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N-Benzyl Substitution of Polyhydroxypyrrolidines: The Way to Selective Inhibitors of Golgi ?-Mannosidase?II.

ABSTRACT: Inhibition of the biosynthesis of complex N-glycans in the Golgi apparatus influences progress of tumor growth and metastasis. Golgi ?-mannosidase?II (GMII) has become a therapeutic target for drugs with anticancer activities. One critical task for successful application of GMII drugs in medical treatments is to decrease their unwanted co-inhibition of lysosomal ?-mannosidase (LMan), a weakness of all known potent GMII inhibitors. A series of novel N-substituted polyhydroxypyrrolidines was synthesized and tested with modeled GH38 ?-mannosidases from Drosophila melanogaster (GMIIb and LManII). The most potent structures inhibited GMIIb (Ki =50-76??m, as determined by enzyme assays) with a significant selectivity index of IC50 (LManII)/IC50 (GMIIb) >100. These compounds also showed inhibitory activities in in?vitro assays with cancer cell lines (leukemia, IC50 =92-200??m) and low cytotoxic activities in normal fibroblast cell lines (IC50 >200??m). In addition, they did not show any significant inhibitory activity toward GH47 Aspergillus saitoi?1,2-mannosidase. An appropriate stereo configuration of hydroxymethyl and benzyl functional groups on the pyrrolidine ring of the inhibitor may lead to an inhibitor with the required selectivity for the active site of a target ?-mannosidase.

SUBMITTER: Sestak S

PROVIDER: S-EPMC6176901 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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N-Benzyl Substitution of Polyhydroxypyrrolidines: The Way to Selective Inhibitors of Golgi α-Mannosidase II.

Šesták Sergej S Bella Maroš M Klunda Tomáš T Gurská Soňa S Džubák Petr P Wöls Florian F Wilson Iain B H IBH Sladek Vladimir V Hajdúch Marián M Poláková Monika M Kóňa Juraj J

ChemMedChem 20180206 4

Inhibition of the biosynthesis of complex N-glycans in the Golgi apparatus influences progress of tumor growth and metastasis. Golgi α-mannosidase II (GMII) has become a therapeutic target for drugs with anticancer activities. One critical task for successful application of GMII drugs in medical treatments is to decrease their unwanted co-inhibition of lysosomal α-mannosidase (LMan), a weakness of all known potent GMII inhibitors. A series of novel N-substituted polyhydroxypyrrolidines was synth ...[more]

PMID: 29323461

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Project description:The development of effective inhibitors of Golgi α-mannosidase II (GMII, E.C.3.2.1.114) with minimal off-target effects on phylogenetically-related lysosomal α-mannosidase (LMan, E.C.3.2.1.24) is a complex task due to the complicated structural and chemical properties of their active sites. The pKa values (and also protonation forms in some cases) of several ionizable amino acids, such as Asp, Glu, His or Arg of enzymes, can be changed upon the binding of the inhibitor. Moreover, GMII and LMan work under different pH conditions. The pKa calculations on large enzyme-inhibitor complexes and FMO-PIEDA energy decomposition analysis were performed on the structures of selected inhibitors obtained from docking and hybrid QM/MM calculations. Based on the calculations, the roles of the amino group incorporated in the ring of the imino-D-lyxitol inhibitors and some ionizable amino acids of Golgi-type (Asp270-Asp340-Asp341 of Drosophila melanogaster α-mannosidase dGMII) and lysosomal-type enzymes (His209-Asp267-Asp268 of Canavalia ensiformis α-mannosidase, JBMan) were explained in connection with the observed inhibitory properties. The pyrrolidine ring of the imino-D-lyxitols prefers at the active site of dGMII the neutral form while in JBMan the protonated form, whereas that of imino-L-lyxitols prefers the protonation form in both enzymes. The calculations indicate that the binding mechanism of inhibitors to the active-site of α-mannosidases is dependent on the inhibitor structure and could be used to design new selective inhibitors of GMII. A series of novel synthetic N-substituted imino-D-lyxitols were evaluated with four enzymes from the glycoside hydrolase GH38 family (two of Golgi-type, Drosophila melanogaster GMIIb and Caenorhabditis elegans AMAN-2, and two of lysosomal-type, Drosophila melanogaster LManII and Canavalia ensiformis JBMan, enzymes). The most potent structures [N-9-amidinononyl and N-2-(1-naphthyl)ethyl derivatives] inhibited GMIIb (Ki = 40 nM) and AMAN-2 (Ki = 150 nM) with a weak selectivity index (SI) toward Golgi-type enzymes of IC50(LManII)/IC50(GMIIb) = 35 or IC50(JBMan)/IC50(AMAN-2) = 86. On the other hand, weaker micromolar inhibitors, such as N-2-naphthylmethyl or 4-iodobenzyl derivatives [IC50(GMIIb) = 2.4 μM and IC50 (AMAN-2) = 7.6 μM], showed a significant SI in the range from 111 to 812.

Project description:?-1,2 mannosidases, key enzymes in N-glycosylation, are required for the formation of mature glycoproteins in eukaryotes. Aberrant regulation of ?-1,2 mannosidases can result in cancer, although the underlying mechanisms are unclear. Here, we report the distinct roles of ?-1,2 mannosidase subtypes (MAN1A, MAN1B, ERMAN1, MAN1C) in the formation of hepatocellular carcinoma (HCC). Clinicopathological analyses revealed that the clinical stage, tumor size, ?-fetoprotein level, and invasion status were positively correlated with the expression levels of MAN1A1, MAN1B1, and MAN1A2. In contrast, the expression of MAN1C1 was decreased as early as stage I of HCC. Survival analyses showed that high MAN1A1, MAN1A2, and MAN1B1 expression levels combined with low MAN1C1 expression levels were significantly correlated with shorter overall survival rates. Functionally, the overexpression of MAN1A1 promoted proliferation, migration, and transformation as well as in vivo migration in zebrafish. Conversely, overexpression of MAN1C1 reduced the migration ability both in vitro and in vivo, decreased the colony formation ability, and shortened the S phase of the cell cycle. Furthermore, the expression of genes involved in cell cycle/proliferation and migration was increased in MAN1A1-overexpressing cells but decreased in MAN1C1-overexpressing cells. MAN1A1 activated the expression of key regulators of the unfolded protein response (UPR), while treatment with endoplasmic reticulum stress inhibitors blocked the expression of MAN1A1-activated genes. Using the MAN1A1 liver-specific overexpression zebrafish model, we observed steatosis and inflammation at earlier stages and HCC formation at a later stage accompanied by the increased expression of the UPR modulator binding immunoglobulin protein (BiP). These data suggest that the up-regulation of MAN1A1 activates the UPR and might initiate metastasis. Conclusion: MAN1A1 represents a novel oncogene while MAN1C1 plays a role in tumor suppression in hepatocarcinogenesis. (Hepatology Communications 2017;1:230-247).

Dataset Information

N-Benzyl Substitution of Polyhydroxypyrrolidines: The Way to Selective Inhibitors of Golgi ?-Mannosidase?II.

Publications

N-Benzyl Substitution of Polyhydroxypyrrolidines: The Way to Selective Inhibitors of Golgi α-Mannosidase II.

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