Castanospermine

Castanospermine inhibits all forms of α- and β-glucosidases, especially glucosidase l (required for glucoprotein processing by transfer of mannose and glucose from asparagine-linked lipids). target：α- and β-glucosidases. IC 50: 1.2 uM [2] in vitro :Castanospermine, [(1 S,6S,7R,8R,8aR)-1 ,6,7,8-tetrahydroxyoctahydroindolizine] is a potent and specific inhibitor of mammalian and plant α-and β-D-glucosidases in vitro [1] in vivo: Experiments in vivo with castanospermine, an inhibitor of the glucosidases that convert protein N-linked high mannose carbohydrates to complex oligosaccharides, resulted in significant inhibition of tumor growth in nude mice.[3]

References:
[1]. Bryan G, Anthony C et al. The structural basis of the inhibition of human glycosidases by castanospermine analogues. Biochem. J. (1990) 269, 227-231. [2]. Eisaku Tsujii et al. Nectrisine Is a Potent Inhibitor of a-Glucosidases, Demonstrating Activities Similarly at Enzyme and Cellular Levels. Biochemical and Biophysical Research Communications 220, 459-466 (1996) [3]. Pili R et al. The alpha-glucosidase I inhibitor castanospermine alters endothelial cell glycosylation, preventsangiogenesis, and inhibits tumor growth. Cancer Res. 1995 Jul 1;55(13):2920-6.

Effect of brefeldin A and castanospermine on resistant cell lines as supplements in anticancer therapy.[Pubmed:26985570]

Oncol Rep. 2016 May;35(5):2896-906.

In the present study, we analyzed the influence of brefeldin A (BFA) and Castanospermine (CAS) on the activity, stability and localization of P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) in various resistant cell lines. The impact of BFA and CAS on cell viability was assessed using the MTT test. Western blotting (WB) was performed to assess the effect of the inhibitors on the expression of the investigated proteins. Immunofluorescence was employed to assess the effect of BFA and CAS on the cellular localization of the proteins. Flow cytometry was used to verify the functional role of inhibitors on drug uptake and efflux. The MTT test showed that BFA had a significant effect on cell viability in LoVo/Dx and W1PR cell lines. WB analysis demonstrated that BFA partially blocked Pgp N-glycosylation and induced BCRP degradation and CASP 3-dependent apoptosis in W1TR cells; however, the BFA activity was p53-independent. CAS had no effect on the stability of Pgp but increased the level of non-glycosylated BCRP. The expression of p53 protein decreased in all of the cells that were treated with CAS. Immunofluorescence revealed that BFA caused a more granular Pgp signal in W1PR and BCRP in A2780T1 cells. Furthermore, BFA caused morphological changes in LoVo/Dx and W1TR cell lines. CAS also induced a granular signal in all of the cell lines, except W1TR. The flow cytometry showed higher dye accumulation in sensitive cell lines. We observed an increase in the mean fluorescence intensity (MFI) of Rho123 in LoVo/Dx cells treated with BFA and CAS, but no differences were observed in W1PR. BFA had no effect on the MFI of W1TR, but CAS led to an increase in the level of intracellular H33342 in W1TR and A2780T1 cells. These results suggest that these compounds are likely to be useful as supplements in anticancer therapy.

Effects of Castanospermine on Inflammatory Response in a Rat Model of Experimental Severe Acute Pancreatitis.[Pubmed:27986123]

Arch Med Res. 2016 Aug;47(6):436-445.

BACKGROUND AND AIMS: Acute pancreatitis (AP) is an acute inflammatory disorder characterized by autodigestion of pancreatic tissue resulting in local pancreatic injury or systemic inflammatory response. Castanospermine (CAST) is an alkaloid from the Castanospermum australe, known as an anti-inflammatory agent and immunosuppressant in animal experiments. However, whether CAST can attenuate AP remains unclear. This study investigated the effects of CAST on sodium taurocholate (STC)-induced severe acute pancreatitis (SAP) in rats and the pertinent mechanism. METHODS: SAP was induced in rats by a retrograde infusion of 5% STC (1 mL/kg) into the biliopancreatic duct. CAST (10, 50, 100, 200 and 500 mg/kg body weight) was then administered via intraperitoneal injection. Measurement of serum amylase, lipase, alanine aminotransferase, aspartate aminotransferase, creatinine, blood urea nitrogen and pancreas pathological grading was used to estimate the severity of pancreatitis. Serum levels of interleukin (IL) -1beta, IL-6 and IL-10 were studied by enzyme-linked immunosorbent assay (ELISA). Nuclear factor (NF) -kappaB, tumor necrosis factor (TNF)-alpha, intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 expression in pancreas was evaluated by immunohistochemistry. RESULTS: Administration of CAST following SAP was found to ameliorate the acute pancreatic tissue injury and exhibit a more appropriately protective effect at the dose of 200 mg/kg body weight. In addition, it decreased the interleukin production in serum and NF-kappaB activation, TNF-alpha, ICAM-1 and VCAM-1 up-regulation in pancreatic tissue. CONCLUSIONS: Our study demonstrated that CAST exerts a protective effect on SAP in rats.

Synthesis of multibranched australine derivatives from reducing castanospermine analogues through the Amadori rearrangement of gem-diamine intermediates: selective inhibitors of beta-glucosidase.[Pubmed:25390345]

J Org Chem. 2014 Dec 5;79(23):11722-8.

A practical one-pot synthesis of bi- and triantennated australine analogues from a pivotal sp(2)-iminosugar-type reducing Castanospermine precursor is reported. The transformation involves a gem-diamine intermediate that undergoes the indolizidine --> pyrrolizidine Amadori-type rearrangement and proceeds under strict control of the generalized anomeric effect to afford a single diastereomer. The final compounds behave as selective competitive inhibitors of beta-glucosidase and are promising candidates as pharmacological chaperones for Gaucher disease.

Interaction between castanospermine an immunosuppressant and cyclosporin A in rat cardiac transplantation.[Pubmed:27011919]

World J Transplant. 2016 Mar 24;6(1):206-14.

AIM: To investigate the interaction between Castanospermine and cyclosporin A (CsA) and to provide an explanation for it. METHODS: The alkaloid Castanospermine was prepared from the seeds of Castanospermum austral consistently achieving purity. Rat heterotopic cardiac transplantation and mixed lymphocyte reactivity were done using genetically inbred strains of PVG (donor) and DA (recipient). For the mixed lymphocyte reaction stimulator cells were irradiated with 3000 rads using a linear accelerator. Cyclosporin A was administered by gavage and venous blood collected 2 h later (C2). The blood levels of CsA (Neoral) were measured by immunoassay which consisted of a homogeneous enzyme assay (EMIT) on Cobas Mira. Statistical analyses of interactions were done by an accelerated failure time model with Weibull distribution for allograft survival and logistic regression for the mixed lymphocyte reactivity. RESULTS: Castanospermine prolonged transplant survival times as a function of dose even at relatively low doses. Cyclosporin A also prolonged transplant survival times as a function of dose particularly at doses above 2 mg/kg. There were synergistic interactions between Castanospermine and CsA in the prolongation of cardiac allograft survival for dose ranges of CsA by Castanospermine of (0 to 2) mg/kg by (0 to 200) mg/kg (HR = 0.986; 95%CI: 0.981-0.992; P < 0.001) and (0 to 3) mg/kg by (0 to 100) mg/kg (HR = 0.986; 95%CI: 0.981-0.992; P < 0.001) respectively. The addition of Castanospermine did not significantly increase the levels of cyclosporin A on day 3 or day 6 for all doses of CsA. On the contrary, cessation of Castanospermine in the presence of CsA at 2 mg/kg significantly increased the CsA level (P = 0.002). Castanospermine inhibited mixed lymphocyte reactivity in a dose dependent manner but without synergistic interaction. CONCLUSION: There is synergistic interaction between Castanospermine and CsA in rat cardiac transplantation. Neither the mixed lymphocyte reaction nor the metabolism of CsA provides an explanation.

Interference with HIV-induced syncytium formation and viral infectivity by inhibitors of trimming glucosidase.[Pubmed:2959866]

Nature. 1987 Nov 5-11;330(6143):74-7.

Human immunodeficiency virus (HIV), the causative agent of AIDS, infects human lymphocytes and monocytes. An interaction between the viral envelope gp 120 and CD4 protein is required to initiate an infectious cycle. HIV infection in vitro induces syncytium formation by cell-to-cell fusion; this aspect of viral cytopathogenicity is even more dependent on gp120-CD4 interactions. That gp120 is extremely heavily glycosylated (31-36 N-linked glycans per molecule), suggests involvement of N-linked glycans in the gp120-CD4 interaction. We therefore investigated the effects of Castanospermine, 1-deoxynojirimycin (dNM) and 1-deoxymannojirimycin (dMM), three trimming glycosidase inhibitors which perturb N-linked glycan structure, on induction of the formation of syncytium between HIV-infected and CD4-expressing cells. The glucosidase inhibitors Castanospermine and dNM, but not the mannosidase inhibitor dMM, inhibited syncytium formation and interfered with infectivity. The potential of glucosidase inhibitors as anti-HIV therapeutic agents deserves further investigation, especially because dNM and related compounds show little toxicity in vitro and in vivo.

Inhibition of human immunodeficiency virus syncytium formation and virus replication by castanospermine.[Pubmed:2825177]

Proc Natl Acad Sci U S A. 1987 Nov;84(22):8120-4.

Castanospermine (1,6,7,8-tetrahydroxyoctahydroindolizine) is a plant alkaloid that modifies glycosylation by inhibiting alpha-glucosidase I. Castanospermine is shown to inhibit syncytium formation induced by the envelope glycoprotein of the human immunodeficiency virus and to inhibit viral replication. The decrease in syncytium formation in the presence of Castanospermine can be attributed to inhibition of processing of the envelope precursor protein gp160, with resultant decreased cell surface expression of the mature envelope glycoprotein gp120. In addition, Castanospermine may cause defects in steps involved in membrane fusion after binding of CD4 antigen. The antiviral effects of Castanospermine may be due to modifications of the envelope glycoprotein that affect the ability of the virus to enter cells after attachment to the CD4 cell receptor.

Studies on the mechanism of castanospermine inhibition of alpha- and beta-glucosidases.[Pubmed:6424575]

Arch Biochem Biophys. 1984 May 1;230(2):668-75.

Castanospermine (1,6,7,8-tetrahydroxyoctahydroindolizine) is an indolizidine alkaloid that was isolated from the Australian plant, Castanospermum australe. This alkaloid was found to be a potent inhibitor of lysosomal alpha- and beta-glucosidases. In this report, the mechanism of inhibition of amyloglucosidase (an exo-1,4-alpha-glucosidase) and almond emulsin beta-glucosidase was examined. Castanospermine proved to be a competitive inhibitor of amyloglucosidase at both pH 4.5 and 6.0 when assayed with the p-nitrophenyl-alpha-D-glucoside. It was also a competitive inhibitor of almond emulsin beta-glucosidase at pH 6.5, but in this case previous studies had shown that inhibition was of the mixed type at pH 4.5 to 5.0. Th pH of the incubation mixture had a marked effect on the inhibition. Thus, in all cases, Castanospermine was a much better inhibitor at pH 6.0 to 6.5 than it was at lower pH values. The pK for Castanospermine was found to be 6.09, indicating that the alkaloid was probably more active in the unprotonated form. This was also suggested by the fact that the N-oxide of Castanospermine, while still a competitive inhibitor, was 50 to 100 times less active than was Castanospermine, and its activity was not markedly altered by pH. These results probably explain why Castanospermine is a good inhibitor of the glycoprotein processing enzyme, glucosidase I, since this is a neutral enzyme.

Castanospermine inhibits all forms of α- and β-glucosidases, especially glucosidase l (required for glucoprotein processing by transfer of mannose and glucose from asparagine-linked lipids).

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