Antiproliferative Phenothiazine Hybrids as Novel Apoptosis Inducers against MCF-7 Breast Cancer.

We designed a series of novel phenothiazine-1,2,3-triazole hybrids by the molecular hybridization strategy and evaluated their antiproliferative activity against three cancer cell lines (MDA-MB-231, MDA-MB-468 and MCF-7). For the structure-activity relationships, the importance of 1,2,3-triazole and substituents on phenyl ring was explored. Among these phenothiazine-1,2,3-triazole hybrids, compound 9f showed the most potent inhibitory effect against MCF-7 cells, with an IC50 value of 0.8 µM. Importantly, compound 9f could induce apoptosis against MCF-7 cells by regulating apoptosis-related proteins (Bcl-2, Bax, Bad, Parp, and DR5). These potent phenothiazine-1,2,3-triazole hybrids as novel apoptosis inducers might be used as antitumor agents in the future.

Diastereoselective construction of 4-indole substituted chromans bearing a ketal motif through a three-component Friedel-Crafts alkylation/ketalization sequence.

The first TfOH-catalyzed three-component Friedel-Crafts alkylation/ketalization sequence of indoles, alcohols and ortho-hydroxychalcones was developed to afford a wide range of 4-indole substituted chromans bearing a ketal motif in 77-99% yields. Notably, only a simple filtration was needed to purify them. By altering methanol to CHCl3, 2,4-bisindole substituted chroman with the same indole substituent at the C2 and C4 positions was afforded. Moreover, 2,4-bisindole substituted chromans with different indole substituents could be obtained by treatment of 4-indole monosubstituted chromans with another indole molecule.

Neuroprotective effects of Yiqihuoxue calm wind capsule on ischemic stroke in rats.

Stroke remains the third leading cause of death and of adult disability worldwide. Vascular occlusion, followed by ischemic cascade, leads to irreversible tissue injury. Recombinant tissue plasminogen activator is the only FDA approved drug for the current treatment of acute ischemic stroke. However, traditional Chinese medicine has a long history and rich clinical experience in the treatment and rehabilitation of ischemic stroke. Using a classical middle cerebral artery occlusion (MCAO) stroke model, we tested the effectiveness of Yiqihuoxue calm wind (YCW) capsule on neurological function, gross pathology and oxidative stress status in MCAO rats. YCW capsule (3.36 and 6.72 g·kg-1 of crude drug) could significantly lower Longa's score and superoxide dismutase (SOD) level, together with less necrotic cells and infarcted area. In addition to elevated MDA and downregulated iNOS expression, YCW capsule exhibited its neuroprotective effects via free radical scavenging and NO inhibition.

A copper-catalyzed tandem reaction for the construction of coumarin fused 9H-pyrrolo[1,2-a]indoles.

An efficient copper-catalyzed Friedel-Crafts alkylation/cyclization/isomerization sequence of 3-arylcarbonyl coumarins and 3-methyl indole was developed to afford a wide range of functionalized coumarin fused 9H-pyrrolo[1,2-a]indoles, which feature a 6-6-5-5-6 pentacyclic core, in 34-99% yields. Moreover, gram-scale experiment and chemical transformations were conducted to demonstrate the synthetic value of this protocol.

A Copper-Catalyzed Friedel-Crafts Alkylation/Cyclization Sequence: an Approach to Functionalized Pyrrolo[1,2-a]indole Spirooxindoles and 9H-Pyrrolo[1,2-a]indoles.

An efficient Cu(OTf)2-catalyzed Friedel-Crafts alkylation/cyclizaiton sequence of 3-substituted indoles with isatin-derived oxodienes was developed, and a series of structurally complex and diverse pyrrolo[1,2-a]indole spirooxindoles were first obtained in up to 99% yields. This protocol proved to be quite general and was also robust for the synthesis of 9H-pyrrolo[1,2-a]indoles.

The absorption enhancement of norisoboldine in the duodenum of adjuvant-induced arthritis rats involves the impairment of P-glycoprotein.

Lindera aggregata (Sims) Kosterm root has been used in traditional Chinese medicine for the treatment of rheumatism palsy, dyspepsia and frequent urination for a long time. Norisoboldine, the main active constituent of this herb drug, possesses outstanding anti-arthritis activity. However, the in vivo disposition of norisoboldine is known to a limited extent, especially under the pathological condition of rheumatoid arthritis (RA). The aim of this study is to investigate whether and how the absorption of norisoboldine is altered in adjuvant-induced arthritis (AIA) rats. Comparative studies of the intestinal absorption of norisoboldine in normal and AIA rats at different pathological stages of the arthritis were performed using in situ single-pass intestinal perfusion, and the effects of an inhibitor of efflux proteins were also investigated. Norisoboldine was shown to be a substrate of P-glycoprotein (P-gp), as P-gp inhibitor verapamil markedly increased the permeability coefficient (Peff ) of norisoboldine by 88% in the intestine of normal rats. Compared with normal rats, AIA rats displayed increased Peff values of norisoboldine by 84% and 86% on day 5 and day 10 after the appearance of the secondary response of arthritis, respectively. Verapamil could eliminate the difference of intestinal absorption of norisoboldine between normal and AIA rats. Further studies showed that impaired expression and activity of P-gp in AIA rats play a decisive role in the absorption enhancement of norisoboldine. Notably, the impairment of P-gp function positively correlated with the severity of arthritis. Copyright © 2016 John Wiley & Sons, Ltd.

Madecassoside ameliorates bleomycin-induced pulmonary fibrosis in mice by downregulating collagen deposition.

This study aimed to explore the protective effects of madecassoside (Mad), a triterpenoid saponin isolated from Centella asiatica herbs, on experimental pulmonary fibrosis (PF) and underlying mechanisms. PF model was established in mice by endotracheal instillation with bleomycin (5 mg/kg). Mice were orally administered with Mad (10, 20, 40 mg/kg) and prednisone (5 mg/kg) for 7 or 21 days. Mad (20, 40 mg/kg) significantly improved lung pathological changes and reduced collagen deposition. In the aspect of collagen synthesis, Mad (20, 40 mg/kg) reduced the expressions of α-smooth muscle actin and transforming growth factor-ß1 (TGF-ß1), and inhibited the phosphorylations of Smad2 and Smad3 in the lung tissues. However, in vitro, Mad showed little effect on TGF-ß1-induced phosphorylation of either Smad2 or Smad3 in primary mouse lung fibroblasts. Moreover, Mad (20, 40 mg/kg) attenuated oxidative damage and inflammation presented at the early stage of PF, evidenced by reduced total leukocytes in the bronchoalveolar lavage fluid, decreased myeloperoxidase activity and malondialdehyde level, and increased super-oxide dismutase activity and glutathione level in lung tissues. On the other hand, Mad (40 mg/kg) elevated the matrix metalloproteinase 1/tissue inhibitor of metalloproteinase 1 ratio in lung tissues of PF mice mainly by downregulating tissue inhibitor of metalloproteinase 1 expression. The present study demonstrated that Mad can ameliorate PF by preventing the deposition of extracellular matrix, which might be achieved mainly through attenuating inflammation and oxidative stress and consequent TGF-ß1 overexpression.