurally similar to S1P, whose immunosuppressive effect has been recognized in many immune diseases. However, the mechanism underlying fingolimod's action on experimental autoimmune myasthenia gravis is still far from clear. The aim of this study was to investigate the efficacy and possible mechanism of fingolimod on experimental autoimmune myasthenia gravis. Our results showed that pretreatment with fingolimod improved experimental autoimmune myasthenia gravis symptoms in a dose-dependent manner, including decreased anti-acetylcholine receptor-2α autoantibody titer, reduced compound muscle action potential decrement, and increased acetylcholine receptor content. Further investigation indicated that fingolimod inhibited lymphocyte proliferation responses and also regulated the balance of Th1/Th2 cells and Treg/Th17 cells. Moreover, fingolimod suppressed the secretion of pro-inflammatory or inflammatory cytokines IL-17A, IL-6, and INF-γ, but did not noticeably alter the secretion of immunosuppressive cytokines TGF-ß1 and IL-4. In conclusion, our results suggest that fingolimod has a preventive effect on experimental autoimmune myasthenia gravis by interfering with lymphocyte function.

Talin2 regulates invasion of human breast cancer MDA-MB-231 cells via alteration of the tumor microenvironment.

The talin proteins are a key component of the extracellular matrix-integrin-cytoskeleton system, and our previous study suggested that talin2 contributes to the tumor invasion and metastasis processes regulated by the tumor microenvironment. In the present study, the specific effects of talin2 on the invasive ability of breast cancer cells, as well as the underlying mechanism, were investigated by creating two MDA-MB-231 cell lines with stable talin2 knockdown by specific RNA interference. Initially, it was confirmed that the expression levels of talin2 in human breast cancer tissues were upregulated compared with in normal adjacent tissues. Subsequently, invasion and wound healing assays revealed that depletion of talin2 in MDA-MB-231 cells decreased their migratory and invasive abilities. Western blot analysis demonstrated that knockdown of talin2 in MDA-MB-231 cells caused marked downregulation of the tumor microenvironment markers hypoxia-inducible factor 1α, phosphorylated ribosomal protein S6 kinase, phosphorylated protein kinase B and phosphorylated mechanistic target of rapamycin. Furthermore, knockdown of talin2 decreased the basal contents of glucose and lactic acid in the breast cancer cell line. In conclusion, the findings of the present study demonstrated that talin2 knockdown may inhibit the invasive ability of human breast cancer MDA-MB-23l cells via alterations in the tumor microenvironment.

Design, synthesis and structure-activity relationship study of aminopyridine derivatives as novel inhibitors of Janus kinase 2.

Janus Kinase 2 (JAK2) is a kind of intracellular non-receptor protein tyrosine kinase and has been certified as an important target for the treatment of myeloproliferative neoplasms and rheumatoid arthritis. However, the low selectivity and potential safety issues restrict the clinical applications of JAK2 inhibitors. Here we found that crizotinib showed good inhibitory activity against JAK2 by enzymatic assays (IC50 = 27 nM). Then we carried out structure-based drug design and synthesized a series of compounds with an aminopyridine scaffold. Finally, compound 12k and 12l were identified as the promising inhibitors of JAK2, which exhibited high inhibitory activity (IC50 = 6 nM and 3 nM, respectively) and selectivity for JAK2 over JAK1 and JAK3, and showed potent antiproliferative activities toward HEL human erythroleukemia cells. Moreover, 12k suppressed symptoms of the collagen-induced arthritis (CIA) model in rats.

Talin2 regulates breast cancer cell migration and invasion by apoptosis.

Talin is a key component molecule of the extracellular matrix-integrin-cytoskeleton. It serves an important role in the activation of integrin, which, in turn, is known to mediate physiological and pathological processes, including cell adhesion, growth, tumorigenesis, and metastasis. In vertebrates, there are two Talin genes, Talin1 and Talin2. Talin1 is known to regulate focal adhesion dynamics, cell migration and cell invasion; however, the precise role of Talin2 in cancer remains unclear. In the present study, the functional role of Talin2 was examined in the MDA-MB-231 breast cancer cell line. Talin2 knockdown significantly inhibited growth, migratory capacity and invasiveness of MDA-MB-231 cells, and promoted apoptosis. The expression levels of Talin2 in breast cancer cells and in the peritumoral normal breast tissues were also determined by immunohistochemistry. Talin2 was identified to be overexpressed in breast cancer tissues compared with that in the peritumoral breast tissues. In addition, the knockdown of Talin2 by specific RNA interference markedly inhibited cell growth, and caused the downregulation of the apoptotic markers, cleaved Caspase-3 and phosphorylation of poly ADP-ribose polymerase. These findings demonstrate that Talin2 expression is upregulated in human breast cancer and that downregulation of Talin2 may serve as a useful therapeutic target in patients with breast cancer.