Psychoactive Plant Database - Neuroactive Phytochemical Collection

1. Bioorg Chem. 2024 Sep;150:107578. doi: 10.1016/j.bioorg.2024.107578. Epub 2024
 Jun 18.

(5S)-5-Benzylswainsonines as potent and selective inhibitors of Golgi 
α-mannosidase II: synthesis, enzyme evaluation and molecular modelling.

Kalník M(1), Gabko P(1), Kóňa J(2), Šesták S(1), Moncoľ J(3), Bella M(4).

Author information:
(1)Institute of Chemistry, Slovak Academy of Sciences, Dúbravská cesta 9, SK-845 
38 Bratislava, Slovakia.
(2)Institute of Chemistry, Slovak Academy of Sciences, Dúbravská cesta 9, SK-845 
38 Bratislava, Slovakia; Medical Vision, Civic Research Association, Záhradnícka 
4837/55, SK-82108 Bratislava, Slovakia.
(3)Department of Inorganic Chemistry, Faculty of Chemical and Food Technology, 
Radlinského 9, SK-812 37 Bratislava, Slovakia.
(4)Institute of Chemistry, Slovak Academy of Sciences, Dúbravská cesta 9, SK-845 
38 Bratislava, Slovakia. Electronic address: maros.bella@savba.sk.

Development of novel anti-cancer therapeutics based on Golgi α-mannosidase II 
(GMII) inhibition is considerably impeded by an undesired co-inhibition of 
lysosomal α-mannosidase leading to severe side-effects. In this contribution, we 
describe a fully stereoselective synthesis of 
(5S)-5-[4-(halo)benzyl]swainsonines as highly potent and selective inhibitors of 
GMII. The synthesis starts from a previously reported aldehyde readily available 
from l-ribose, and the key features include an intramolecular reductive 
amination with substrate-controlled stereoselectivity and a late-stage 
derivatisation of the benzyl group via ipso-substitution. These novel 
swainsonine analogues were found to be nanomolar inhibitors of the Golgi-type 
α-mannosidase AMAN-2 (Ki = 23-75 nM) with excellent selectivity (selectivity 
index = 205-870) over the lysosomal-type Jack bean α-mannosidase. Finally, 
molecular docking and pKa calculations were performed to provide more insight 
into the structure of the inhibitor:enzyme complexes, and a pair interaction 
energy analysis (FMO-PIEDA) was carried out to rationalise the observed potency 
and selectivity of the inhibitors.

Copyright © 2024 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.bioorg.2024.107578
PMID: 38955002 [Indexed for MEDLINE]

Conflict of interest statement: Declaration of competing interest The authors 
declare that they have no known competing financial interests or personal 
relationships that could have appeared to influence the work reported in this 
paper.


2. Org Biomol Chem. 2022 Nov 23;20(45):8932-8943. doi: 10.1039/d2ob01545e.

1,4-Dideoxy-1,4-imino-D- and L-lyxitol-based inhibitors bind to Golgi 
α-mannosidase II in different protonation forms.

Kóňa J(1)(2), Šesták S(1), Wilson IBH(3), Poláková M(1).

Author information:
(1)Institute of Chemistry, Center for Glycomics, Slovak Academy of Sciences, 
Dúbravska cesta 9, 845 38 Bratislava, Slovakia. chemkona@savba.sk.
(2)Medical Vision, Civic Research Association, Záhradnícka 4837/55, 82108 
Bratislava, Slovakia.
(3)Department of Chemistry, University of Natural Resources and Life Sciences, 
1190 Vienna, Austria.

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.

DOI: 10.1039/d2ob01545e
PMCID: PMC7614232
PMID: 36322142 [Indexed for MEDLINE]

Conflict of interest statement: Conflicts of interest: There are no conflicts to 
declare.


3. Folia Histochem Cytobiol. 2021;59(2):134-143. doi: 10.5603/FHC.a2021.0015.
Epub  2021 Jun 21.

Golgi a-mannosidase II mediates the formation of vascular smooth muscle foam 
cells under inflammatory stress.

Zha K(1), Ye Q(2).

Author information:
(1)Department of Cardiology, The Affiliated Hospital of Southwest Medical 
University, No. 25, Taiping street, Jiangyang District, 646000 Luzhou, China.
(2)Department of Cardiology, The Affiliated Hospital of Southwest Medical 
University, No. 25, Taiping street, Jiangyang District, 646000 Luzhou, China. 
art006023@yeah.net.

INTRODUCTION: Vascular smooth muscle cells (VSMCs)-based foam cell formation is 
a crucial factor in the atherosclerosis process. We aimed to explore the 
mechanism of Golgi a-mannosidase II (GMII) effects on the VSMCs-based foam cell 
formation.
MATERIAL AND METHODS: VSMCs were exposed to different concentrations of 
low-density lipoproteins (LDLs), lipopolysaccharide (LPS), and/or GMII inhibitor 
(swainsonine). The qRT-PCR and western blot were used for expression analysis. 
Oil Red O staining was used to verify changes of lipid droplets in VSMCs. The 
translocation of the SCAP from the endoplasmic reticulum (ER) to Golgi was 
detected by immunofluorescence (IF).
RESULTS: LPS disrupted the LDLs-mediated regulation of LDL receptor (LDLr) and 
increased intracellular cholesterol ester, which was inversely inhibited by 
swainsonine. The activity of a-mannosidase II and GMII expression were decreased 
by LDLs but increased by the addition of LPS. Conversely, LPS-induced 
enhancement was reversed by swainsonine. Additionally, swainsonine reversed the 
LPS-induced increase of intracellular lipid droplets in the presence of LDLs. 
Expression analysis demonstrated that LDLr, SCAP, and SREBP2 were up-regulated 
by LPS, but reversed by swainsonine in LDLs-treated cells. IF staining revealed 
that swainsonine inhibited the translocation of SCAP to Golgi under inflammatory 
stress.
CONCLUSIONS: Collectively, swainsonine restrained LDLr expression to suppress 
the formation of VSMCs-based foam cells by reducing SREBP2 and SCAP under 
inflammatory stress conditions, suggesting that GMII contributes to the 
formation of VSMCs-based foam cells under inflammatory stress.

DOI: 10.5603/FHC.a2021.0015
PMID: 34151999 [Indexed for MEDLINE]


4. J Am Chem Soc. 2020 Jul 29;142(30):13021-13029. doi: 10.1021/jacs.0c03880.
Epub  2020 Jul 16.

Manno-epi-cyclophellitols Enable Activity-Based Protein Profiling of Human 
α-Mannosidases and Discovery of New Golgi Mannosidase II Inhibitors.

Armstrong Z(1), Kuo CL(2), Lahav D(2), Liu B(2), Johnson R(1), Beenakker TJM(2), 
de Boer C(2), Wong CS(2), van Rijssel ER(2), Debets MF(2), Florea BI(2), Hissink 
C(2), Boot RG(2), Geurink PP(3), Ovaa H(3), van der Stelt M(2), van der Marel 
GM(2), Codée JDC(2), Aerts JMFG(2), Wu L(1), Overkleeft HS(2), Davies GJ(1).

Author information:
(1)Structural Biology Laboratory, Department of Chemistry, The University of 
York, York YO10 5DD, United Kingdom.
(2)Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC 
Leiden, The Netherlands.
(3)Oncode Institute & Department of Cell and Chemical Biology, Leiden University 
Medical Centre, Einthovenweg 20, 2333 ZC Leiden, The Netherlands.

Golgi mannosidase II (GMII) catalyzes the sequential hydrolysis of two mannosyl 
residues from GlcNAcMan5GlcNAc2 to produce GlcNAcMan3GlcNAc2, the precursor for 
all complex N-glycans, including the branched N-glycans associated with cancer. 
Inhibitors of GMII are potential cancer therapeutics, but their usefulness is 
limited by off-target effects, which produce α-mannosidosis-like symptoms. 
Despite many structural and mechanistic studies of GMII, we still lack a potent 
and selective inhibitor of this enzyme. Here, we synthesized 
manno-epi-cyclophellitol epoxide and aziridines and demonstrate their covalent 
modification and time-dependent inhibition of GMII. Application of fluorescent 
manno-epi-cyclophellitol aziridine derivatives enabled activity-based protein 
profiling of α-mannosidases from both human cell lysate and mouse tissue 
extracts. Synthesized probes also facilitated a fluorescence polarization-based 
screen for dGMII inhibitors. We identified seven previously unknown inhibitors 
of GMII from a library of over 350 iminosugars and investigated their binding 
modalities through X-ray crystallography. Our results reveal previously 
unobserved inhibitor binding modes and promising scaffolds for the generation of 
selective GMII inhibitors.

DOI: 10.1021/jacs.0c03880
PMID: 32605368 [Indexed for MEDLINE]


5. Oncol Res Treat. 2020;43(6):264-275. doi: 10.1159/000505931. Epub 2020 May 13.

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

Li C(1), Guo L(2), Chen F(1), Yu W(1), Rao T(1), Ruan Y(1).

Author information:
(1)Department of Urology, Renmin Hospital of Wuhan University, Wuhan, China.
(2)Department of Urology, Jingzhou First People's Hospital, Jingzhou, China, 
guolinjiejzrm@163.com.

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.

© 2020 S. Karger AG, Basel.

DOI: 10.1159/000505931
PMID: 32403105 [Indexed for MEDLINE]