THE JOURNAL OF ALTERNATIVE AND COMPLEMENTARY MEDICINE Volume 20, Number 3, 2014, pp. 195–205 ª Mary Ann Liebert, Inc. DOI: 10.1089/acm.2013.0088
Alkaloids as Aldose Reductase Inhibitors, with Special Reference to Berberine Sakshi Gupta, MPharm, Nirmal Singh, PhD, and Amteshwar Singh Jaggi, PhD
Abstract
Aldose reductase is the rate-limiting enzyme of the polyol pathway that leads to conversion of glucose to sorbitol. Its increased activity, which results in abnormal activation of the polyol pathway, is implicated in the development of long-term complications of diabetes mellitus. Different plant species and their active components have shown potent in vitro and in vivo aldose reductase inhibitory activity. Among different phytoconstituents, alkaloids that contain isoquinoline/bis(isoquinoline)and related ring structures (such as berberine, palmatine, coptisine, and jateorrhizine) have shown very potent aldose reductase inhibitory activity. The structural activity relationship has revealed the importance of hydrophobic and hydrophilic groups of isoquinoline/bis(isoquinoline)for binding to an enzyme. The dioxymethylene group in the D ring (hydrophobic group) of these alkaloids binds tightly to the site adjacent to the anionic binding site (active site), while the methoxyl groups (polar) bind to the site adjacent to the nicotinamide ring of the coenzyme. On the basis of these findings, it may be proposed that the presence of isoquinoline/bis(isoquinoline)ring structures is the most important requirement for alkaloids to behave as potent aldose reductase inhibitors. Thus, other plants may also be screened for the same activity. The present review discusses these isoquinoline/bis(isoquinoline)-based alkaloids as aldose reductase inhibitors that may be used to manage diabetic complications and may substitute for the chemically synthesized aldose reductase inhibitors.
Introduction
A
ldose reductase (alditol: nicotinamide adenine dinucleotide phosphate [NADP] + 1-oxidoreductase, EC 1.1.1.21) is a monomeric reduced -NADP oxidase (NADPH)– dependent enzyme and a member of the aldo–keto reductase super family.1 Aldose reductase is found in almost all mammalian cells, but high levels are detected in the cornea, lens, retina, kidney, and myelin sheath.2 It is the first and ratelimiting enzyme in the polyol pathway, and increased activity of aldose reductase–dependent polyol pathway is involved in many diabetic complications, including nephropathy, neuropathy, cataract formation, and cardiovascular problems.3,4 In the polyol pathway, it uses NADPH as a cofactor to reduce glucose to sorbitol, which is subsequently acted upon by sorbitol dehydrogenase (SDH) to convert it into fructose.5 The conversion of sorbitol to fructose by sorbitol dehydrogenase is associated with depletion of cellular NAD + ; glutathione (reduced form) stores; and accumulation of malondialdehyde, a lipid peroxidation end product.6 Aldose reductase is a single-polypeptide domain composed of 315 amino acid residues.7 The peptide chain at the
amino terminal folds into a b/a-barrel structural motif containing eight parallel b strands that are connected to each other by eight peripheral a-helical segments running antiparallel to the b sheet. The active site is located in a large and deep cleft in the C-terminal end of the b barrel, and the NADPH cofactor binds in an extended conformation to the bottom of the active site.8 The active site of the enzyme is located on nicotinamide coenzyme and is buried at the bottom of a deep cleft, with C5 and the hydride donor C4 as accessible atoms with three distinct binding pockets. The first pocket is usually occupied by the anion head of ligand and thus named ‘‘anion binding pocket’’ or ‘‘hydrophilic pocket,’’ comprising Tyr48, His110, Trp20, Trp111, Ser159, and Asn160 residues and the positively charged nicotinamide moiety of the cofactor NADP + . The second is a hydrophobic pocket, known as a specificity pocket, and is lined by the residues Trp219, Trp20, Leu300, Cys298, Cys303, Trp111, Cys303, and Phe122.8 The residues of hydrophobic groups, including Trp20, Phe122, and Trp219, fully face the active site and make the major contacts with a potential substrate and inhibitors. The specificity pocket displays a high degree of flexibility. The third pocket is another
Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, India.
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196 hydrophobic pocket formed by the residues Trp20, Trp111, Phe122, and Trp219.9 It has been reported that Tyr48, His110, and Trp111 residues of the hydrophilic group are involved in hydrogen-bonding interactions with a substrate at the bottom of the active site (Fig. 1).8 Pharmacologic use of aldose reductase inhibitors has been recognized as an important strategy in the prevention and attenuation of long-term diabetic complications.10–12 Among the marketed preparations, two chemical classes of aldose reductase inhibitors (i.e., carboxylic acid and spiromide inhibitors [Fig. 2; note that throughout this article, numbers in parentheses refer to the numbered labels in the corresponding figures]) have been used clinically for management of diabetic complications.6 Saraswat and coworkers demonstrated that carboxylic acid inhibitors, such as zopolrestat (1), ponalrestat and tolrestat, (2) (Fig. 2) have poor tissue penetration and are less potent in vivo, whereas the spiromide inhibitors, such as spirohydantoin (3) (Fig. 2) cause skin reactions and liver toxicity.13 Therefore, development and evaluation of new effective and safe aldose reductase inhibitors are needed. Studies have shown that indigenous plants, such as Cuminum cyminum (seeds), Citrus limon (fruits), Allium cepa (bulb), and Malus pumila (fruit), possess the potent aldose reductase inhibitory and, consequently, diabetic complication– attenuating properties.13–15 Among the phyto-constituents, flavonoids such as quercetin, luteolin, kaempferol, myricetin, apigenin, flavones, chrysin, diosmetin tamarixetin, ombuin, and ayanin exhibit potent in vitro aldose reductase inhibitory activity in rat lenses.16–18 Moreover, flavonol glycosides, such as myricitrin, mearnsitrin, quercitrin, desmanthin-1, guaijaverin, and astilbin, also exhibit aldose reductase inhibitory activity in vitro.19–22 Coumarins, such as umbelliferone, scoparone, scopoletin, esculetin, and scopolin, have potent aldose reductase inhibitory activity.16 Terpenoids, such as glycyrrhizin glycyrrhetinic acid, lambertic acid,
FIG. 1. Diagrammatic representation of active site of the aldose reductase. The active site comprises three pockets: anion binding or hydrophilic pocket (comprising Tyr48, His110, Trp111, and Trp 20 protein residues and the positively charged nicotinamide moiety of the cofactor nicotinamide adenine dinucleotide phosphate + ), specificity pocket (comprising Leu300, Cys298 and Phe122 protein residues), and hydrophobic pocket (comprising Phe122 and Trp219 protein residues).
GUPTA ET AL. cryptotanshinone, tanshinone I, and sugiol have also shown aldose reductase inhibitory activity.23,24 Gallotannins and ellagitannins types of tannins isolated from plant sources have also shown inhibitory activity.23,25 Phenolic compounds, such as cyanidin-3-O-b-glucoside, peonidin-3-O-bglucoside, and ferulic acid, demonstrate potent aldose reductase inhibitory activity.26 Plant-derived alkaloids have aldose reductase inhibitory activity in in vitro as well as in in vivo studies, along with beneficial effects in diabetic complications.27,28 An alkaloidrich extract isolated from Capparis deciduas plant has shown potent aldose reductase inhibitory activity in streptozocin (60 mg/kg intraperitoneally)-treated diabetic mice.27 The isoquinoline and bis(isoquinoline)-type of alkaloids, such as berberine, has been extensively studied as an aldose reductase inhibitor. Based on these, structurally related alkaloids have also been explored for aldose reductase inhibitory activity. The present review describes various isoquinoline, bis(isoquinoline), and other structurally related alkaloids as aldose reductase inhibitors with special reference to berberine. Berberine Berberine (4) (Fig. 3.) (simplest isoquinoline alkaloid) and related alkaloids are found in plants such as Berberis aristata, Coptis chinensis, Coptis japonica, Cortex phellodendri, Coscinium fenestratum, Hydrastis canadensis, and Tinospora cordifolia.18–30 It has shown various pharmacologic activities, such as antidiarrheal, antibacterial, anti-inflammatory, anticancer, and neuroprotective (Alzheimer’s disease and Huntington’s disease).31–33 Berberine has also shown protective effects in diabetes and related complications. It decreases fasting blood glucose, total cholesterol, and triglyceride levels; urinary protein excretion; serum creatinine levels; and blood urea nitrogen levels and suppresses histologic and ultrastructural
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FIG. 2. Commercially available synthetic carboxylic acid and spiromide– based aldose reductase inhibitors. Zopolrestat (1), tolrestat (2), spirohydantoin (3). A, alkyl group; n varies from 1 to 6.
alterations in the kidney of streptozotocin-treated diabetic rats.34,35 Recently, administration of berberine in patients with type 2 diabetes was shown to exert hypolipidemic and antidyslipidemic effects.36 Xie and coworkers revealed that berberine upregulates Akt, possibly via an insulin signaling pathway, eventually lowering high blood glucose in alloxaninduced diabetic mice.37 Shen and coworkers demonstrated that berberine exerts antidiabetic action by activating cyclic adenosine monophosphate protein kinase and targeting insulin gene.38 It also decreases the postprandial plasma glucose levels of streptozotocin-diabetic rats by inhibiting the increased activities of intestinal disaccharidases and elevating plasma insulin levels.39 The possible mechanisms for nephroprotective effects of berberine may be related to inhibition of glycosylation and augmentation of antioxidation activity.34 Nakai and coworkers studied the inhibitory activities of aporphine, benzylisoquinoline, and bis(isoquinoline)alkaloidal types (berberine) in rabbit lens aldose reductase and suggested the key role of the isoquinoline ring in aldose reductase inhibition.40 All these compounds contain benzoquinolidine ring, as in GPA 1734 (8,9-dihydroxy-7-methyl-benzo-(b) quinolizium bromide), which is a potent inhibitor of aldose reductase.40 Bis(isoquinoline) alkaloids (Fig. 3), such as berberine, exhibit more potent aldose reductase inhibitory
activity (50% inhibitory concentration [IC50] values of 5.2 · 10 - 5 M) as compared with aporphine and benzylisoquinoline types (IC50 values of 10 - 4 M). Furthermore, reduction of the A ring of berberine, leading to formation of canadine (tetrahydroberberine) (5) (Fig. 3) significantly reduces aldose reductase inhibitory activity (IC50 values of 4.9 · 10 - 4 M), suggesting the requirement of unsaturated A ring for aldose reductase inhibition.40 Lee and coworkers compared the inhibitory activities of chloroform extract–derived berberine chloride alkaloid from the roots of Coptis japonica with commercially available berberine sulfate, berberine iodide, and quercitrin. All the salts of berberine alkaloids demonstrated potent in vitro rat lens aldose reductase inhibitory activity (IC50 values of 13.98, 13.45, and 32.84 nM), values similar to those of quercitrin, a flavonoid used as a positive standard (IC50 values of 11.15 nM). Among different salts of berberine, berberine chloride (IC50 values of 13.98 nM) and berberine sulfate (IC50 values of 13.45 nM) exhibited more potent aldose reductase inhibitory activity (2.5 times) compared with berberine iodide (IC50 values of 32.84 nM).41 Liu and coworkers demonstrated that berberine attenuates high glucose-induced increases in aldose reductase gene expression in the cultured mesangial cells.42 The same group of scientists also reported the aldose reductase inhibitory activity of berberine in
FIG. 3. Bis(isoquinoline)alkaloids berberine (4), tetrahydroberberine (5), palmatine (6), and tetrahydropalmatine (7) as aldose reductase inhibitors.
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FIG. 4. Representation of binding of berberine to the active site of aldose reductase. Dioxymethylene moiety of berberine binds to the hydrophobic pocket of the active site (comprising Trp219 residue), and the methoxyl groups along with polar nitrogen interact with the anion-binding pocket of the active site (comprising Trp111, His110, and Tyr48 residues).
streptozotocin-induced (60 mg/kg) diabetic rats with diabetic nephropathy. Administration of berberine (200 mg/kg per day for 12 weeks) downregulated the messenger RNA and protein expression of aldose reductase in rat kidneys and ameliorated renal dysfunction by inhibiting the polyol pathway.28,42 The aldose reductase inhibitory effects of berberine were similar to those of epalrestat, a well-known aldose reductase inhibitor. Increased aldose reductase activity due to enhanced aldose reductase gene expression has been shown in streptozotocin-treated diabetic rats.43 An increased aldose reductase activity is also associated with structural changes in the glomeruli of nephropathic patients.44 Palmatine Palmatine (Fig. 3), structurally related to berberine with a bis(isoquinoline)ring, is derived from such plants as Coptis japonica, Tinospora cordifolia, and Coptis chinensis and also possesses aldose reductase inhibitory activity.41,45,30 Nakai and coworkers also demonstrated the potent aldose reductase inhibitory activities of palmatine (IC50 values of 3.8 · 10 - 5 M) against aldose reductase in rabbit lenses. Similar to berberine, reduction of the A ring of palmatine, leading to formation of tetrahydropalmatine (7) (Fig. 3), also significantly reduced aldose reductase inhibitory activity (IC50 values of 7.6 · 10 - 4 M),40 again suggesting the key role of unsaturated A ring of bis(isoquinoline)alkaloids in aldose reductase inhibition. Kubo and coworkers also demonstrated the aldose reductase inhibitory activity of tetrahydropalmatine derived from the methanolic fraction of tubers from various Corydalis species (C. stenantha, C. thalictrifolia, C. racemosa, and C. pallida) in rat lenses.46 Lee and colleagues compared aldose reductase inhibitory activity of commercially available palmatine sulfate
FIG. 5. Benzisoquinoline/ phenylisoquinoline-type alkaloids dehydrocorydaline (8), papaverine (9), and demethylpapaverine (10) as aldose reductase inhibitors.
with palmatine iodide derived from chloroform fraction of Coptis japonica roots. The IC50 values of palmatine sulfate and palmatine iodide were 51.78 and 68.0 nM, suggesting that sulfate salts are more potent (1.3 times) than the iodide salts of palmatine.41 Recently, aldose reductase inhibitory activity of palmatine derived from alkaloidal fraction of Tinospora cordifolia stems in rat lenses (IC50 value of 3.45 lg/mL) has also been shown.30 Berberine Versus Palmatine Nakai and coworkers reported palmatine (IC50 values of 3.8 · 10 - 5 M) as more potent aldose reductase inhibitor compared with berberine (IC50 values of 5.2 · 10 - 5 M).40 In contrast, Lee demonstrated that berberines are somewhat more potent than palmatines, with IC50 values of berberine chloride (13.98 nM), berberine sulfate (13.45 nM), and berberine iodide (32.84 nM) significantly lower than those of palmatine sulfate (51.78 nM) and palmatine iodide (68.0 nM).41 The presence of the oxidized form of dioxymethylene group in the A and D rings of isoquinoline has been suggested as an important structural feature contributing to aldose reductase inhibition.45 Accordingly, the relative high potency of berberine may be attributed to the presence of the oxidized form of dioxymethylene group in the A ring as compared with dimethoxy groups in the corresponding A ring of palmatine. The ligand binding site in the aldose reductase is a deep, elliptical pocket with the nicotinamide ring of the NADPH cofactor at the base. There is involvement of Tyr 48 and Lys 77 and the nicotinamide ring in the catalytic region. The aldose reductase– active site includes specific anionic site delineated by the C4N of the nicotinamide coenzyme, the Og, of Tyr48, and
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FIG. 6. Aporphine alkaloids nandazurine (11), nantenine (12), domesticine (13), d-glaucine (14), and magnoflorine (15) as aldose reductase inhibitors. the Ne of His110. The hydrophobic region of the inhibitor binds in a ‘‘specificity’’ hydrophobic pocket in the active site, which is accessible after a conformational change of the enzyme.47 The important structural features of aldose reductase inhibitors include the presence of polar and nonpolar hydrophobic system, with polar groups attached to the hydrophobic ring system. The polar moiety of a inhibitor binds in a conserved active anion-binding site (catalytic site) and also interacts with NADP + (nicotinamide ring) of the coenzyme by forming hydrogen bonds with Tyr48, His110, and Trp111 residues of the coenzyme (present within the active binding
site) to hold the polar moiety firmly in the catalytic site.48 On the other hand, the hydrophobic ring systems of inhibitors are bound tightly in a deep pocket (adjacent to the anion-binding site of the coenzyme), which opens as a result of polar group binding to the active site, leading to the conformational change in the walls of the active site of coenzyme (Fig. 4).8 From the structures of alkaloids, it may be proposed that the dioxymethylene group of the D ring is the hydrophobic group and that it is tightly bound adjacent to the anionic binding site. On the other hand, the methoxyl groups are polar in nature and may bind to site adjacent to the nicotinamide ring of the coenzyme (Fig. 4).
FIG. 7. Protoberberine type alkaloids l-tetrahydrocoptisine (16), dl-corydaline (17), coptisine (18), groenlandicine (19) and jateorrhizine (20) as aldose reductase inhibitors.
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FIG. 8. Other structurally related alkaloids different to bis(isoquinoline)or isoquinoline protopine (21) and l-tetrahydrocolumbamine (22) as aldose reductase inhibitors.
Benzisoquinoline/Phenylisoquinoline Type Dehydrocorydaline (8) (Fig. 5), a phenylisoquinoline alkaloid, is obtained from the quaternary fraction of methanolic extract of tubers of various Corydalis species (such as C. stenantha, C. thalictrifolia, C. racemosa, and C. pallida) and exhibits potent aldose reductase inhibitory activity (44.5% at 50 lM) in rat lenses.46 Papaverine (9) and demethylpapavarine (10) (benzylisoquinoline type alkaloids) (Fig. 5) exhibit aldose reductase inhibitory activity (IC50 values of 1.4 · 10 - 4 and 1.9 · l0 - 4 M, respectively) in rat lens.40 The same group of scientists demonstrated that papaverine and berberine exhibit potent aldose reductase inhibitory activity alone; however, in combination they antagonize the aldose reductase inhibitory activity of each other in a competitive manner, with no clear mechanism.40 Aporphine Nakai and coworkers demonstrated that aporphine-type alkaloids, such as nandazurine (11), isoboidine, nantenine (o-methyl domesticine) (12), and domesticine (13) (Fig. 6) exhibit potent aldose reductase inhibitory activity, with IC50 values of 2.0 · 10 - 4, 2.7 · 10 - 4, 4.3 · 10 - 4, 7.6 · 10 - 4 M, respectively in rat lenses.40 d-glaucine (14) (Fig. 6) derived from the quaternary fraction of methanolic extract of tubers
FIG. 9. Alkaloids other than isoquinoline: 5-epidihydrolyfoline N-oxide (23), decamine N-oxide (24), lagerstroemine N-oxide (25), lagerine N-oxide (26), and piplartine (27).
of various Corydalis species (C. stenantha, C. thalictrifolia, C. racemosa, and C. pallida) exhibits aldose reductase inhibitory activity (16.5% at 50 lM) in rat lenses.46 Later in 2008, one more aporphine alkaloid magnoflorine (15) (Fig. 6) obtained from the butanolic fraction of rhizome of Coptis chinensis possessed aldose reductase inhibitory activity (IC50 > 50 lg/ mL) in rat lenses.45 Magnoflorine, also derived from alkaloidal fraction of Tinospora cordifolia stems, has shown an IC50 value of 1.25 lg/mL, similar to the positive control quercetin, with an IC50 of 1.08 lg/mL against aldose reductase in rat lenses.30 Protoberberine Type l-Tetrahydrocoptisine (16) (Fig. 7), a protoberberine alkaloid, is obtained from the quaternary fraction of the methanolic extract of tubers of various Corydalis species (C. stenantha, C. thalictrifolia, C. racemosa, and C. pallida) and exhibits aldose reductase inhibitory activity (5.7% at 50 lM) in rat lenses. dl-Corydaline (17) (Fig. 7), also derived from the quaternary fraction of methanolic extract of tubers of various Corydalis species (C. stenantha, C. thalictrifolia, C. racemosa, and C. pallida), exhibit structural similarities with berberine and exhibits aldose reductase inhibitory activity (6.7% at 50 lM) in rat lenses.46 Jung and coworkers evaluated protoberberine alkaloids, such as coptisine (18), groenlandicine
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FIG. 10. Bis(isoquinoline)/isoquinoline or other related alkaloids (-)-3-methoxyputerine (28), ( + )-norguattevaline (29), ( + )3-methoxyguattescidine (30), 3-ethoxyoxoputerine (31), ( + )-cassyformine (32), ( + )-filiformine (33), lettowianthine (34), 11methoxylettowianthine (35), isoboldine (36), norisoboldine (37), thaliporphine (38), corytuberine (39), reticuline (40), taspine (41), liriodenine (42), atherospermidine (43), stephalagine (44), discretine (45), desmorostratine (46), discretine N-oxide (47), dehydrodiscretine (48), pseudocolumbamine (49), predicentrin (50), asimilobine (51), stepholidine (52), ( + )-N-(methoxylcarbonyl)-N-nordicentrin (53), ( + )-N-(methoxylcarbonyl)-N-norpredicentrine (54), ( + )-N-(methoxylcarbonyl)-N-norbulbodione (55), ( + )-N-(methoxylcarbonyl)-N-norisocorydione (56), ( + )-8-methoxyisolaurenine-N- oxide (57), xylopine (58), anonaine (59), and romucosine (60) may be explored for their aldose reductase inhibitory activity.
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FIG. 10.
(19), and jateorrhizine (20) (Fig. 7), derived from the butanolic fraction of Coptis chinensis rhizomes for their aldose reductase inhibitory activity. Coptisine and groenlandicine possess potent aldose reductase inhibitory activities, with IC50 values of 37.9 and 45.2 lg/mL, respectively, in rat lenses and 66.7 and 51.2 lg/mL, respectively, in recombinant human lenses. On the other hand, jateorrhizine exhibited aldose reductase inhibitory activity, with an IC50 value greater than 50 M.45 On the basis of these results, it was proposed that in protoberberine-type alkaloids, the presence of dioxymethylene group in the D ring and the oxidized form of the dioxymethylene group in the A ring are the prime requirements for aldose reductase inhibitory activities in rat and human recombinant lenses.45 In contrast, a recent study has demonstrated the potent aldose reductase inhibitory activity of jateorrhizine derived from stem of Tinospora cordifolia alkaloidal extract, with an IC50 value of 3.23 lg/mL in rat lenses.30 It suggests that more studies are needed to establish the aldose reductase inhibitory activity of these protoberberine type alkaloids. Others Other structurally related alkaloids but different to bis(isoquinoline)or isoquinoline, such as protopine (21) (Fig. 8)
(Continued)
and l-tetrahyrocolumbamine (22) (Fig. 8), derived from the quaternary fraction of the methanolic extract of tubers of various Corydalis species (C. stenantha, C. thalictrifolia, C. racemosa, and C. pallida), have also been shown to possess aldose reductase inhibitory activity (IC50 values of 10.9 and < 5, respectively, at 50 lM concentration) in vitro in rat lenses.46 Alkaloids Other than Isoquinoline/(BIS)Isoquinoline Type Recent studies have suggested that alkaloids other than isoquinoline/bis(isoquinoline) also exhibit aldose reductase inhibitory activity. In 2011, three biphenylquinolizidine Noxide alkaloids—5-epi-dihydrolyfoline N oxide, decamine N-oxide (24), and lagerstroemine N-oxide (25)—and one biphenyl ether quinolizidine N-oxide alkaloid—lagerine Noxide (26) (Fig. 9)— isolated from the ethanolic extract of the aerial parts of Lagerstroemia indica were shown to posses aldose reductase inhibitory activity (25%–32% inhibitions at a concentration of 50 lM) against aldose reductase in rat lenses.49 Rao and coworkers reported aldose reductase inhibitory activity of piplartine (27) (Fig. 9) alkaloid derived from the chloroform extract of Piper chaba against aldose reductase in recombinant human lenses, with an IC50 of 160 mM. On
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the basis of the structural similarities of available aldose reductase inhibitors and piplartine, it was proposed that the imide functionality (-CO-NH-CO-) plays a critical role in aldose reductase inhibitory activity.50
measure against diabetic complications related to increased activity of aldose reductase.
1. Future Directions
The authors are also grateful to Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, India, for supporting this study.
On the basis of the preceding discussion, it may be proposed that the presence of bis(isoquinoline)/isoquinoline or other related ring structures is the primary requirement for a compound to exhibit potent aldose reductase inhibitory activity. Therefore, more plant species containing these ring structures may also be explored to identify the potent aldose reductase inhibitors. The following plants containing bis-(isoquinoline)/isoquinoline ring structures (Fig. 10) may be evaluated for their aldose reductase inhibitory activity. 1. Alkaloids such as (-)-3-methoxyputerine (28), ( + )-norguattevaline (29), ( + )-3-methoxyguattescidine (30) and 3-methoxyoxoputerine (31) (Figure 10), present in the alkaloidal fraction of stem bark of Guatteria foliosa.51 2. Alkaloids such as ( + )-cassyformine (32), ( + )-filiformine (33) (Fig. 10), present in the methanolic extract of fresh herbs of Cassytha filiformis II.52 3. Alkaloids such as lettowianthine (34) and 11-methoxylettowianthine (35) (Fig. 10) present in the ethanolic extract of root bark of Lettowianthus stellatus.18 4. Alkaloids such as isoboldine (36), norisoboldine (37), thaliporphine (38), corytuberine (39), reticuline (40), and taspine (41) (Fig. 10) present in the crude extract of Croton lechleri (leaves and latex).53 5. Alkaloids such as liriodenine (42), atherospermidine (43), and stephalagine (44) (Fig. 10) present in the ethanolic extract of the stems of Stephania dinklage.54 6. Alkaloids such as discretine (45), desmorostratine (46), discretine N-oxide (47), dehydrodiscretine (48), pseudocolumbamine (49), and predicentrin (50) (Fig. 10) present in the methanolic extract of stem bark of Desmos rostrata.55 7. Alkaloids such as reticuline (40), asimilobine (51), and stepholidine (52) (Fig. 10) present in the Diploclisia affinis.56 8. Alkaloids such as ( + )-N-(methoxylcarbonyl)-N-nordicentrin (53), ( + )-N-(methoxylcarbonyl)-N-norpredicentrine (54), ( + )-N-(methoxylcarbonyl)-N-norbulbodione (55), ( + )-N-(methoxylcarbonyl)-N-norisocorydione (56), and ( + )-8-methoxyisolaurenine-N-oxide (57) (Fig. 10) present in the ethanolic extract of bark of the Litsea cubeba.57 9. Alkaloids such as xylopine (58), anonaine (59), and romucosine (60) (Fig. 10) present in the crude alkaloidal fraction of Annona crassiflora leaves.58 Conclusion From the evidence presented here, it may be concluded that isoquinoline/bis(isoquinoline)type and other structurally related alkaloids exhibit potent aldose reductase inhibitory activity. Accordingly, these moieties may be used as a structural template for development of more potent aldose reductase inhibitors. Furthermore, more plant species may also be explored having alkaloids exhibiting structural similarities with isoquinoline type alkaloids as an effective
Acknowledgments
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204 15. Lee HS. Cuminaldehyde: aldose reductase and a-glucosidase inhibitor derived from Cuminum cyminum L. seeds. J Agric Food Chem 2008;53:2446–2450. 16. Jung HA, Islam MD, Kwon YS, Jin SE, Son YK, Park JJ, Sohn HS, Choi JS. Extraction and identification of three major aldose reductase inhibitors from Artemisia montana. Food Chem Toxicol 2011;49:376–384. 17. Matsuda H, Morikawa T, Yoshikawa M. Antidiabetogenic constituents from several natural medicine. J Pure Appl Chem 2002;74:1301–1308. 18. Nkunya MH, Jonker SA, Makangara JJ, Waibel R, Achenbach H. Aporphinoid alkaloids and other constituents from Lettowianthus stellatus. Phytochemistry 2000;53:1067–1073. 19. Jung M, Park M, Lee HC, Lee HC, Kang YH, Kang ES, Kim SK. Antidiabetic agents from medicinal plants. J Curr Med Chem 2006;13:1203–1218. 20. Haraguchi H, Kanada M, Fukuda A, Naruse K, Okamura N, Yagi A. An inhibitor of aldose reductase and sorbitol accumulation from Antho cepharus. J Planta Med 1998;64: 68–69. 21. Yoshikawa M, Shimada H, Nishida N, Li Y, Toguchida, I, Yamahara J, Matsuda H. Antidiabetic principles of natural medicines. II. Aldose reductase and alpha-glucosidase inhibitors from Brazilian natural medicine, the leaves of Myrcia multiflora DC. (Myrtaceae): Structures of myrciacitrins I and II and myrciaphenones A and B. J Chem Pharm Bull 1998;46:113–119. 22. Haraguchi H, Ohmi I, Fukuda A, Tamura Y, Mizutani K, Tanaka O, Chou WH. Inhibition of aldose reductase and sorbitol accumulation by astilbin and taxifolin dihydroflavonols in Engelhardtia chrysolepis. J Biosci Biotechnol Biochem 1997;61:651–654. 23. de la Fuente JA, Manzanaro S. Aldose reductase inhibitors from natural sources. Nat Prod Rep 2003;20:243–251. 24. Lee YS, Kim SH, Jung SH, Kim JK, Pan CH, Lim SS. Aldose reductase inhibitory compounds from Glycyrrhiza uralensis. J Biol Pharm Bull 2010;33:917–921. 25. Ueda H, Tachibana Y, Moriyasu M, Kawanishi K, Alves SM. Aldose reductase inhibitors from the fruits of Caesalpinia ferrea Mart. J Phytomedicine 2001;8:377–381. 26. Yawadio R, Tanimori S, Morita N. Identification of phenolic compounds isolated from pigmented rices and their aldose reductase inhibitory activities. Food Chem 2007;101:1616– 1625. 27. Sharma B, Salunke R, Balomajumder C, Daniel S, Roy P. Anti-diabetic potential of alkaloid rich fraction from Capparis decidua on diabetic mice. J Ethnopharmacol 2010;127: 457–462. 28. Liu WH, Hei ZQ, Nie H, Tang FT, Huang HQ, Li XJ, Deng YH, Chen SR, Guo FF, Huang WG, Chen FY, Liu PQ. Berberine ameliorates renal injury in streptozotocin-induced diabetic rats by suppression of both oxidative stress and aldose reductase. Chin Med J (Engl) 2008;121:706–712. 29. Chatuphonprasert W, Nemoto N, Sakuma T, Jarukamjorn K. Modulations of cytochrome P450 expression in diabetic mice by berberine. Chem Biol Interact 2012;196:23–29. 30. Patel MB, Mishra S. Isoquinoline alkaloids from Tinospora cordifolia inhibit rat lens aldose reductase. Phytother Res 2012;26:1342–1347. 31. Xian YF, Lin ZX, Ip S.P, Su ZR, Chen JN, Lai XP. Comparison of the neuropreotective effect of Cortex Phellodendri chinensis and Cortex Phellodendri amurensis against betaamyloid-induced neurotoxicity in PC12 cells. Phytomedicine 2013;20:187–193.
GUPTA ET AL. 32. Chen XW, Di YM, Zhang J, Zhou ZW, Li CG, Zhou SF. Interaction of herbal compounds with biological targets: a case study with berberine. Sci World J 2012;2012:708292. 33. Tillhon M, Guama´n Ortiz LM, Lombardi P, Scovassi AI. Berberine: new perspectives for old remedies. Biochem Pharmacol 2012;84:126–-1267. 34. Wu D, Wen W, Qi CL, Zhao RX, Lu¨ JH, Zhong CY, Chen YY. Ameliorative effect of berberine on renal damage in rats with diabetes induced by high-fat diet and streptozotocin. Phytomedicine 2012;19:712–718. 35. Wang FL, Tang LQ, Yang F, Zhu LN, Cai M, Wei W. Renoprotective effects of berberine and its possible molecular mechanisms in combination of high-fat diet and low-dose streptozotocin-induced diabetic rats. Mol Biol Rep 2013; 40:2405–2418. 36. Dong H, Wang N, Zhao L, Lu F. Berberine in the treatment of type 2 diabetes mellitus: a systemic review and metaanalysis. Evid Based Complement Alternat Med 2012;2012: 591654. 37. Xie X, Li W, Lan T, Liu W, Peng J, Huang K, Huang J, Shen X, Liu P, Huang H. Berberine ameliorates hyperglycemia in alloxan-induced diabetic C57BL/6 mice through activation of Akt signaling pathway. Endocr J 2011;58: 761–768. 38. Shen N, Huan Y, Shen ZF. Berberine inhibits mouse insulin gene promoter through activation of AMP activated protein kinase and may exert beneficial effect on pancreatic b-cell. Eur J Pharmacol 2012;694:120–126. 39. Liu SZ, Deng YX, Chen B, Zhang XJ, Shi QZ, Qiu XM. Antihyperglycemic effect of the traditional Chinese scutellaria-coptis herb couple and its main components in streptozotocin-induced diabetic rats. J Ethnopharmacol 2013; 145:490–498. 40. Nakai N, Fujii Y, Kobashi K, Nomura K. Aldose reductase inhibitors: flavonoids, alkaloids, acetophenones, benzophenones, and spirohydantoins of chroman. Arch Biochem Biophys 1985;239:491–496. 41. Lee HS. Rat lens aldose reductase inhibitory activities of Coptis japonica root-derived isoquinoline alkaloids. J Agric Food Chem 2002;50:7013–7016. 42. Liu W, Liu P, Tao S, Deng Y, Li X, Lan T, Zhang X, Guo F, Huang W, Chen F, Huang H, Zhou SF. Berberine inhibits aldose reductase and oxidative stress in rat mesangial cells cultured under high glucose. Arch Biochem Biophys 2008; 475:128–134. 43. Ghahary A, Luo JM, Gong YW, Chakrabarti S, Sima AA, Murphy LJ. Increased renal aldose reductase activity, immunoreactivity, and mRNA in streptozotocin-induced diabetic rats. Diabetes 1989;38:1067–1071. 44. Kasajima H, Yamagishi S, Sugai S, Yagihashi N, Yagihashi S. Enhanced in situ expression of aldose reductase in peripheral nerve and renal glomeruli in diabetic patients. Virchows Arch 2001;439:46–54. 45. Jung HA, Yoon NY, Bae HJ, Min BS, Choi JS. Inhibitory activities of the alkaloids from Coptidis rhizoma against aldose reductase. Arch Pharm Res 2008;31:1405–1412. 46. Kubo M, Matsuda H, Tokuoka K, Kobayashi Y, Ma S, Tanaka T. Studies of anti-cataract drugs from natural sources. I. Effects of a methanolic extract and the alkaloidal components from Corydalis tuber on in vitro aldose reductase activity. Biol Pharm Bull 1994;17:458–459. 47. Miyamoto S. Molecular modelling and structure based drug discovery of studies of aldose reductase inhibitors. CBIJ 2002;2:74–85.
ALKALOIDS AND ALDOSE REDUCTASE 48. El-Kabbani O, Podjarny A. Selectivity determinants of the aldose and aldehyde reductase inhibitor-binding sites. Cell Mol Life Sci 2007;64:1970–1978. 49. Lee I, Youn U, Kim H, Min B, Kim JS, Bae K. Biphenyl and biphenyl ether quinolizidine N-oxide alkaloids from Lagerstroemia indica L. Planta Med 2011;77:2037–2041. 50. Rao VR, Muthenna P, Shankaraiah G, Akileshwari C, Babu KH, Suresh G, Babu KS, Chandra Kumar RS, Prasad KR, Yadav PA, Petrash JM, Reddy G.B, Rao JM. Synthesis and biological evaluation of new piplartine analogues as potent aldose reductase inhibitors (ARIs). Eur J Med Chem 2012; 57:344–361. 51. Mahiou V, Roblot F, Hocquemiller R, Cave´ A, Rojas de Arias A, Inchausti A, Yaluff G, Fournet A, Angelo A. New aporphine alkaloids from Guatteria foliosa. J Nat Prod 1994;57:890–895. 52. Chang FR, Chao YC, Teng CM. Chemical constituents from Cassytha filiformis II. J Nat Prod 1998;61:863–866. 53. Milanowski DJ, Winter RE, Elvin-Lewis MP, Lewis WH. Geographic distribution of three alkaloid chemotypes of Croton lechleri. J Nat Prod 2002;65:814–819. 54. Goren AC, Zhou BN, Kingston DG. Cytotoxic and DNA damaging activity of some aporphine alkaloids from Stephania dinklagei. Planta Med 2003;69:867–868.
205 55. Nguyen NT, Pham VC, Litaudon M, Gue´ritte F, Grellier P, Nguyen VT, Nguyen VH. Antiplasmodial alkaloids from Desmos rostrata. J Nat Prod 2008;71:2057–2059. 56. Wang EJ, Ma YB, Zhang XM. Five alkaloids from vine stems of Diploclisia affinis. Zhongguo Zhong Yao Za Zhi 2008;33: 2503–2505. 57. Zhang W, Hu JF, Lv WW, Zhao QC, Shi GB. Antibacterial, antifungal and cytotoxic isoquinoline alkaloids from Litsea cubeba. Molecules 2012;17:12950–12960. 58. Egydio APM, Valvassoura TA, Santos DYAC. Geographical variation of isoquinoline alkaloids of Annona crassiflora Mart. from cerrado, Brazil. Biochem Syst Ecol 2012;46:145–151.
Address correspondence to: Amteshwar Singh Jaggi, PhD Department of Pharmaceutical Sciences and Drug Research Punjabi University Patiala-147002 India E-mail: [email protected]
Alkaloids as Aldose Reductase Inhibitors, with Special Reference to Berberine Sakshi Gupta, MPharm, Nirmal Singh, PhD, and Amteshwar Singh Jaggi, PhD
Abstract
Aldose reductase is the rate-limiting enzyme of the polyol pathway that leads to conversion of glucose to sorbitol. Its increased activity, which results in abnormal activation of the polyol pathway, is implicated in the development of long-term complications of diabetes mellitus. Different plant species and their active components have shown potent in vitro and in vivo aldose reductase inhibitory activity. Among different phytoconstituents, alkaloids that contain isoquinoline/bis(isoquinoline)and related ring structures (such as berberine, palmatine, coptisine, and jateorrhizine) have shown very potent aldose reductase inhibitory activity. The structural activity relationship has revealed the importance of hydrophobic and hydrophilic groups of isoquinoline/bis(isoquinoline)for binding to an enzyme. The dioxymethylene group in the D ring (hydrophobic group) of these alkaloids binds tightly to the site adjacent to the anionic binding site (active site), while the methoxyl groups (polar) bind to the site adjacent to the nicotinamide ring of the coenzyme. On the basis of these findings, it may be proposed that the presence of isoquinoline/bis(isoquinoline)ring structures is the most important requirement for alkaloids to behave as potent aldose reductase inhibitors. Thus, other plants may also be screened for the same activity. The present review discusses these isoquinoline/bis(isoquinoline)-based alkaloids as aldose reductase inhibitors that may be used to manage diabetic complications and may substitute for the chemically synthesized aldose reductase inhibitors.
Introduction
A
ldose reductase (alditol: nicotinamide adenine dinucleotide phosphate [NADP] + 1-oxidoreductase, EC 1.1.1.21) is a monomeric reduced -NADP oxidase (NADPH)– dependent enzyme and a member of the aldo–keto reductase super family.1 Aldose reductase is found in almost all mammalian cells, but high levels are detected in the cornea, lens, retina, kidney, and myelin sheath.2 It is the first and ratelimiting enzyme in the polyol pathway, and increased activity of aldose reductase–dependent polyol pathway is involved in many diabetic complications, including nephropathy, neuropathy, cataract formation, and cardiovascular problems.3,4 In the polyol pathway, it uses NADPH as a cofactor to reduce glucose to sorbitol, which is subsequently acted upon by sorbitol dehydrogenase (SDH) to convert it into fructose.5 The conversion of sorbitol to fructose by sorbitol dehydrogenase is associated with depletion of cellular NAD + ; glutathione (reduced form) stores; and accumulation of malondialdehyde, a lipid peroxidation end product.6 Aldose reductase is a single-polypeptide domain composed of 315 amino acid residues.7 The peptide chain at the
amino terminal folds into a b/a-barrel structural motif containing eight parallel b strands that are connected to each other by eight peripheral a-helical segments running antiparallel to the b sheet. The active site is located in a large and deep cleft in the C-terminal end of the b barrel, and the NADPH cofactor binds in an extended conformation to the bottom of the active site.8 The active site of the enzyme is located on nicotinamide coenzyme and is buried at the bottom of a deep cleft, with C5 and the hydride donor C4 as accessible atoms with three distinct binding pockets. The first pocket is usually occupied by the anion head of ligand and thus named ‘‘anion binding pocket’’ or ‘‘hydrophilic pocket,’’ comprising Tyr48, His110, Trp20, Trp111, Ser159, and Asn160 residues and the positively charged nicotinamide moiety of the cofactor NADP + . The second is a hydrophobic pocket, known as a specificity pocket, and is lined by the residues Trp219, Trp20, Leu300, Cys298, Cys303, Trp111, Cys303, and Phe122.8 The residues of hydrophobic groups, including Trp20, Phe122, and Trp219, fully face the active site and make the major contacts with a potential substrate and inhibitors. The specificity pocket displays a high degree of flexibility. The third pocket is another
Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, India.
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196 hydrophobic pocket formed by the residues Trp20, Trp111, Phe122, and Trp219.9 It has been reported that Tyr48, His110, and Trp111 residues of the hydrophilic group are involved in hydrogen-bonding interactions with a substrate at the bottom of the active site (Fig. 1).8 Pharmacologic use of aldose reductase inhibitors has been recognized as an important strategy in the prevention and attenuation of long-term diabetic complications.10–12 Among the marketed preparations, two chemical classes of aldose reductase inhibitors (i.e., carboxylic acid and spiromide inhibitors [Fig. 2; note that throughout this article, numbers in parentheses refer to the numbered labels in the corresponding figures]) have been used clinically for management of diabetic complications.6 Saraswat and coworkers demonstrated that carboxylic acid inhibitors, such as zopolrestat (1), ponalrestat and tolrestat, (2) (Fig. 2) have poor tissue penetration and are less potent in vivo, whereas the spiromide inhibitors, such as spirohydantoin (3) (Fig. 2) cause skin reactions and liver toxicity.13 Therefore, development and evaluation of new effective and safe aldose reductase inhibitors are needed. Studies have shown that indigenous plants, such as Cuminum cyminum (seeds), Citrus limon (fruits), Allium cepa (bulb), and Malus pumila (fruit), possess the potent aldose reductase inhibitory and, consequently, diabetic complication– attenuating properties.13–15 Among the phyto-constituents, flavonoids such as quercetin, luteolin, kaempferol, myricetin, apigenin, flavones, chrysin, diosmetin tamarixetin, ombuin, and ayanin exhibit potent in vitro aldose reductase inhibitory activity in rat lenses.16–18 Moreover, flavonol glycosides, such as myricitrin, mearnsitrin, quercitrin, desmanthin-1, guaijaverin, and astilbin, also exhibit aldose reductase inhibitory activity in vitro.19–22 Coumarins, such as umbelliferone, scoparone, scopoletin, esculetin, and scopolin, have potent aldose reductase inhibitory activity.16 Terpenoids, such as glycyrrhizin glycyrrhetinic acid, lambertic acid,
FIG. 1. Diagrammatic representation of active site of the aldose reductase. The active site comprises three pockets: anion binding or hydrophilic pocket (comprising Tyr48, His110, Trp111, and Trp 20 protein residues and the positively charged nicotinamide moiety of the cofactor nicotinamide adenine dinucleotide phosphate + ), specificity pocket (comprising Leu300, Cys298 and Phe122 protein residues), and hydrophobic pocket (comprising Phe122 and Trp219 protein residues).
GUPTA ET AL. cryptotanshinone, tanshinone I, and sugiol have also shown aldose reductase inhibitory activity.23,24 Gallotannins and ellagitannins types of tannins isolated from plant sources have also shown inhibitory activity.23,25 Phenolic compounds, such as cyanidin-3-O-b-glucoside, peonidin-3-O-bglucoside, and ferulic acid, demonstrate potent aldose reductase inhibitory activity.26 Plant-derived alkaloids have aldose reductase inhibitory activity in in vitro as well as in in vivo studies, along with beneficial effects in diabetic complications.27,28 An alkaloidrich extract isolated from Capparis deciduas plant has shown potent aldose reductase inhibitory activity in streptozocin (60 mg/kg intraperitoneally)-treated diabetic mice.27 The isoquinoline and bis(isoquinoline)-type of alkaloids, such as berberine, has been extensively studied as an aldose reductase inhibitor. Based on these, structurally related alkaloids have also been explored for aldose reductase inhibitory activity. The present review describes various isoquinoline, bis(isoquinoline), and other structurally related alkaloids as aldose reductase inhibitors with special reference to berberine. Berberine Berberine (4) (Fig. 3.) (simplest isoquinoline alkaloid) and related alkaloids are found in plants such as Berberis aristata, Coptis chinensis, Coptis japonica, Cortex phellodendri, Coscinium fenestratum, Hydrastis canadensis, and Tinospora cordifolia.18–30 It has shown various pharmacologic activities, such as antidiarrheal, antibacterial, anti-inflammatory, anticancer, and neuroprotective (Alzheimer’s disease and Huntington’s disease).31–33 Berberine has also shown protective effects in diabetes and related complications. It decreases fasting blood glucose, total cholesterol, and triglyceride levels; urinary protein excretion; serum creatinine levels; and blood urea nitrogen levels and suppresses histologic and ultrastructural
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FIG. 2. Commercially available synthetic carboxylic acid and spiromide– based aldose reductase inhibitors. Zopolrestat (1), tolrestat (2), spirohydantoin (3). A, alkyl group; n varies from 1 to 6.
alterations in the kidney of streptozotocin-treated diabetic rats.34,35 Recently, administration of berberine in patients with type 2 diabetes was shown to exert hypolipidemic and antidyslipidemic effects.36 Xie and coworkers revealed that berberine upregulates Akt, possibly via an insulin signaling pathway, eventually lowering high blood glucose in alloxaninduced diabetic mice.37 Shen and coworkers demonstrated that berberine exerts antidiabetic action by activating cyclic adenosine monophosphate protein kinase and targeting insulin gene.38 It also decreases the postprandial plasma glucose levels of streptozotocin-diabetic rats by inhibiting the increased activities of intestinal disaccharidases and elevating plasma insulin levels.39 The possible mechanisms for nephroprotective effects of berberine may be related to inhibition of glycosylation and augmentation of antioxidation activity.34 Nakai and coworkers studied the inhibitory activities of aporphine, benzylisoquinoline, and bis(isoquinoline)alkaloidal types (berberine) in rabbit lens aldose reductase and suggested the key role of the isoquinoline ring in aldose reductase inhibition.40 All these compounds contain benzoquinolidine ring, as in GPA 1734 (8,9-dihydroxy-7-methyl-benzo-(b) quinolizium bromide), which is a potent inhibitor of aldose reductase.40 Bis(isoquinoline) alkaloids (Fig. 3), such as berberine, exhibit more potent aldose reductase inhibitory
activity (50% inhibitory concentration [IC50] values of 5.2 · 10 - 5 M) as compared with aporphine and benzylisoquinoline types (IC50 values of 10 - 4 M). Furthermore, reduction of the A ring of berberine, leading to formation of canadine (tetrahydroberberine) (5) (Fig. 3) significantly reduces aldose reductase inhibitory activity (IC50 values of 4.9 · 10 - 4 M), suggesting the requirement of unsaturated A ring for aldose reductase inhibition.40 Lee and coworkers compared the inhibitory activities of chloroform extract–derived berberine chloride alkaloid from the roots of Coptis japonica with commercially available berberine sulfate, berberine iodide, and quercitrin. All the salts of berberine alkaloids demonstrated potent in vitro rat lens aldose reductase inhibitory activity (IC50 values of 13.98, 13.45, and 32.84 nM), values similar to those of quercitrin, a flavonoid used as a positive standard (IC50 values of 11.15 nM). Among different salts of berberine, berberine chloride (IC50 values of 13.98 nM) and berberine sulfate (IC50 values of 13.45 nM) exhibited more potent aldose reductase inhibitory activity (2.5 times) compared with berberine iodide (IC50 values of 32.84 nM).41 Liu and coworkers demonstrated that berberine attenuates high glucose-induced increases in aldose reductase gene expression in the cultured mesangial cells.42 The same group of scientists also reported the aldose reductase inhibitory activity of berberine in
FIG. 3. Bis(isoquinoline)alkaloids berberine (4), tetrahydroberberine (5), palmatine (6), and tetrahydropalmatine (7) as aldose reductase inhibitors.
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FIG. 4. Representation of binding of berberine to the active site of aldose reductase. Dioxymethylene moiety of berberine binds to the hydrophobic pocket of the active site (comprising Trp219 residue), and the methoxyl groups along with polar nitrogen interact with the anion-binding pocket of the active site (comprising Trp111, His110, and Tyr48 residues).
streptozotocin-induced (60 mg/kg) diabetic rats with diabetic nephropathy. Administration of berberine (200 mg/kg per day for 12 weeks) downregulated the messenger RNA and protein expression of aldose reductase in rat kidneys and ameliorated renal dysfunction by inhibiting the polyol pathway.28,42 The aldose reductase inhibitory effects of berberine were similar to those of epalrestat, a well-known aldose reductase inhibitor. Increased aldose reductase activity due to enhanced aldose reductase gene expression has been shown in streptozotocin-treated diabetic rats.43 An increased aldose reductase activity is also associated with structural changes in the glomeruli of nephropathic patients.44 Palmatine Palmatine (Fig. 3), structurally related to berberine with a bis(isoquinoline)ring, is derived from such plants as Coptis japonica, Tinospora cordifolia, and Coptis chinensis and also possesses aldose reductase inhibitory activity.41,45,30 Nakai and coworkers also demonstrated the potent aldose reductase inhibitory activities of palmatine (IC50 values of 3.8 · 10 - 5 M) against aldose reductase in rabbit lenses. Similar to berberine, reduction of the A ring of palmatine, leading to formation of tetrahydropalmatine (7) (Fig. 3), also significantly reduced aldose reductase inhibitory activity (IC50 values of 7.6 · 10 - 4 M),40 again suggesting the key role of unsaturated A ring of bis(isoquinoline)alkaloids in aldose reductase inhibition. Kubo and coworkers also demonstrated the aldose reductase inhibitory activity of tetrahydropalmatine derived from the methanolic fraction of tubers from various Corydalis species (C. stenantha, C. thalictrifolia, C. racemosa, and C. pallida) in rat lenses.46 Lee and colleagues compared aldose reductase inhibitory activity of commercially available palmatine sulfate
FIG. 5. Benzisoquinoline/ phenylisoquinoline-type alkaloids dehydrocorydaline (8), papaverine (9), and demethylpapaverine (10) as aldose reductase inhibitors.
with palmatine iodide derived from chloroform fraction of Coptis japonica roots. The IC50 values of palmatine sulfate and palmatine iodide were 51.78 and 68.0 nM, suggesting that sulfate salts are more potent (1.3 times) than the iodide salts of palmatine.41 Recently, aldose reductase inhibitory activity of palmatine derived from alkaloidal fraction of Tinospora cordifolia stems in rat lenses (IC50 value of 3.45 lg/mL) has also been shown.30 Berberine Versus Palmatine Nakai and coworkers reported palmatine (IC50 values of 3.8 · 10 - 5 M) as more potent aldose reductase inhibitor compared with berberine (IC50 values of 5.2 · 10 - 5 M).40 In contrast, Lee demonstrated that berberines are somewhat more potent than palmatines, with IC50 values of berberine chloride (13.98 nM), berberine sulfate (13.45 nM), and berberine iodide (32.84 nM) significantly lower than those of palmatine sulfate (51.78 nM) and palmatine iodide (68.0 nM).41 The presence of the oxidized form of dioxymethylene group in the A and D rings of isoquinoline has been suggested as an important structural feature contributing to aldose reductase inhibition.45 Accordingly, the relative high potency of berberine may be attributed to the presence of the oxidized form of dioxymethylene group in the A ring as compared with dimethoxy groups in the corresponding A ring of palmatine. The ligand binding site in the aldose reductase is a deep, elliptical pocket with the nicotinamide ring of the NADPH cofactor at the base. There is involvement of Tyr 48 and Lys 77 and the nicotinamide ring in the catalytic region. The aldose reductase– active site includes specific anionic site delineated by the C4N of the nicotinamide coenzyme, the Og, of Tyr48, and
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FIG. 6. Aporphine alkaloids nandazurine (11), nantenine (12), domesticine (13), d-glaucine (14), and magnoflorine (15) as aldose reductase inhibitors. the Ne of His110. The hydrophobic region of the inhibitor binds in a ‘‘specificity’’ hydrophobic pocket in the active site, which is accessible after a conformational change of the enzyme.47 The important structural features of aldose reductase inhibitors include the presence of polar and nonpolar hydrophobic system, with polar groups attached to the hydrophobic ring system. The polar moiety of a inhibitor binds in a conserved active anion-binding site (catalytic site) and also interacts with NADP + (nicotinamide ring) of the coenzyme by forming hydrogen bonds with Tyr48, His110, and Trp111 residues of the coenzyme (present within the active binding
site) to hold the polar moiety firmly in the catalytic site.48 On the other hand, the hydrophobic ring systems of inhibitors are bound tightly in a deep pocket (adjacent to the anion-binding site of the coenzyme), which opens as a result of polar group binding to the active site, leading to the conformational change in the walls of the active site of coenzyme (Fig. 4).8 From the structures of alkaloids, it may be proposed that the dioxymethylene group of the D ring is the hydrophobic group and that it is tightly bound adjacent to the anionic binding site. On the other hand, the methoxyl groups are polar in nature and may bind to site adjacent to the nicotinamide ring of the coenzyme (Fig. 4).
FIG. 7. Protoberberine type alkaloids l-tetrahydrocoptisine (16), dl-corydaline (17), coptisine (18), groenlandicine (19) and jateorrhizine (20) as aldose reductase inhibitors.
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FIG. 8. Other structurally related alkaloids different to bis(isoquinoline)or isoquinoline protopine (21) and l-tetrahydrocolumbamine (22) as aldose reductase inhibitors.
Benzisoquinoline/Phenylisoquinoline Type Dehydrocorydaline (8) (Fig. 5), a phenylisoquinoline alkaloid, is obtained from the quaternary fraction of methanolic extract of tubers of various Corydalis species (such as C. stenantha, C. thalictrifolia, C. racemosa, and C. pallida) and exhibits potent aldose reductase inhibitory activity (44.5% at 50 lM) in rat lenses.46 Papaverine (9) and demethylpapavarine (10) (benzylisoquinoline type alkaloids) (Fig. 5) exhibit aldose reductase inhibitory activity (IC50 values of 1.4 · 10 - 4 and 1.9 · l0 - 4 M, respectively) in rat lens.40 The same group of scientists demonstrated that papaverine and berberine exhibit potent aldose reductase inhibitory activity alone; however, in combination they antagonize the aldose reductase inhibitory activity of each other in a competitive manner, with no clear mechanism.40 Aporphine Nakai and coworkers demonstrated that aporphine-type alkaloids, such as nandazurine (11), isoboidine, nantenine (o-methyl domesticine) (12), and domesticine (13) (Fig. 6) exhibit potent aldose reductase inhibitory activity, with IC50 values of 2.0 · 10 - 4, 2.7 · 10 - 4, 4.3 · 10 - 4, 7.6 · 10 - 4 M, respectively in rat lenses.40 d-glaucine (14) (Fig. 6) derived from the quaternary fraction of methanolic extract of tubers
FIG. 9. Alkaloids other than isoquinoline: 5-epidihydrolyfoline N-oxide (23), decamine N-oxide (24), lagerstroemine N-oxide (25), lagerine N-oxide (26), and piplartine (27).
of various Corydalis species (C. stenantha, C. thalictrifolia, C. racemosa, and C. pallida) exhibits aldose reductase inhibitory activity (16.5% at 50 lM) in rat lenses.46 Later in 2008, one more aporphine alkaloid magnoflorine (15) (Fig. 6) obtained from the butanolic fraction of rhizome of Coptis chinensis possessed aldose reductase inhibitory activity (IC50 > 50 lg/ mL) in rat lenses.45 Magnoflorine, also derived from alkaloidal fraction of Tinospora cordifolia stems, has shown an IC50 value of 1.25 lg/mL, similar to the positive control quercetin, with an IC50 of 1.08 lg/mL against aldose reductase in rat lenses.30 Protoberberine Type l-Tetrahydrocoptisine (16) (Fig. 7), a protoberberine alkaloid, is obtained from the quaternary fraction of the methanolic extract of tubers of various Corydalis species (C. stenantha, C. thalictrifolia, C. racemosa, and C. pallida) and exhibits aldose reductase inhibitory activity (5.7% at 50 lM) in rat lenses. dl-Corydaline (17) (Fig. 7), also derived from the quaternary fraction of methanolic extract of tubers of various Corydalis species (C. stenantha, C. thalictrifolia, C. racemosa, and C. pallida), exhibit structural similarities with berberine and exhibits aldose reductase inhibitory activity (6.7% at 50 lM) in rat lenses.46 Jung and coworkers evaluated protoberberine alkaloids, such as coptisine (18), groenlandicine
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FIG. 10. Bis(isoquinoline)/isoquinoline or other related alkaloids (-)-3-methoxyputerine (28), ( + )-norguattevaline (29), ( + )3-methoxyguattescidine (30), 3-ethoxyoxoputerine (31), ( + )-cassyformine (32), ( + )-filiformine (33), lettowianthine (34), 11methoxylettowianthine (35), isoboldine (36), norisoboldine (37), thaliporphine (38), corytuberine (39), reticuline (40), taspine (41), liriodenine (42), atherospermidine (43), stephalagine (44), discretine (45), desmorostratine (46), discretine N-oxide (47), dehydrodiscretine (48), pseudocolumbamine (49), predicentrin (50), asimilobine (51), stepholidine (52), ( + )-N-(methoxylcarbonyl)-N-nordicentrin (53), ( + )-N-(methoxylcarbonyl)-N-norpredicentrine (54), ( + )-N-(methoxylcarbonyl)-N-norbulbodione (55), ( + )-N-(methoxylcarbonyl)-N-norisocorydione (56), ( + )-8-methoxyisolaurenine-N- oxide (57), xylopine (58), anonaine (59), and romucosine (60) may be explored for their aldose reductase inhibitory activity.
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FIG. 10.
(19), and jateorrhizine (20) (Fig. 7), derived from the butanolic fraction of Coptis chinensis rhizomes for their aldose reductase inhibitory activity. Coptisine and groenlandicine possess potent aldose reductase inhibitory activities, with IC50 values of 37.9 and 45.2 lg/mL, respectively, in rat lenses and 66.7 and 51.2 lg/mL, respectively, in recombinant human lenses. On the other hand, jateorrhizine exhibited aldose reductase inhibitory activity, with an IC50 value greater than 50 M.45 On the basis of these results, it was proposed that in protoberberine-type alkaloids, the presence of dioxymethylene group in the D ring and the oxidized form of the dioxymethylene group in the A ring are the prime requirements for aldose reductase inhibitory activities in rat and human recombinant lenses.45 In contrast, a recent study has demonstrated the potent aldose reductase inhibitory activity of jateorrhizine derived from stem of Tinospora cordifolia alkaloidal extract, with an IC50 value of 3.23 lg/mL in rat lenses.30 It suggests that more studies are needed to establish the aldose reductase inhibitory activity of these protoberberine type alkaloids. Others Other structurally related alkaloids but different to bis(isoquinoline)or isoquinoline, such as protopine (21) (Fig. 8)
(Continued)
and l-tetrahyrocolumbamine (22) (Fig. 8), derived from the quaternary fraction of the methanolic extract of tubers of various Corydalis species (C. stenantha, C. thalictrifolia, C. racemosa, and C. pallida), have also been shown to possess aldose reductase inhibitory activity (IC50 values of 10.9 and < 5, respectively, at 50 lM concentration) in vitro in rat lenses.46 Alkaloids Other than Isoquinoline/(BIS)Isoquinoline Type Recent studies have suggested that alkaloids other than isoquinoline/bis(isoquinoline) also exhibit aldose reductase inhibitory activity. In 2011, three biphenylquinolizidine Noxide alkaloids—5-epi-dihydrolyfoline N oxide, decamine N-oxide (24), and lagerstroemine N-oxide (25)—and one biphenyl ether quinolizidine N-oxide alkaloid—lagerine Noxide (26) (Fig. 9)— isolated from the ethanolic extract of the aerial parts of Lagerstroemia indica were shown to posses aldose reductase inhibitory activity (25%–32% inhibitions at a concentration of 50 lM) against aldose reductase in rat lenses.49 Rao and coworkers reported aldose reductase inhibitory activity of piplartine (27) (Fig. 9) alkaloid derived from the chloroform extract of Piper chaba against aldose reductase in recombinant human lenses, with an IC50 of 160 mM. On
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the basis of the structural similarities of available aldose reductase inhibitors and piplartine, it was proposed that the imide functionality (-CO-NH-CO-) plays a critical role in aldose reductase inhibitory activity.50
measure against diabetic complications related to increased activity of aldose reductase.
1. Future Directions
The authors are also grateful to Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, India, for supporting this study.
On the basis of the preceding discussion, it may be proposed that the presence of bis(isoquinoline)/isoquinoline or other related ring structures is the primary requirement for a compound to exhibit potent aldose reductase inhibitory activity. Therefore, more plant species containing these ring structures may also be explored to identify the potent aldose reductase inhibitors. The following plants containing bis-(isoquinoline)/isoquinoline ring structures (Fig. 10) may be evaluated for their aldose reductase inhibitory activity. 1. Alkaloids such as (-)-3-methoxyputerine (28), ( + )-norguattevaline (29), ( + )-3-methoxyguattescidine (30) and 3-methoxyoxoputerine (31) (Figure 10), present in the alkaloidal fraction of stem bark of Guatteria foliosa.51 2. Alkaloids such as ( + )-cassyformine (32), ( + )-filiformine (33) (Fig. 10), present in the methanolic extract of fresh herbs of Cassytha filiformis II.52 3. Alkaloids such as lettowianthine (34) and 11-methoxylettowianthine (35) (Fig. 10) present in the ethanolic extract of root bark of Lettowianthus stellatus.18 4. Alkaloids such as isoboldine (36), norisoboldine (37), thaliporphine (38), corytuberine (39), reticuline (40), and taspine (41) (Fig. 10) present in the crude extract of Croton lechleri (leaves and latex).53 5. Alkaloids such as liriodenine (42), atherospermidine (43), and stephalagine (44) (Fig. 10) present in the ethanolic extract of the stems of Stephania dinklage.54 6. Alkaloids such as discretine (45), desmorostratine (46), discretine N-oxide (47), dehydrodiscretine (48), pseudocolumbamine (49), and predicentrin (50) (Fig. 10) present in the methanolic extract of stem bark of Desmos rostrata.55 7. Alkaloids such as reticuline (40), asimilobine (51), and stepholidine (52) (Fig. 10) present in the Diploclisia affinis.56 8. Alkaloids such as ( + )-N-(methoxylcarbonyl)-N-nordicentrin (53), ( + )-N-(methoxylcarbonyl)-N-norpredicentrine (54), ( + )-N-(methoxylcarbonyl)-N-norbulbodione (55), ( + )-N-(methoxylcarbonyl)-N-norisocorydione (56), and ( + )-8-methoxyisolaurenine-N-oxide (57) (Fig. 10) present in the ethanolic extract of bark of the Litsea cubeba.57 9. Alkaloids such as xylopine (58), anonaine (59), and romucosine (60) (Fig. 10) present in the crude alkaloidal fraction of Annona crassiflora leaves.58 Conclusion From the evidence presented here, it may be concluded that isoquinoline/bis(isoquinoline)type and other structurally related alkaloids exhibit potent aldose reductase inhibitory activity. Accordingly, these moieties may be used as a structural template for development of more potent aldose reductase inhibitors. Furthermore, more plant species may also be explored having alkaloids exhibiting structural similarities with isoquinoline type alkaloids as an effective
Acknowledgments
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Address correspondence to: Amteshwar Singh Jaggi, PhD Department of Pharmaceutical Sciences and Drug Research Punjabi University Patiala-147002 India E-mail: [email protected]
