Aloperine

The herbs of Sophora alopecuroides L.

Discovery and evolution of aloperine derivatives as novel anti-filovirus agents through targeting entry stage.[Pubmed:29494844]

Eur J Med Chem. 2018 Apr 10;149:45-55.

Preventing filoviruses in the entry stage is an attractive antiviral strategy. Taking Aloperine, a Chinese natural herb with an endocyclic skeleton, as the lead, 23 new Aloperine derivatives were synthesized and evaluated for their anti-filovirus activities including ebola virus (EBOV) and marburg virus (MARV) using pseudotyped virus model. Structure-activity relationship (SAR) analysis indicated that the introduction of a 12N-dichlorobenzyl group was beneficial for the potency. Compound 2e exhibited the most potent anti-EBOV and anti-MARV effects both in vitro and in vivo. It also displayed a good pharmacokinetic and safety profile in vivo, indicating an ideal druglike feature. The primary mechanism study showed that 2e could block a late stage of viral entry, mainly through inhibiting cysteine cathepsin B activity of host components. We consider compound 2e to be a promising broad-spectrum anti-filovirus agent with the advantages of a unique chemical scaffold and a specific biological mechanism.

Structure Optimization of Aloperine Derivatives as HIV-1 Entry Inhibitors.[Pubmed:29152054]

ACS Med Chem Lett. 2017 Oct 9;8(11):1199-1203.

As a step toward developing novel anti-HIV agents, we have identified a class of quinolizidines, including Aloperine, that inhibit HIV at 1-5 muM by blocking viral entry. In this study, we have optimized the structure of Aloperine and derived compounds with markedly improved activity. Our structural optimization has yielded an Aloperine derivative 19 with approximately a 15-fold increase in anti-HIV-1 activity. Our mechanism of action study reveals that compound 19 does not inhibit binding of HIV-1 to receptors but arrests the virus from fusion with the membrane. Binding of the compound to HIV-1gp120 might be responsible for its anti-HIV-1 entry activity.

In Vitro Antitumor Activity of Aloperine on Human Thyroid Cancer Cells through Caspase-Dependent Apoptosis.[Pubmed:29361731]

Int J Mol Sci. 2018 Jan 21;19(1). pii: ijms19010312.

The global incidence of thyroid cancer, one of the most common endocrine malignancies, is especially high among women. Although most patients with thyroid cancers exhibit a good prognosis with standard treatment, there are no effective therapies for patients with anaplastic thyroid cancers or cancers that have reached an advanced or recurrent level. Therefore, it is important to develop highly effective compounds for treating such patients. Aloperine, a natural compound isolated from Sophora alopecuroides, has been reported to possess antioxidant, anti-inflammatory, anti-neuronal injury, anti-renal injury, antitumor, anti-allergic, and antiviral properties. In this study, we show that Aloperine can inhibit cell growth in human anaplastic thyroid cancers and multidrug-resistant papillary thyroid cancers. Moreover, it could suppress in vitro tumorigenesis and promote cellular apoptosis. Further analysis demonstrated the involvement of caspase-dependent apoptosis, including intrinsic and/or extrinsic pathways, in Aloperine-induced cellular apoptosis. However, cell cycle regulation was not detected with Aloperine treatment. This study suggests the potential therapeutic use of Aloperine in human anaplastic thyroid cancers and multidrug-resistant papillary thyroid cancers.

Aloperine Protects Mice against Bleomycin-induced Pulmonary Fibrosis by Attenuating Fibroblast Proliferation and Differentiation.[Pubmed:29674691]

Sci Rep. 2018 Apr 19;8(1):6265.

Aloperine is a quinolizidine alkaloid extracted from Sophora alopecuroides. It has been proven to alleviate oxidative stress and effectively promote tumor cell apoptosis in mice. Herein, we investigated whether Aloperine could also mediate its protective effects on bleomycin (BLM)-induced pulmonary fibrosis. Pathological staining, western blot, RT-PCR and flow cytometry were used to evaluate the impact of Aloperine on the development of pulmonary fibrosis. The effect of Aloperine on fibroblast proliferation, differentiation and related signaling pathways were next investigated to demonstrate the underlying mechanisms. In the present report, we showed that Aloperine provided protection for mice against BLM-induced pulmonary fibrosis as manifested by the attenuated lung injury and reduced fibrosis along with alleviated fibroblast proliferation and differentiation. Additionally, we provided in vitro evidence revealing that Aloperine inhibited cellular proliferation in PDGF-BB-stimulated mouse lung fibroblasts by repressed PI3K/AKT/mTOR signaling and fibroblast to myofibroblast differentiation by repressed TGF-beta/Smad signaling. Overall, our data showed that Aloperine could protect the mice against BLM-induced pulmonary fibrosis by attenuated fibroblast proliferation and differentiation, which indicated that Aloperine may be therapeutically beneficial for IPF patients.

Aloperine Protects Mice against DSS-Induced Colitis by PP2A-Mediated PI3K/Akt/mTOR Signaling Suppression.[Pubmed:29056830]

Mediators Inflamm. 2017;2017:5706152.

Colitis is a major form of inflammatory bowel disease which involved mucosal immune dysfunction. Aloperine is an alkaloid isolated from the shrub Sophora alopecuroides L. and has been recognized as an effective treatment for inflammatory and allergic diseases. The present study aimed to examine the molecular mechanisms underlying Aloperine-mediated colitis protection. We found that Aloperine treatment improved colitis induced by dextran sodium sulfate (DSS) based on body weight, disease activity index, colonic length, and spleen index. Aloperine also effectively attenuated DSS-induced intestinal inflammation based on the pathological score and myeloperoxidase expression and activity in colon tissues. In addition, Aloperine regulated T-cell proportions and promoted Foxp3 expression in the spleens and mesenteric lymph nodes of DSS-induced colitis mice and in the spleens of the Foxp3(GFP) mice. Aloperine inhibited Jurkat and mouse naive T-cell apoptosis. Furthermore, Aloperine inhibited PI3K/Akt/mTOR signaling and upregulated PP2A expression in the DSS-induced colitis mice and in Jurkat cells, but LB-100 (PP2A inhibitor) resulted in an elevated Akt activity in Jurkat cells, activated T-cells, and human splenic mononuclear cells. Aloperine inhibited T-cell and lymphocyte proliferation, but LB-100 reverse these effects. In conclusion, Aloperine regulates inflammatory responses in colitis by inhibiting the PI3K/Akt/mTOR signaling in a PP2A-dependent manner.

Discovery and evolution of aloperine derivatives as a new family of HCV inhibitors with novel mechanism.[Pubmed:29232582]

Eur J Med Chem. 2018 Jan 1;143:1053-1065.

Aloperine (1), a Chinese natural product with a unique endocyclic scaffold, was first identified to be a potent hepatitis C virus (HCV) inhibitor in our laboratory. Thirty-four new Aloperine derivatives were designed, synthesized and evaluated for their anti-HCV activities taking 1 as the lead. Among them, compound 7f exhibited the potential potency with EC50 values in a micromolar range against both wild-type and direct-acting antiviral agents (DAAs)-resistant variants, and synergistically inhibited HCV replication with approved DAAs. Furthermore, it also owned a good oral pharmacokinetic and safety profile, suggesting a highly druglike nature. The primary mechanism showed that 7f might target host components, distinctly different from the DAAs currently used in clinic. Therefore, we consider Aloperine derivatives to be a novel class of anti-HCV agents, and compound 7f has been selected as a promising antiviral candidate for further investigation.

Aloperine is an alkaloid in sophora plants such as Sophora alopecuroides L, which has shown anti-cancer, anti-inflammatory and anti-virus properties. Aloperine is widely used to treat patients with allergic contact dermatitis eczema and other skin inflammation in China. Aloperine induces apoptosis and autophagy in HL-60 cells.

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