Studies on α-glucosidase, aldose reductase and glycation inhibitory properties of sesquiterpenes and flavonoids of Zingiber zerumbet Smith

Article abstract of DOI:10.1080/14786419.2014.956741

Eight known phytochemicals, four sesquiterpenes and four flavonoids of Zingiber zerumbet were screened against α-glucosidase enzyme, aldose reductase enzyme and antiglycation property under in vitro conditions. The results established kaempferol-3-O-methylether as a potent inhibitor of α-glucosidase enzyme with an IC₅₀ value of 7.88 M. In aldose reductase enzyme inhibition assay, all the compounds except zerumbone epoxide showed good to excellent inhibition properties. Among these, the flavonoid compounds were found to be potent aldose reductase inhibitors compared with the four sesquiterpenes. In addition, compounds such as α-humulene, kaempferol, kaempferol-3-O-methylether and 3″,4″-O-diacetylafzelin displayed potent antiglycation properties. From overall results, we found that kaempferol and kaempferol-3-O-methylether are potent inhibitors of α-glucosidase enzyme, aldose reductase enzyme and glycation reaction, the three main targets of drugs for the treatment of diabetes and its complications.

Full text of DOI:10.1080/14786419.2014.956741

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Studies on α-glucosidase, aldose
reductase and glycation inhibitory
properties of sesquiterpenes and
flavonoids of Zingiber zerumbet Smith
K.R. Ajisha, K.A. Antub, M.P. Riyab, M.R. Preetharanib, K.G.
Raghub, B.P. Dhanyaa & K.V. Radhakrishnana
a Chemical Sciences & Technology Division, CSIR – National
institute for Inderdisciplinary Science and Technology,
Thiruvananthapuram 695 019, Kerala, India
b Agroprocessing and Natural Products Division, CSIR – National
Institute for Interdisciplinary Science and Technology, Trivandrum
695 019, India
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Published online: 09 Sep 2014.
To cite this article: K.R. Ajish, K.A. Antu, M.P. Riya, M.R. Preetharani, K.G. Raghu, B.P. Dhanya
& K.V. Radhakrishnan (2014): Studies on α-glucosidase, aldose reductase and glycation inhibitory
properties of sesquiterpenes and flavonoids of Zingiber zerumbet Smith, Natural Product Research:
Formerly Natural Product Letters, DOI: 10.1080/14786419.2014.956741
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Natural Product Research, 2014
http://dx.doi.org/10.1080/14786419.2014.956741
SHORT COMMUNICATION
Studies on a-glucosidase, aldose reductase and glycation inhibitory
properties of sesquiterpenes and flavonoids of Zingiber zerumbet Smith
K.R. Ajisha, K.A. Antub, M.P. Riyab, M.R. Preetharanib, K.G. Raghub, B.P. Dhanyaa and
K.V. Radhakrishnana*
aChemical Sciences & Technology Division, CSIR – National institute for Inderdisciplinary Science and
Technology, Thiruvananthapuram 695 019, Kerala, India; bAgroprocessing and Natural Products
Division, CSIR – National Institute for Interdisciplinary Science and Technology, Trivandrum 695 019,
India
(Received 30 May 2014; final version received 18 August 2014)
Eight known phytochemicals, four sesquiterpenes and four flavonoids of Zingiber
zerumbet were screened against a-glucosidase enzyme, aldose reductase enzyme and
antiglycation property under in vitro conditions. The results established kaempferol-3-
O-methylether as a potent inhibitor of a-glucosidase enzyme with an IC50 value of
7.88 mM. In aldose reductase enzyme inhibition assay, all the compounds except
zerumbone epoxide showed good to excellent inhibition properties. Among these, the
flavonoid compounds were found to be potent aldose reductase inhibitors compared
with the four sesquiterpenes. In addition, compounds such as a-humulene, kaempferol,
kaempferol-3-O-methylether and 300,400-O-diacetylafzelin displayed potent antiglyca-
tion properties. From overall results, we found that kaempferol and kaempferol-3-O-
methylether are potent inhibitors of a-glucosidase enzyme, aldose reductase enzyme
and glycation reaction, the three main targets of drugs for the treatment of diabetes and
its complications.
Keywords: Zingiber zerumbet Smith; zerumbone; a-glucosidase enzyme; aldose
reductase enzyme; anti-glycation reaction
1. Introduction
Zingiber zerumbet Smith from Zingiberaceae family is an edible medicinal plant with a broad
range of biological properties such as anti-tumour, anti-cancer, anti-inflammatory and anti-HIV
(Ozaki et al. 1991; Dai et al. 1997; Kirana et al. 2003; Murakami, Miyamoto, et al. 2004;
Murakami, Tanaka, et al. 2004; Murakami & Ohigashi 2007; Szabolcs et al. 2007; Aggarwal
et al. 2008; Sulaiman et al. 2010; Taha et al. 2010; Abdelwahab et al. 2011, 2012; Sung et al.
2012). In traditional medicine, zerumbet has been used as a cure for swelling, stomach ache,
toothache, sores and loss of appetite (Huang et al. 2005; Prakash et al. 2011; Singh et al. 2012).
It is widely distributed in India, Bangladesh, Nepal, Malaysia and Sri Lanka. Phytochemical
investigation of rhizomes of Z. zerumbet shows that it contains mainly two classes of compounds
namely terpenes and flavonoids (Singh et al. 2012). Recent studies reveal that most of the
biological properties of Z. zerumbet are due to the presence of a sesquiterpene, zerumbone
(Prakash et al. 2011). The content of zerumbone in the rhizome oil is about 50–80% (Baby et al.
2009). However, no detailed study is available on Z. zerumbet with respect to diabetes except the
study by Tzeng et al. (2013a, 2013b) who reported the protective property of the ethanolic
extract of Z. zerumbet and its active ingredient, zerumbone, against streptozotocin-induced
*Corresponding author. Email: radhu2005@gmail.com
q 2014 Taylor & Francis

2
K.R. Ajish et al.
diabetic nephropathy in rats. However, we have isolated seven compounds and screened them
for the inhibitory potential against a-glucosidase enzyme, aldose reductase enzyme and protein
glycation. These targets are very important to control the secondary complications of diabetes.
Nowadays, type 2 diabetes has developed worldwide into an epidemic (Danaei et al. 2011).
Hyperglycaemia due to faulty insulin secretion and function is the major determinant of diabetes
and its secondary complications. Intestinal a-glucosidase aids in the breakdown of disaccharides
to monosaccharide. Its inhibition is an attractive drug target as first line of treatment for diabetes
to control the postprandial hyperglycaemia. In addition, there are reports regarding additional
therapeutic properties of a-glucosidase inhibitors such as protection against pancreatic b-cell
apoptosis, inhibition of attachment of macrophage to vascular endothelium and amelioration of
development of atherosclerosis (Osonoi et al. 2010). Similarly, enzyme aldose reductase is
mainly responsible for sorbitol accumulation in diabetic patients via polyol pathway. Inhibitors
of aldose reductase are important therapeutic agents to prevent diabetic retinopathy (Chung &
Chung 2005). Protein glycation is another consequence of hyperglycaemia in which the excess
glucose present in the blood reacts non-enzymatically with proteins resulting in advanced
glycation end products (AGEs). This forms stable cross-links with other peptides, enzymes,
structural proteins etc. and alters their biological function (Vasan et al. 2001; Ahmed 2005). The
formation and accumulation of AGEs have been implicated in the progression of diseases such
as Alzheimer’s disease, cardiovascular disease and stroke, and development of antiglycation
agents is now in high demand in the pharma industry (Goldin et al. 2006). Moreover, bioactives
of natural origin is more attractive in the present scenario of drug research due to burden of
complication from undesired effects of synthetic drugs and high cost. Under this study, eight
compounds were isolated from Z. zerumbet and evaluated for its activity as antiglycation agents,
inhibitors of a-glucosidase and aldose reductase.
2. Results and discussion
Compounds 1–7 were isolated, further characterised and identified using various spectroscopic
techniques and in comparison with literature reports (Dev 1960; Damodaran & Dev 1965;
Masuda et al. 1991; Nakatani et al. 1991; Kitayama et al. 1999; Jang et al. 2004; Chung et al.
2007; Kader et al. 2009; Neuenschwander et al. 2012) (Figure 1). Compounds 1–4 were isolated
from the hexane extract by column chromatography using silica gel (100–200 mesh).
Compound 1 was eluted out using hexane. It was a pale yellow liquid and confirmed as a-
humulene. Compound 2 was obtained as a white crystalline solid (mp ¼ 678C) and was
Figure 1. Structures of isolated compounds 1–8.

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3
determined to be zerumbone. The amount of zerumbone obtained was 75 g and thus the yield
was found to be 50%.
A colourless liquid was obtained next to zerumbone and counted as compound 3. By using
various spectroscopic techniques, the compound was confirmed as zerumbol. Compound 4 was
1
obtained as a white crystalline solid with a pleasant aroma. The H NMR and IR spectrum
showed the presence of an epoxide moiety and the other data being similar to those for
compound 2.
Compound 5 was obtained as a yellow solid. UV studies along with other spectroscopic
studies revealed the compound as a flavonol namely kaempferol. Compound 6 also was obtained
as a yellow solid. The spectroscopic analysis indicated the presence of an extra methoxy group
and the other peaks being similar to those for compound 5. Thus, compound 6 was determined to
be kaempferol-3-O-methyl ether. Compound 7 was isolated as a yellow amorphous solid.
Various spectroscopic studies showed compound 7 as a flavonol glycoside with rhamnose as the
1
glycoside moiety and kaempferol as the flavonol part. The H NMR clearly indicated the
presence of two acetyl moieties in the rhamnoside group. In order to confirm the presence and
position of acetyl substituents, we carried out alkaline hydrolysis of compound 7 which afforded
another kaempferol glycoside namely afzelin (8). By comparing the spectra of these two
compounds, we were able to locate the position of the acetyl group, and the compound was
confirmed as kaempferol-3-O-(3,4-di-O-acetyl-a-L-rhamnopyranoside) or 300,400-O-diacetylaf-
zelin.
All the eight compounds were screened against a-glucosidase enzyme by using procedures
reported earlier (Apostolidis et al. 2007; Priya et al. 2011), with slight modifications. A wide
range of concentrations starting from 5 to 500 mM was checked for each compound. It is clear
from the results that kaempferol (5) and kaempferol-3-O-methylether (or isokaempferide, 6)
showed potent inhibitory activity with an IC50 value of 9.00 and 7.88 mM, respectively
(Table S1). Interestingly enough, both compounds exhibited significantly better activity
compared with the standard (acarbose) used in the study. The acarbose showed an IC50 value of
47.2 mM. The glycosylated derivatives (compounds 7 and 8) showed inferior activity compared
with the non-glycosylated partners (5 and 6) with a higher IC50 value of 64.18 and 81.16 mM,
respectively. This observation was in good agreement with the recent literature reports (Jianbo
et al. 2013) in which the authors clearly says that flavonoids show better inhibition against a-
glucosidase enzyme compared with their respective glycosylated derivatives. In the case of four
sesquiterpenes, all of them showed poor activity compared with the flavonoids and the standard
acarbose. Thus, we conclude that the flavonoid constituents of Z. zerumbet contribute more to
the inhibition process of a-glucosidase enzyme compared with their sesquiterpene components.
Aldose reductase enzyme is primarily known for catalysing the reduction of glucose to
sorbitol via NADPH. In diabetic patients, since the glucose level is high, the sorbitol formation
and accumulation will also be high (Chung et al. 2003). These conditions in turn produce high
osmotic pressure in eye leading to retinopathy in diabetic patients (Gabbay 1973; Kashyap &
Defronzo 2007). Therefore, it is very important from a therapeutic point of view to inhibit the
action of aldose reductase in diabetic patients. Herein, we report a series of phytochemicals
isolated from Z. zerumbet with aldose reductase inhibition properties under in vitro conditions.
All the phytochemicals except zerumbone epoxide showed promising inhibitory potential
(Figure 2). The compound with highest activity was afzelin which displayed an IC50 value of
5.54 mM (Table S2). In this assay, flavonoid class of compounds also exhibited greater activity
compared with the sesquiterpene compounds. The standard was zopolrestat with an IC50 value
1.34 mM.
All the eight compounds were tested for their ability to inhibit the formation of AGEs using
the procedure reported earlier (Riya et al. 2013). In this study, a total of six groups were present
for each compound. Results were expressed in terms of relative fluorescence units. Among the

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K.R. Ajish et al.
85
80
75
70
65
60
55
50
45
40
35
30
25
20
15
10
5
compound 1
compound 2
compound 3
compound 5
compound 6
compound 7
compound 8
0
0
20
40
60
80
100
Concentration (µM)
Figure 2. Aldose reductase inhibition by compounds 1–3 and 5–8.
eight compounds tested, significant decrease (P , 0.05) in fluorescence was observed in
compounds 1 and 5–7 at 100 mM concentration. However, compound 6 was found to be most
active under both day 1 and day 7 experiments. Quercetin (100 mM) showed significant
(P , 0.05) reduction in fluorescence with respect to the control (Figure S1).
3. Conclusion
In conclusion, we have isolated seven phytochemicals from Z. zerumbet and synthesised a
natural product from one of the isolated compounds. All the eight compounds were screened for
a-glucosidase enzyme, aldose reductase enzyme and protein glycation reaction. Kaempferol and
kaempferol-3-O-methylether were found to be potent a-glucosidase, aldose reductase as well as
protein glycation inhibitors. Compared with the four sesquiterpene components of Z. zerumbet,
the flavonoid constituents exhibited a greater activity against both a-glucosidase and aldose
reductase enzymes. However, in preventing the protein glycation reaction, compounds a-
humulene, kaempferol, kaempferol-3-O-methylether and 300,400-O-diacetylafzelin displayed
promising inhibitory activities. This study reveals that the bioactives isolated from Z. zerumbet
are potential agents for the control and management of diabetes via inhibition of a-glucosidase
enzyme, aldose reductase enzyme and protein glycation reaction. Therefore, a detailed study
involving in vivo models is recommended to obtain new chemical entities from natural resources
which are safe and cost-efficient compared with existing drugs.
Supplementary material
Experimental details relating to this article are available online, alongside Tables S1 and S2 and
Figure S1.
Funding
Authors thank the Council of Scientific and Industrial Research (CSIR), the UGC and the ICMR for
research fellowships. The authors also thank the CSIR, New Delhi [12th FYP Project] and the NAPAHA
CSC (0130)] for financial assistance.

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