<i>N</i>‐Benzyl Substitution of Polyhydroxypyrrolidines: The Way to Selective Inhibitors of Golgi α‐Mannosidase II

Šesták, Sergej; Bella, Maroš; Klunda, Tomáš; Gurská, Soňa; Džubák, Petr; Wöls, Florian; Wilson, Iain B. H.; Sládek, Vladimı́r; Hajdúch, Marián; Poláková, Monika; Kóňa, Juraj

doi:10.1002/cmdc.201700607

Cited by 20 publications

(29 citation statements)

References 92 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Little is known about the role of GM II in cancer development. Currently, increased expression of GM II has been found in bladder cancer and leukemia [23, 24]. Moreover, head and neck cancer showed a high expression level of GM II [25], and this was associated with a poor clinical prognosis in patients [15].…”

Section: Introductionmentioning

confidence: 99%

Golgi Alpha-Mannosidase II as a Novel Biomarker Predicts Prognosis in Clear Cell Renal Cell Carcinoma

Guo

Chen

et al. 2020

Oncol Res Treat

View full text Add to dashboard Cite

Objective: Golgi alpha-mannosidase II (GM II) is one of the crucial enzymes in the process of N-glycan processing. The aim of our study was to examine the clinical significance of GM II in patients with clear cell renal cell carcinoma (ccRCC). Methods: Quantitative reverse transcription polymerase chain reaction analysis and immunohistochemical staining were used to analyze GM II expression in patients with ccRCC. The clinical data of 62 patients with ccRCC were collected to analyze the clinical significance of GM II. The clinical significance among GM II expression, clinicopathological staging, and histological grade of ccRCC was explored. Survival analyses were performed to identify the relevance between the expression of GM II and the overall survival of patients with ccRCC. A uni-/multivariate Cox regression model was used to detect risk factors affecting the prognosis of patients with ccRCC. Subsequently, the proliferation and migration of ccRCC cells were detected after transfecting with GM II-short hairpin RNA (shRNA). Results: The results of these comparisons suggested that GM II expression of ccRCC tissues was dramatically higher than that of para-carcinoma tissues (p < 0.05). GM II expression in the high-differentiation group was lower than that in the median- and low-differentiation groups (p < 0.05). GM II expression in stage I and II tissues was lower than that in stage III and IV tissues (p < 0.05). The expression levels of GM II in the group without lymph node metastasis were lower than those in the group with lymph node metastasis (p < 0.05). Survival analysis indicated that patients with ccRCC with high GM II expression generally had decreased overall survival. Uni-/multivariate Cox model analyses further suggested an association between GM II expression and prognosis of patients with breast cancer. High GM II expression is a potential and independent prognostic biomarker in ccRCC. The inhibition of GM II by transfecting with GM II-shRNA could reduce the proliferation and migration of ccRCC. Conclusion: GM II expression in human ccRCC tissues was upregulated compared with that found in normal human renal tissue, and GM II may promote the progression and migration of ccRCC. Furthermore, the GM II gene may be used as a promising tumor marker for the diagnosis and prognosis of ccRCC.

show abstract

Section: Introductionmentioning

confidence: 99%

Golgi Alpha-Mannosidase II as a Novel Biomarker Predicts Prognosis in Clear Cell Renal Cell Carcinoma

Guo

Chen

et al. 2020

Oncol Res Treat

View full text Add to dashboard Cite

show abstract

“…The benzyl moiety was chosen to be (4-halo)benzyl as the pyrrolidines 1 bearing these structural fragments were the most effective and selective against GMIIb [30]. The synthesis of modified pyrrolidine derivatives 2 – 5 (Fig.…”

Section: Introductionmentioning

confidence: 99%

“…1 ) were found to be more potent and selective inhibitors of the target enzyme. Moreover, proposed N -benzyl substituent at the pyrrolidine core was also confirmed to be essential for selectivity [ 30 ].…”

Section: Introductionmentioning

confidence: 99%

“…In this study, we explored structure–activity relationships (SAR) of pyrrolidine derivatives 1 with different modifications at position 5. The benzyl moiety was chosen to be (4-halo)benzyl as the pyrrolidines 1 bearing these structural fragments were the most effective and selective against GMIIb [ 30 ]. The synthesis of modified pyrrolidine derivatives 2 – 5 ( Fig.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Synthesis of 1,4-imino-L-lyxitols modified at C-5 and their evaluation as inhibitors of GH38 α-mannosidases

Bella¹,

Šesták²,

Moncóľ³

et al. 2018

Beilstein J. Org. Chem.

Self Cite

View full text Add to dashboard Cite

A synthetic approach to 1,4-imino-L-lyxitols with various modifications at the C-5 position is reported. These imino-L-lyxitol cores were used for the preparation of a series of N-(4-halobenzyl)polyhydroxypyrrolidines. An impact of the C-5 modification on the inhibition and selectivity against GH38 α-mannosidases from Drosophila melanogaster, the Golgi (GMIIb) and lysosomal (LManII) mannosidases and commercial jack bean α-mannosidase from Canavalia ensiformis was evaluated. The modification at C-5 affected their inhibitory activity against the target GMIIb enzyme. In contrast, no inhibition effect of the pyrrolidines against LManII was observed. The modification of the imino-L-lyxitol core is therefore a suitable motif for the design of inhibitors with desired selectivity against the target GMIIb enzyme.

show abstract

“…7) GM inhibitors additionally interrupt cell-cell communication, making them promising anti-cancer drug candidates. [8][9][10] A representative pathway of N-glycan processing and an outline of cell-cell communication are presented in Fig. 1.…”

mentioning

confidence: 99%

Identification of Small-Molecule Inhibitors of Human Golgi Mannosidase <i>via</i> a Drug Repositioning Screen

Koyama

Hakamata

Hirano

et al. 2018

CHEMICAL & PHARMACEUTICAL BULLETIN

View full text Add to dashboard Cite

Three Golgi mannosidases (GMs), namely Golgi α-mannosidases IA, IB, and IC, remove mannose residues from N-glycans and regulate the quality control and transportation of nascent proteins. GM inhibitors regulate several biological events such as cell-cell communication, differentiation, and apoptosis in cancer cells. As a result, GM inhibitor-based therapies have gained significant attention for cancer treatment. However, to date, no GM inhibitor has been approved and none is in clinical development for anti-cancer treatment. Meanwhile, drug repositioning plays an important role in identifying potential inhibitors that vary in molecular structure and properties to bypass much of the early cost and time. We performed a drug repositioning screen of a compound library that included approved drugs. The estrogen receptor antagonists tamoxifen and raloxifene inhibited human GMs at the cellular level. Sulindac, a nonsteroidal anti-inflammatory drug, also inhibited GMs. Our results demonstrated the efficacy of this screening strategy and revealed lead compounds for anti-cancer drug development.

show abstract

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

Cited by 20 publications

References 92 publications

Golgi Alpha-Mannosidase II as a Novel Biomarker Predicts Prognosis in Clear Cell Renal Cell Carcinoma

Golgi Alpha-Mannosidase II as a Novel Biomarker Predicts Prognosis in Clear Cell Renal Cell Carcinoma

Synthesis of 1,4-imino-L-lyxitols modified at C-5 and their evaluation as inhibitors of GH38 α-mannosidases

Identification of Small-Molecule Inhibitors of Human Golgi Mannosidase <i>via</i> a Drug Repositioning Screen

Contact Info

Product

Resources

About