Berberine Derivatives with Different Pharmacological

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REVIEW ARTICLE

Berberine Derivatives with Different Pharmacological Activities via Structural Modifications Daipeng Xiao1, Zhenbao Liu3, Shanshan Zhang1, Mi Zhou2, Fen He1, Ming Zou2, Junying Peng2, Xiong xie1, Yanfei Liu1,* and Dongming Peng2,* 1

Department of Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Central South University, Changsha 410083, PR China; 2Department of Medicinal Chemistry, School of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, PR China; 3Department of Pharmaceutics, School of Pharmaceutical Sciences, Central South University, Changsha 410013, PR China

ARTICLE HISTORY Received: August 26, 2016 Revised: January 25, 2017 Accepted: March 15, 2017 DOI: 10.2174/1389557517666170321103139

Abstract: Berberine, a quaternary ammonium protoberberine alkaloid with an isoquinoline scaffold isolated from medicinal herbs, exhibits a wide spectrum of pharmacological activities. Berberine has been used in traditional Chinese medicine and Ayurvedic medicine. However, it has poor bioavailability, which seriously limits its application and development. The chemical transformation of natural products is an effective method to improve pharmacological activities. Researches have been carried out on the modification of berberine to obtain better pharmacological properties. In this paper, the structural modifications of berberine for different biological activities and its underlying mechanisms are reviewed.

Keywords: Berberine, bioavailability, chemical transformation, mechanisms, pharmacological activities, structural modification. 1. INTRODUCTION Berberine (Fig. 1), a protoberberine alkaloid, is widely distributed in several medicinal herbs, such as Coptidis rhizoma, Berberis aristata (5% in roots and 4.2% in stem-bark), Phellodendron amurense bark (2–4%), and Hydrastis canadensis [1-4]. The extracts containing berberine from these medical plants have been employed in Chinese medicine and Ayurvedic medicine for hundreds of years with a wide range of pharmacological effects [5-8]. However, berberine has a high solubility and low permeability [9-13], low bioavailability [14], and the corresponding low therapeutic efficiency [10, 14], so patients have to be treated with multiple dosing of berberine. Systematic chemical modification of natural or synthetic compounds with known pharmacological activities is a common practice in drug design [15]. As structural modification is an effective method to improve the efficacy of drugs [5], the modification of berberine activities becomes

feasible. Due to its multiple pharmacological activities, such as anti-hyperglycemic [16-18], anti-tumor [19-21], antimicrobial [22-24], anti-inflammatory [25, 26], anti-alzheimer [27-29], anti-atherosclerosis [30] and anti-malarial [31-33], berberine becomes a leading compound for new promising drug development. There are many positions can be modified, recently, the structural modifications of berberine mainly focus on its C-8, C-9, C-12, C-13 positions for different pharmaceutical purposes [1]. This review would provide useful information for further studies on structural modification of berberine for promoting the clinical application of berberine-based drugs. In addition, the mechanisms underlying the relationship between structural modification and pharmacological effects are reviewed. O 3 O

*Address correspondence to these authors at the Department of Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Central South University, P.O. Box: 410-083, Changsha, PR China; Tel/Fax: +86-731-88879616; E-mail: [email protected]; and Department of Department of Medicinal Chemistry, School of Pharmacy, Hunan University of Chinese Medicine, P.O. Box: 410-208, Changsha, PR China; Tel/Fax: +86731-85555868; E-mail: [email protected] 1389-5575/17 $58.00+.00

4

5

A

B

2 1

13

Fig. (1). Structures of berberine. © 2017 Bentham Science Publishers

6 N C

7

8

9O D 10 12 O 11

2

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2. BERBERINE DERIVATIVES FOR HYPOGLYCEMIC ACTIVITY The hypoglycemic effect of berberine has been reported since 1988 [34]. In order to elucidate the molecular mechanism of antidiabetic effects of berberine, several clinical trials have been implemented [35]. The major mechanism of the activity may be related to insulin-independent inhibition of mitochondrial function, stimulation of glycolysis and activation of adenosine monophosphate-activated protein kinase (AMPK) pathway. Berberine increases the activation of cardiac 5′-adenosine monophosphate-activated protein kinase and protein kinase B, and reduced the activation of glycogen synthase kinase 3β (GSK3β) in the treatment of diabetic animals [36]. Wei et al. found that berberine had a significant effect on balancing the level of fasting blood glucose (FBG), postprandial blood glucose (PBG) and glycosylated hemoglobin [37]. Berberine also acts as an α-glucosidase inhibitor, which reduces glucose absorption in intestinal cells. Berberine decreases blood insulin level via enhancing insulin sensitivity in type 2 diabetic patients. Berberine regulates peroxisome proliferator-activated receptors and positive transcription elongation factor b (P-TEFb) expression in diabetic adipocytes [38]. Additionally, berberine lowers insulin resistance in diet-induced obese rats, an effect similar to metformin [39]. Sixteen protoberberine derivatives were synthesized and their hypoglycemic activity was screened in a cell-membrane chromatography model and then in an alloxan-induced diabetic mode, which indicated that the methylenedioxy function at C-2 and C-3 may be indispensable for the binding activity of protoberberine derivatives to β-cell membranes and positively charged nitrogen atoms in the ring C may play an important role in binding interactions via electrostatic effect [40]. Moreover, Bian et al. had found that the binding activity changed with different alkyl derivatives when tetrahydroberberine was alkylated to quaternary ammonium salts. Compounds 1a and 1b appeared no binding activity while 1c displayed high binding affinity and the most effective hypoglycemic effect, which suggested that the electrostatic effects of positively charged nitrogen atoms of berberine may be non-specific binding forces and the quaternary ammonium salt structure that has an aromatic ring C is not a key part of berberine derivatives to show hypoglycemic effect and the hydrophobic force of alkyl groups at position N-7 may play an important role in the binding of quaternary salts (1a-c, Fig. 2) [40]. Protoberberine-type alkaloids with the dioxymethylene group in the ring D and the oxidized form of the dioxymethylene group in the ring A were partly provided with the rat lens aldose reductase (RLAR) and human recombinant aldose reductase (HRAR) inhibitory activities (epiberberine, coptisine and groenlandicine with IC50 values of 168.1, 187.3, 154.2 µM for HRAR and 100.1, 118.4, 140.1 µM for RLAR) [41]. The 12-aminomethyl berberrubine derivatives were synthesized and evaluated for their anti-diabetic activities against type II diabetes mellitus in 3T3-L1 adipocytes and L6 myotubes. The insulin-resistant reversal activity and glucose transport activity of the berberrubine derivatives are mostly comparable to or even better than berberine at different concentrations in 3T3-L1 adipocytes and L6 myotubes.

Xiao et al.

Among the 12-(substituted aminomethyl) berberrubine derivatives, the compound 2 (Fig. 2) showed the best activity and the sensitization reached 1.26 fold of rosiglitazone [42]. The results indicated that introducing aminomethyl groups to the 12-position of berberrubine could remarkably improve the insulin-resistant reversal activity and stimulate glucose transport activity against type II diabetes mellitus by enhancing their ability binding to the target of drug mainly through hydrophobic and conjugated effects [42, 43]. In vitro tests indicated that the α-glycosidase inhibitory activity of compound 3 (IC50, 5.88 µM) was 1.2-fold higher than that of the standard, acarbose (IC50, 7.01 µM), which showed that the compound 3 (Fig. 2) may be used as an anti-diabetic agent [44]. It had been reported that alkylation and acylation of berberine on the benzene ring D could enhance activity and ameliorate bioavailability. The methoxyl at the 9-position could form an electrostatic attraction with the quaternary ammonium ion at the 7-position, which leads to the decreasing of the electropositivity of berberine. However, exchanging the methoxyl group from the 9-position to the 11position increases the distance between quaternary ammonium ion and methoxyl group. Pseudoberberine bearing 10,11-dimethoxy 4 (Fig. 2) improved glucose-lowering in vivo efficacy and bioavailability due to the low affinity to Pglycoprotein. With improved pharmacokinetics in vivo and biological activity in vitro, 4 showed an enhanced hypoglycemic effect than that of berberine in diabetic mice [45]. Berberine analogues with 9-methoxy and 10-hydroxy on the ring D exhibited potent activity of glucose-lowering activity. In addition, the hydroxyl group at position C-10 of berberine could act as a bridge to introduce proper chemical groups for optimizing drug-bioavailability in vivo [46]. The 8,8dimetheyldihydroberberine 5a-c (Fig. 2) with better stability and bioavailability over berberine and dihydroberberine [47], which improved glucose tolerance, and decreased tissue triglyceride accumulation and insulin resistance in dietinduced obese. Berberine was proved to possess up-regulating activity on insulin receptor (InsR) and low-density-lipoprotein receptor (LDLR) [48]. Some appropriate modifications on phenyl ring A or D of berberine might keep the up-regulatory activities according to the structure-activity relationships analysis. 10-hydroxylberberine presented activities on the gene expression of either LDLR or InsR. Poly-nuclear molecular compound 6 (Fig. 2) containing berberrubine and magnolol was synthesized as anti-diabetic agents, the toxicity of which is 10% of that of berberrubine and magnolol [49]. Moreover, bioavailability, the absorption rate, metabolism time, and blood-sugar-reducing effect of berberrubine-magnolol dimers are better than those of the individual chemical species. Berberrubine-magnolol dimers significantly increased glucose metabolism in transgenic aP2-SREBP-1c mice and promoted the metabolism of glucose in streptozotocin-induced type II diabetic mice. Combined with metformin, the first-line drug for the treatment of type II diabetes [50], berberine presented a less toxicity, better dissolution, and increased stability of the pharmaceutical composition. Halogenation, which is another frequent approach for the modifications of natural compounds [51], plays an important

Berberine Derivatives with Different Pharmacological Activities

Mini-Reviews in Medicinal Chemistry, 2017, Vol. 17, No. 0

O

O

O

N

N R

O

O

O

N

O

N

O

O

N

O O

OH

1a-c

OH

O

N H

2

1a: R=CH3 1b: R=CH2CH3 1c: R=CH2C6H5

N

OH OH

3

O

O

O

O

O

3

O O O

N

O

N

N

O

O RR

4

n

5a-c OH

5a: R=CH3 5b: R=CH2CH3 5c: R=CH2CH2CH3 O

N

O O

X=I, Br, Cl

O

O

O

X

6

O

O

N+

O O

7

N

O O O

O

R O

O

9a-b

8

9a: R=

O

9b: R= O O

Fig. (2). Structures of berberine derivatives 1-9 for hypoglycemic activity.

role in improving bioactivity. Halogenated berberine homologues were synthesized by replacement of the 8 and 13-Hatom in the ring C of berberine with alkyl side chain and halogens, the hypoglycemic activity of which were evaluated using human hepatoma cell lines (HepG2) and in vitro cytotoxicity assessment assay [52]. The investigation indicated that chloroberberine and bromoberberine presented a promising glucose-lowering effect and the lowest cytotoxicity to HepG2 cell lines among all the berberine derivatives. Compared to halogenated berberine 7, alkylberberine and alkyl bromoberberine displayed inessential hypoglycemic effect. The introduced alkyl groups at the 8-position of berberine could increase the cytotoxicity of berberine derivatives. Berberine-phenylacetic acid derivative 8 showed application in diabetes and diabetes combined with other diseases with improved insulin resistance and increased cell glucose utilization (7 and 8, Fig. 2) [53, 54]. Compounds 9a and 9b (Fig. 2), 9-O-(lipophilic group substituted) berberine derivatives synthesized by Zhang et al., showed a superior hypoglycemic effect than that of berberine and the cytotoxicity main-

tained and even lower than berberine on HepG2 cell lines, which displayed a structure-activity relationship that the introduction of aromatic nucleus with basic group or electrondonating group bearing C-9 to berberine might be conducive to hypoglycemic activity [55]. 3. BERBERINE DERIVATIVES FOR ANTICANCER ACTIVITY Berberine has been reported to have promising anticancer effects on different tumor cell lines, such as glioblastoma, hepatoma, melanoma, colon, breast, prostate and so on [5663]. It has been reported that berberine suppresses cancer cell proliferation via interactions with various targets. The rapid proliferation of cancer cells is associated with the loss of critical checkpoint partially. Berberine can change the expression of oncogenes and carcinogen-related genes and inhibit carcinogenesis-related enzymes [64]. Some mechanisms of anticancer effects of berberine have been reported including inhibiting tumor cell invasion and proliferation,

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Xiao et al.

inducing autophagic cell death and suppressing angiogenesis and metastasis [65]. Investigation indicated that berberine in a concentration (0-50 µM) induced the expression of tumor suppressor gene p53 [66]. Telomerase inhibition and topoisomerase poisoning are considered to be hypothetical reasons for anticancer activity [67-69]. Studies had found that berberine had the inhibitory effect on arylamine Nacetyltransferase activity [70]. Furthermore, it had been reported that berberine may provide protection against breast cancer by altering the ratio of CYP1A1/CYP1B1 (the estrogen metabolizing enzymes) [71].

cancer activity. Berberine alkaloids with a hydroxyl group at 9-position were served as the selective topoisomerase II poison, while derivatives with methoxy group at 9-position had less activity [75]. It had been demonstrated that the calf thymus DNA-binding affinities of polyamino protoberberines increase with the increase of the number of NH2 groups within four [76]. Berberine analogs with substitutions at the 9-position showed better DNA binding capacity. The 9-O-Naryl/arylalkyl carbonyl methyl substituted berberine analogs 10a-c (Fig. 3) were investigated and found to possess a remarkable enhancement of the DNA binding affinity (Table 1) [77]. Ferrocyanide quenching and viscosity studies confirmed that all these analogs (10a-c) bound to DNA via intercalation. The highest binding affinity of 10a was about six times higher than that of berberine under the same conditions. The binding constants and other thermodynamic parameters (10a-c) are depicted in Table 1 [77]. Furthermore, the binding thermodynamics of the interaction of isoquinoline alkaloids coralyne 11 and sanguinarine 12 (Fig. 3) to calf thymus DNA had been investigated (Table 1) [78, 79]. Berberine dimers 13a–f was synthesized via alkylation of

Berberine could induce poisoning of DNA topoisomerase I via inhibition of religation of broken strands of DNA [72]. Some researches demonstrated that that berbereine caused mitochondrial fragmentation and dysfunction via accumulated by mitochondria [73, 74], thus mitochondria might be the target of berberine. The strong nucleic acid binding affinity and related enzyme inhibition have been thought to be the main reason in anticancer activity of berberine. Topoisomerases are important enzymes which are linked to antiO

O N

O

O

N H

N

O

X

O

X N

O N

O

OH N+

O O

O

O

R n

O

O 14a-f

15

O

O

14a(i-v): n=2-6 R=NH2 13b: n=3 R=N(CH3)2 14c(i,ii): n=2,3 R=N(C2H5)2

13a-f 13a:n=0, X=Br 13b:n=1, X=Br 13c:n=2, X=Br 13d:n=3, X=I 13e:n=4, X=I 13f :n=5, X=Br

14d(i,ii): n=2,3 R= N

O

14e: n=3

R= N

14f: n=2

R= N

NH

N O

O

N

O

12

O

O

n

O

11

O

O

O

O

10a-c:n=0-2

N

O

n Ph

OMe

O

O

N

O

O

O

O m

R

O

N

O

H N

O

R n

O

16a-f

N

O O

17a-j

Cl 18

R m=0 1 2

N

O 16a 16c 16e

N 16b 16d 16f

17a: n=2 R=N(CH3)2 17f: n=3 R= N(CH3)2 17b: n=2 R= N

O 17g: n=3 R= N

17c: n=2 R= N

17h: n=3 R= N

17d: n=2 R= OH

17i: n=3 R=

17e: n=2 R=

17j: n=6 R= NH2

Fig. (3). Structures of berberine derivatives 10-18 for anticancer activity.

O

N

Berberine Derivatives with Different Pharmacological Activities

Mini-Reviews in Medicinal Chemistry, 2017, Vol. 17, No. 0

berberrubine (4) with dibromo- or diiodoalkanes of varying lengths from two to six carbons [80, 81]. The result indicated that a propyl chain may be the most suitable interval to bridge the two berberine units to obtain high binding affinity and these berberine dimmers interacted with more base pairs than berberine. Alkylation of berberrubine with 1, 2 dibromoalkane followed by ammonolysis and anion exchange afforded compound 14a-f (Fig. 3) [82-84].

methylpiperazinyl groups of 14d(i) and 14f [82, 86]. The introduction of a side chain especially with a positively charged aza-aromatic terminal group on the 9-position of the berberine had a positive effect on stabilization of Gquadruplex DNA [83, 84, 87]. Berberine derivatives 16a-f (Fig. 3) replaced by varying lengths of polyethylene glycol side chain and piperidine or morpholine as a terminal group were synthesized. The results indicated that the binding affinities decreased with the increasing length of side chain. The presence of metal cation or not had nothing to do with the formation of anti-parallel G-quadruplex of telomeric DNA [83, 84]. Berberine was treated with different primary amines to obtain a series of 9-N-substituted berberine derivatives 17a–j (Fig. 3) that induced and stabilized the formation of intramolecular parallel G-quadruplex in c-myc1 [87]. Adding pyridine ring and amino group to berberine structure enhanced the binding ability and selectivity towards Gquadruplex DNA structure compared to the above 9-Nsubstituted berberine derivatives (17a-j) [88]. Xiong et al. found that compound 18 (Fig. 3), a 9-substituted berberine derivative with a side chain of chlorohexyl group, stabilized endogenous telomeric G-quadruplexes structures and induced the delocalization of single-stranded binding protein and double-stranded binding protein from the telomere accompanied by a rapid telomere uncapping [89]. Besides, compound 18 exhibited the strongest inhibitory effects on the tumor cells because of the dissociation of shelterin proteins. A farnesyl 9-O-substituted berberine 8 synthesized by

Structural and thermodynamics aspects of the DNA binding of five 9-O-ω-amino alkyl ether berberine analogs 14a(iv) were investigated, which showed that the side chain on the nonplanar ring system dramatically affected the affinity of these molecules for DNA. Thermodynamic parameters indicated (Table 1) that the length enhancement of the side chain clearly enhanced the binding affinity, which indicated that the amino alkyl side chain and the chromophoric moiety effectively involved in DNA binding process [85]. Alkylation of berberrubine with 2-iodoethanol in DMF produced 15 (Fig. 3) [82]. The interaction of compounds 15, 14a(i), 14d(i), 14f with DNA was investigated by means of spectrometric titration and ethidium bromide displacement experiments to evaluate their binding affinities and mode of interaction, which showed that the relative binding affinities varied as 14a(i) > 14d(i) >14f >15≥berberine. 14a(i) showed the most efficient binding ability to DNA. The protonated amino group of 14a(i) was less hindered so as to have more strongly interaction with DNA through hydrogen bond and increased electrostatic interactions compared protonated imidazolyl and R2 R3

Cl

O R1

O

R

O N

MeO

OMe

19a-d

20a-b

19a: R1+R2=OCH2O 19b: R1+R2=OCH2O 19c: R1=R2=OMe 19d: R1=R2=OMe

R3= n-C6H13 R3= n-C8H17 R3= n-C6H13 R3= n-C8H17

N

O

N X

MeO

N

MeO

O

R

O

OMe

OMe

HN

21

R= N H

2' 23a:2'-R, X=Cl 23b:3'-R, X=Cl 23c:4'-R, X=Cl

23e:X=Cl R=

23f:X=Br R= O O

N

MeO

O

4' 3' O H N

23d:X=Br R= 23a-f

22

N

O

20a(i-vi): R=(CH2)nPh n=1-6 20b(i-vi): R=(CH2)nCHPh2 n=0-5

O

OMe

O

N

MeO

OMe

5

24

Fig. (4). Structures of berberine derivatives 19-24 for anticancer activity.

O

6

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Lo et al. which has a better hydrophobicity showed a 104fold antiproliferation activity in compare with berberine against human hepatoma HepG2 cell lines after 48 incubation hours [90]. The 13-n-alkyl substituted berberine and palmatine analogues 19a-d were studied (Fig. 4). 13-n-hexyl-berberine 19c exhibited better antitumor activity and less toxic effect than 13-n-octyl-palmatine 19d [91]. The structural effects and thermodynamics of the DNA binding of 13-diphenylalkyl analogue 20b(i-vi) (Fig. 4) were investigated by Bhowmik et al. (Table 1) [92]. The 13-phenylalkyl analogs 20a(i-vi) (Fig. 4) of berberine were studied by Bhowmik et al. for their binding to DNA to understand the mode, mechanism, sequence selectivity and energetics of interaction. With the increasing of the chain length of the substitution in 13phenylalkyl substituted berberines, the affinity increased until the critical length of (CH2)3 was achieved. After which, the binding affinity decreased slightly. In contrast to the enthalpy driven binding of berberine, energetics of the binding suggested an entropy driven binding (Table 1) for the analogs due to the influence of the side chain. Scatchard analysis of the binding data indicated non-cooperative binding of these analogs (20a, 20b) in contrast to the cooperative binding of berberine (Table 1) [93]. X-ray structure of the adduct formed by 20b(iv) and the human telomeric sequence d[TAG3(T2AG3)3] showed that the ligand molecule sandwiched between guanine quartets belonging to different quadruplex units, with its benzhydryl group contributing to the overall stability of the adduct by means of additional πstacking interactions with the DNA residues [94]. Ortiz et al. found that compounds 21, 20a(iii) and 20b(iii) were cytotoxic to two human colon cancer cell lines (HCT116 and SW613-B3) compared to berberine, which induced cell cycle arrest and cell death through apoptosis [95]. Further study on anticancer activity of compounds 21 (Fig. 4) was more effective than that of berberine in delaying the development of spontaneous mammary tumors in mice transgenic for the human epidermal growth factor receptor-2 (HER2) and neu oncogene through reduction of tumor vascularity and inhibition of degradation [96, 97]. The antiproliferative effect of berberine derivatives 20b(iv-vi) and 20a(v-vi) on both wildtype and mutated p53 cell lines was investigated by Ortiz et al., which were more effective than berberine, with an IC50 very similar for both cell lines. Moreover, experiments on the correlation between the biological effects of berberine derivatives and its fluorescence property depending on the nature of the added group indicated that a derivative was more active with increased fluorescence [98]. The 13-substituted piperidino derivative of berberine 22 (Fig. 4) was reported. Its aromatic moieties play a dominant role in quadruplex binding [99]. The complexation of berberine derivatives 23a-f (Fig. 4) with 5-nitro-2-phenylindolylmethyl and 2-naphthalenyl group at 13-position with Gquadruplex DNA molecules was studied [100]. Replacement of the 5-nitro-2-phenylindole moiety with a 2-naphthalenyl at 13-position enhanced the binding affinity to G-quadruplex. 13-substituted indolyl berberine derivative 24 (Fig. 4) exhibited moderate binding affinity [101]. The positively charged nitrogen atom at the 7-position of berberine endued its ability to form complexes with DNA or RNA. The 2- and 3-

Xiao et al.

position replaced with methylenedioxy, the 7-position of the quaternary ammonium and the planar structure were supposed to required elements for biological activity of protoberberine alkaloids, while the 7- or 13- position introduced with electron-donating groups decreased the activity [102]. Structure-cytotoxicity relationships obtained from berberine derivatives indicated that the functional groups played an important role on biological activity. Lipophilic groups at position C-8 or C-13 had a critical effect on the cytotoxicity. For berberine and palmatine derivatives bearing a 13-alkyl side chain, the cytotoxicity enhanced with CH2 units increasing in the side chain. Bromination at C-12 increased the cytotoxicity [103]. Elongating the alkyl side chain at C-8 or C13 improved the cytotoxicity. The methylenedioxy group in ring A is essential for its anticancer activity. There is a vertical relationship between the aromatic ring A and lone pair electron orbits of oxygen atoms of methylenedioxy in berberine, while the introduction of methoxy groups at the same positions are some out of the plane of ring A to avoid steric compression. The intercalative ability of protoberberine alkaloids to bind to duplex DNA might be attributed to this molecular shape. The introduction of the hydroxyl group at C-8 in the ring C and concomitant saturation of double bond between N-7 and C-8 induced the reduction of cytotoxicity in human tumor cells [104]. Trans-quinolizidine planar conformation of berberine alkaloids could enhance its toxicity [105]. Replacing methoxy groups at C-2 and C-3 with a methylenedioxy group or with an ethoxy group at C-9 increased the cytotoxicity, while replacement of a methoxy group by a hydroxyl group decreased cytotoxicity. It caused a decrease on the shift of methoxy groups at C-9 and C-10 to C-10 and C-11 in cytotoxicity. Berberine derivatives bearing a hydroxy group at C-11 decreased the cytotoxicity. The presence of an iminium structure in the protoberberinium salts enhanced cytotoxicity compared to those without iminium structure. 4. BERBERINE DERIVATIVES FOR ANTI-MICROBIAL ACTIVITY Studies had shown that berberine displayed antimicrobial activity against a wide variety of microorganisms including Gram-positive and Gram-negative bacteria, fungi, protozoa, trypanosomes and plasmodia [106-110]. The antimicrobial activity of berberine alkaloids has been reported. Study had shown that berberine can inhibit Vibrio cholera and Escherichia coli enterotoxins without causing histological damage to the intestinal mucosa [111]. Berberine sulphate had been shown to block the attachment of Streptococcus pyrogenes and E. coli to mucosal and epithelial surface [112]. Berberine was reported to inhibit Helicobacter pylori [113]. The inhibitory effects of three protoberberine alkaloids tested on E. coli exposed that the sequence of their pharmacological antimicrobial activity was berberine > coptisine > palmatine [114]. According to results, the group methylenedioxy at C-2 and C-3 position on ring A improved antimicrobial activity more remarkably than methoxyl at those sites, while the antimicrobial activity did not change significantly with methylenedioxy or methoxyl at C-9 and C10 on ring D. The mechanism of antimicrobial activity of berberine was investigated by studying metabolic profiles of

Berberine Derivatives with Different Pharmacological Activities

Table 1.

Mini-Reviews in Medicinal Chemistry, 2017, Vol. 17, No. 0

7

Thermodynamic parameters for the association of berberine and substituted berberine analogs with calf thymus (CT) DNAa.

Compound

Ka×10-5 (M-1)

n

△Go (kcal/mol)

△Ho (kcal/mol)

T△So (kcal/mol)

Berberine

1.77±0.07

4.10

-7.04±0.15

-2.94±0.039

4.10

Coralyne (11)

0.715

0.25

-9.25

-7.06

2.30

Sanguinarine (12)

0.121 ±0.021

1.47 ±0.02

34.15 ± 0.67

29.25 ± 0.67

4.90

10a

7.96±0.04

2.00

-7.91

-1.29

6.62

10b

6.33±0.07

2.44

-7.79

-1.49

6.30

10c

5.18±0.02

2.86

-7.65

-1.79

5.86

14a(i)

3.57

0.49

-7.45

-2.616

4.83

(ii)

5.17

0.268

-7.67

-2.191

5.48

(iii)

7.31

0.200

-7.87

-2.015

5.86

(iv)

11.50

0.185

-8.12

-1.820

6.30

(v)

32.60

0.139

-8.73

-1.667

7.06

20a(i)

0.31±0.02

6.91

-6.04±0.09

+0.87±0.075

6.91

(ii)

2.07±0.15

5.53

-7.13±0.25

-1.59±0.046

5.53

(iii)

11.20±0.8

7.21

-8.12±0.41

-0.91±0.019

7.21

(iv)

7.60±0.13

6.09

-7.89±0.35

-1.79±0.064

6.09

(v)

7.45±0.64

5.68

-7.87±0.18

-2.19±0.041

5.68

(vi)

6.85±0.61

6.27

-7.83±0.21

-1.56±0.024

6.27

20b(i)

0.48±0.04

6.2

6.32±0.11

+1.46±0.02

7.77

(ii)

0.51±0.06

6.0

6.35±0.10

+1.31±0.04

7.65

(iii)

6.89±0.15

4.0

7.87±0.21

-1.71±0.05

6.17

(iv)

11.2±0.55

4.1

8.16±0.35

-1.65±0.06

6.51

(v)

8.58±0.45

4.7

-8.01±0.29

-1.26±0.03

6.75

(vi)

7.36±0.41

6.0

-7.92±0.32

-0.97±0.03

6.95

a

All the data in this table are derived from isothermal titration calorimetry (ITC) experiments and are average of four determinations. The binding affinity (Ka) and standard molar enthalpy change (ΔHo) were determined from ITC profiles fitting to Origin 7.0 software. n is the site size which is the reciprocal of stoichiometry. The values of ΔGo, the standard molar Gibbs energy change and TΔSo, the standard molar entropy contribution were determined using the equations ΔGo= −RTlnKa and TΔSo=ΔHo−ΔGo. R is the gas constant. T is the absolute scale temperature in kelvins. Analogs 11a experiments were measured in citrate-phosphate buffer of 20mM [Na+]. The other analogs experiments were conducted in citratephosphate buffer of 10mM [Na+].

Staphylococcus aureus [115]. According to the result, the mode of antimicrobial activity of berberine should be similar with that of rifampicin and norfloxacin and its target may be on nucleic acid. The highly aromatic nearly planar quaternary structure of berberine has contributed to its ability to intercalate with DNA, which could be a reason for the observed cytotoxic effect [116, 117]. Study on 8-alkyl- and 8phenyl-protoberberines showed that the introduction of hydrocarbon groups at position C-8 increased the antimicrobial activity [118]. The 12-bromo derivatives of the 8-alkyl- and 8-phenyl-protoberberines exhibited higher activity against the tested microorganisms compared to their non-brominated analogs. Experiments with 13-alkylberberine and 3-alkylpalmatine indicated that protoberberinium salts with a high lipophilicity display more potent antibacterial activity. The dioxymethylene at the C-2 and C-3 positions in the ring A, as well as 13-alkyl-substitued derivatives increased the antibacte-

rial activity [119, 120], while 13-hydroxy-substitued derivatives decreased the antibacterial activity [121]. The side alkyl chain at C-13 position of quaternary protoberberines was investigated to have potential activity to increase the fungicidal and herbicidal activity [122]. The antimicrobial activity of 3-alkoxyjatrorrhizine or 8alkylpalmatine derivatives increased with the growth of the aliphatic chain, after which, the antimicrobial activity decreased gradually when the alkyl chain exceeded eight carbon atoms [123, 124]. As the alkyl carbon chain at the C-8 position of berberine increased, the antimicrobial activity enhanced until the critical length of (CH2)7CH3 was reached while the toxicity decreased with the alkyl carbon chain elongated [125]. The 3-octyloxy-8-alkyljatrorrhizine derivatives 25a-d (Fig. 5) presented more antimicrobial activities than 3-octyloxyjatrorrhizine, especially against Gram-positive

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Xiao et al.

OCH3 OCH3

N+

O

O

OCH3 OC8H17

N+

O

OR

O

O

N+

O R 27a-d

R

25a-f

26a-d

25a: R=CH2CH3 25b: R=(CH2)2CH3 25c: R=CH(CH3)2 25d: R=(CH2)3CH3 25e: R=(CH2)5CH3 25f: R=(CH2)7CH3

26a: R=C2H5 26b: R=CH2(CH2)2CH3 26c: R=CH2(CH2)4CH3 26d: R=CH2(CH2)6CH3

O

O

O

27a: R=OCOCH3 27b: R=OCO(CH2)3CH3 27c: R=OCO(CH2)10CH3 27d: R=OCOC6H5

N

O

O O

N N

O O

O

N N

N

N N

O

OH

N H3C(H2C)6

N

N

O

30

29 F

F 28 OR1

O O

OR2

N+

O

O N+

O

N+

O

O

O O

H3C(H2C)7

(CH2)9CH3

O

31a-b

33

32

31a R1+R2=CH2 31b R1=R2=CH2

NO2 H N

O

N H

O

O

O O

O

O O2N

N+

O

O

O

O

34

N+

O

N+

O 35

36

O O

O

H N

O

O

O2N

37

Fig. (5). Structures of berberine derivatives 25-37 for antimicrobial activity.

bacteria. The antimicrobial activities of compounds (25a-d) did not increase as the aliphatic chain elongated. 3-octyloxy8-butyljatrorrhizine (25b) with a n-butyl group at the C-8 position showed the strongest activity against the microbes tested [126]. The antimicrobial activity of 9-O-substituted

palmatine derivatives 26a-f (Fig. 5) were evaluated [127]. Investigation suggested that introducing hydrophilic groups to C-9-O did not contribute to the increasing of antimicrobial activity, which was consistent with what had been reported [128]. The compounds (26a-f) showed increased antimicro-

Berberine Derivatives with Different Pharmacological Activities

bial activity against Gram-positive organisms by 2- to 64fold over palmatine with the growth of the alkyl side chain, after which, the antimicrobial activity decreased gradually when the aliphatic chain exceeded four carbon atoms. Antibacterial activities of the compounds (26a-f) against Gramnegative bacteria and fungi increased 1- to 16-fold than that of palmatine as the aliphatic chain increased and tended to be stable. Nine synthetic protoberberine alkaloids (four 8-alkyldihydroberberines, two 8-alkyl-berberines, and three 12bromo-8-alkyl-berberines), berberine and palmatine were tested for explanation of the connection between structure and antibacterial activity against Helicobacter pylori [129]. In accordance with the experimental results, dihydroberberines showed weaker activity than the corresponding berberines, which indicated that ring C should be aromatic. Replacement of H-8 of berberine by n-butyl group increased antibacterial activity in comparison with other alkyl groups, while introduction of a bromine atom at the C-8 position did not have significant influence on activity. The study on antibacterial activity of 9-O-acyl- and 9-O-benzoyl-substituted berberrubines 27a-d (Fig. 5) against Gram-positive bacteria suggested that their antibacterial activity increased as the length of the carbon chain at the C-9 position increased compared to berberine and berberrubine when the number of carbon atoms in the aliphatic chain not exceeded twelve [130]. Especially, 9-lauroylberberrubine chloride (27c) showed less inhibitory activity against Gram-positive bacteria (Enterococcus fecalis, S. aureus, S. epidermidis, Micrococcus luteus and Bacillus subtilis) but exerted stronger activity against Gram-negative bacterium Klebsiella pneumoniae than kanamycin sulfate. Berberrubine derivatives bearing 9-O-acyl- and 9-O-alkyl-substituents were synthesized and evaluated for antimicrobial activity against Grampositive, Gram-negative bacteria and fungi [131]. Octanoyl, decanoyl and lauroyl derivatives among the acyl analogs, and hexyl, heptyl, octyl, nonyl, decyl and undecyl derivatives among the alkyl analogs all exhibited strong antimicrobial activity against Gram-positive, but no activity against Gram-negative bacteria. As a result, 9-O-alkylberberrubine derivatives were more active than 9-O-acylberberrubine derivatives against Gram-positive bacteria, and 9-Oalkylberberrubine derivatives with C6-C11 alkyl chain possessed potential antimicrobial activity against Gram-positive bacteria. Article reported that the incorporation of berberine moiety into target compounds was an effective way to enhance the antibacterial and antifungal activity [132]. Compound 28 (Fig. 5) with 2,4-difluorobenzyl group exhibited good antibacterial and antifungal activities with low minimum inhibitory concentration (MIC) values ranging from 2 to 8 µg/mL [133, 134]. The competitive interactions indicated that the participation of Mg2+ and Fe3+ ions in compound 28–HSA complex could increase the concentration of free compound 28 and cut down the storage time and halflife of compound 28 in the blood, thus improving its antimicrobial efficacy. The introduction of heterocycles into C-9 position of berberine backbone could enhance the antimicrobial activities and broaden antimicrobial spectrum [132, 133]. Berberine-benzimidazole derivative 29 (Fig. 5) prepared by Jeyakkumar et al. exhibited low MIC value of 2-8 mg/mL against S. aureus, E. coli, and S. typhi, which could

Mini-Reviews in Medicinal Chemistry, 2017, Vol. 17, No. 0

9

be transported by human serum albumin (HSA) and penetrated the membranes of both Gram-positive and Gramnegative bacteria to intercalate into DNA [135]. The interactive investigation revealed that compound 30 (Fig. 5), showed low cell toxicity by down regulating reactive oxygen species (ROS) generation, could effectively intercalate into calf thymus DNA to form 30–DNA complex which might further block DNA replication to exert the powerful antimicrobial activities with low MIC value of 1µg/mL against Eberthella typhosa [136]. Structure–activity relationship suggested that imidazolyl group played a significant role in exerting antibacterial and antifungal efficacy and the introduction of alkyl substituted imidazole fragment into C-12 position of berberine would display weaker antibacterial activity than compound 30. The 13-n-derivatives 31a-b (Fig. 5) exhibited higher activity against Leptosphaeria nodrum compared to 13-butyl and 13-propyl derivatives. From the results, the replacement of methoxyl with ethoxyl at C-9 position increased antibacterial activity. Positively charged nitrogen atom in the aromatized ring C was indispensable to increase the antibacterial activity. The type of the substituents on the rings A and D influenced the antibacterial activity. The tertiary forms of berberine alkaloids did not show significant activity [122]. The 13-n-octylberberine derivatives with different substituents on the ring A and D were synthesized and evaluated for their anti-mycobacterial activities against Mycobacterium tuberculosis H37Rv in vitro [137]. According to structure-activity relationship analysis, n-octyl group at C-13 position might be necessary for the activity, and introduction of substituents at positions 2, 3 and 9, especially an ethoxyl, might significantly enhance the activity. Among them, 13-n-octylberberine compound 32 (Fig. 5) was the most effective anti-tubercular agent. Eighteen 8substituted berberine derivatives were synthesized and evaluated for their antimycobacterial activities against M. tuberculosis H37Rv [138]. Among them, compound 33 (Fig. 5) afforded the best anti-mycobacterial activity against M. tuberculosis strain H37Rv with MIC of 0.5 µg/mL and multi-drug resistant strains with comparable MIC ranges of 0.25-1 µg/mL. Li et al. thought that the nitrogen ion at the 7-position might be blocked by bulky aliphatic groups at 8-position in protoberberine derivatives, which would improve lipid solubility. SAR analysis was investigated by Li et al. showed that the introduction of lipophilic groups at the 8-position of berberine improved the cLogP value. Introduction of a n-decyl at the 8-position and 10,11-dimethoxy on the ring D enhanced the anti-mycobacterial activity. Introduction of various aromatic groups at the position C13 of berberine and berberrubine improved the antifungal activity. The 13-(4-isopropyl benzyl) berberine 34 (Fig. 5) exerted the most potent antifungal activities against Candida species among synthesized compounds [139]. Structureactivity relationship analysis revealed that the derivatives with aromatic groups bearing electron-withdrawing group at the para-position were less active than the derivatives with aromatic groups bearing bulky hydrocarbon group. A covalently linked combination of berberine at C-13 position and 2-phenyl-5-nitro-1H-indole at the ortho position of the indolic 2-phenyl ring via a methylene ether linking group gave a high antibacterial hybrid 35 (Fig. 5), the antibacterial activ-

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Xiao et al.

ity of which was over 382-fold more active than that of berberine against S. aureus [140]. An increase of linker chain length by introduction of an oxygen atom produced a new hybrid 36 (Fig. 5) which had stronger antibacterial activity and multidrug resistance (MDR) pump inhibitory potency than former. Structure-activity relationship study of berberine acting as an antifungal compound was reported, which appeared that the quaternary nitrogen and the aromatic polyciclic and planar structure of berberine could be the pharmacophoric pattern to produce the antifungal effect [141]. The novel scaffold berberine derivative 37 (Fig. 5) was synthesized by Li et al. through reconstruction of berberine, which exhibited remarkable synergistic antifungal activity and low cytotoxicity. Compared with berberine, 37 and fluconazole used concomitantly exhibited a better synergistic antifungal activity and much lower cytotoxicity to human umbilical vein endothelial cells [142]. 5. BERBERINE DERIVATIVES INFLAMMATORY ACTIVITY

FOR

by Lee et al. as potent P2X7 antagonists showed significant inhibitory effects on P2X7R-mediated signaling pathways involved in the immune response including cytokine IL-1β release and phosphorylation of MAPK [149]. 6. BERBERINE DERIVATIVES ALZHEIMER’S DISEASE

ANTI-

A new series of berberine derivatives 41a-e, 42a-e and 43a-e (Fig. 7) was designed, synthesized, and evaluated as AChE inhibitors by Huang et al [153]. Compound 42c linked with phenol by a 4-carbon spacer inhibited AChE with IC50 of 0.097 µM. Molecular modeling studies confirmed that the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE were the target of these berberine hybrids. The preliminary SAR showed that the inhibition of AChE was mainly influenced by the function at the end of the chain, as well as the length of the connecting tether. Huang et al. synthesized and evaluated a series of novel berberine derivatives (44a-e, 45a-d, 46a-d and 47a-h) as inhibitors of both AChE and butyrylcholinesterase (BuChE) (Fig. 7) [154]. Among them, compound 46c, berberine linked with 3methylpyridinium by a 2-carbon spacer, was found to be a potent inhibitor of AChE with an IC50 value of 0.048 µM and compound 45d jointed with 2-thionaphthol by a 4-carbon spacer acted as the most potent inhibitor for BuChE with an IC50 value of 0.078 µM. The preliminary SAR studies

O

O

O

O

O

O O

O N+ O

N

O O

NO2

ANTI-

Alzheimer’s disease (AD) is a neurodegenerative disease that leads to a progressive deterioration of memory and cognition. Several diverse hallmarks, such as deposits of aberrant proteins (β-amyloid [Aβ] and τ-protein), oxidative stress, dyshomeostasis of biometals, and low levels of acetylcholine (ACh) play significant roles in the pathophysiology of the disease [150]. Among them, the deposition of Aβ in the brain is a common pathological mark of AD and one of the potential reasons of the neuronal damage [151]. Inhibition of acetylcholinesterase (AChE) is a common treatment of AD. The cholinergic hypothesis of AD suggests that low levels of ACh in specific regions of the brain is also involved with the etiology of AD [152]. Besides cholinergic hypothesis, numerous studies have indicated that AChE is also involved with the etiology of AD through AChE-induced βamyloid (Aβ) aggregation in recent years. In consideration of these mechanisms, different treatment approaches and major therapeutic strategies could be adopted. In recent years, berberine and its derivatives as acetylcholinesterase and βamyloid aggregation inhibitors have been reported.

The anti-inflammatory mechanism of berberine remained unclear. However, researches on its anti-inflammation had been reported. Berberine had anti-inflammatory activity by inhibiting the production of tumor necrosis factor-α (TNF-α), prostaglandins (PGs), interleukins (ILs) and inducible nitric oxide synthase (iNOS) through mitogen-activated protein kinase (MAPK) activation in macrophages [143]. Berberine inhibited endogenously expressed and 12-O-tetradecanoylphorbol-13-acetate-induced PGE2 synthesis dose-dependently in OC2 and KB oral cancer cells, which was correlated with reduced cyclooxygenase-2 (COX-2) protein synthesis, but not enzyme activity [144]. Moreover, it repressed the expression of COX-2, matrix metalloproteinase (MMP)-2 and MMP-9 through MAPK and nuclear factor-kappa B (NF-κB) signaling pathways [145]. Berberine inhibited both the expression of adipogenic enzymes and inflammatory molecules in 3T3-L1 adipocytes [146]. In addition, berberine inhibited lipopolysaccharide-induced cell proliferation and fibronectin expression through inhibiting the activation of NF-κB signaling pathway in rat mesangial cells [147]. Quaternary protoberberine derivative with 2-nitro-4,5-dimethoxy-benzyl group substituted at C-9 position and alkyl groups at C-13 position, such as compound 38 (Fig. 6), exhibited potent inhibitory efficacy as P2X7R (a plasma membrane receptor for extracellular adenosine-5-triphosphate (ATP) dominantly expressed in inflammation-related cells) antagonists [148]. Protoberberine analogs 39, 40 (Fig. 6) and (38) synthesized

O

FOR

N

O 39

O O 38

Fig. (6). Structures of berberine derivatives 38-40 for anti-inflammatory activity.

O 40

Berberine Derivatives with Different Pharmacological Activities

Mini-Reviews in Medicinal Chemistry, 2017, Vol. 17, No. 0 O

O

O O

O

N+

O O

N+

O O

O n

O

O

n X

O

46a: R=H, n=2 46b: R=H, n=3 46c: R=CH3, n =2 46d: R=CH3, n=3

N+ H N

O

N+

O O

Y 47a-h

O

O

O R

O

O

O

N Br

R

N Br

n

46a-d

45a: X=O, n=3 45b: X=O, n=4 45c: X=S, n=3 45d: X=S, n=4

n X

O

N Br

O

O

O

O

45a-d

R

44a: R=H 44b: R=CH3 44c: R=OCH3 44d: R=Cl 44e: R=NO2

O

43a-e: n=2-6

N Br

O

44a-d

O n

O

N Br H N O

O

O

O

O

N+

O

N N N 42a-e: n=2-6

41a-e: n=2-6

O

O

O n

NH

11

X

Y

49

48

X = (CH2)n, (CH2)mCO; n = 2-10; m = 1-9 Y = NRAr, OAr; Ar = substituted aryl R = H, Me, Et, Pr, i-Pr

47a(i): R=CH3, X=O, Y=C i: n=3 47b(i,ii): R=OCH3, X=O, Y=C ii: n=4 47c(i,ii): R=Cl, X=O, Y=C 47d(i,ii): R=Br, X=O, Y=C 47e(i,ii): R=NO2, X=O, Y=C 47f(ii): R=H, X=O, Y=C 47g(i): R=H, X=NH, Y=C 47h(i): R=H, X=NCH3, Y=C

Fig. (7). Structures of berberine derivatives 41-49 for alzheimer’s disease.

showed that the bulk of the scaffold of berberine derivatives at the end of the chain affected the AChE inhibitory activities dramatically and the length of alkylene linkage had less effect on the inhibition of both AChE and BuChE. The berberine analogues substitued at C-9 position by naphthol or para-substituents of phenyl at the end of the chain presented less AChE inhibitory activity than derivatives that had no substituent on the aromatic rings at the same site of the chain. The replacement of alkylene chain with an acyl alkyl dramatically decreased the inhibitory activity (with the IC50 values ranging from 0.535 to 6.50 µM), while the replacement of the oxygen atom with a N atom (47g) or sulfur atom (45d) at the X position created a weak effect on AChE inhibitory activity. However, inhibition of BuChE was dramatically increased with sulfur atom substitution at the X position. Moreover, kinetic studies and molecular modeling simulations of the AChE-inhibitor complex indicated that a mix-competitive binding mode existed for these berberine derivatives. Compound 48 (Fig. 7) with a cyclohexylamino group linked at the 9-position of berberine by a three carbon spacer gave the most potent inhibitor activity with an IC50 of 0.020 µM for AChE [155]. 9-Substituted derivatives of ber-

berine 49 (Fig. 7) were synthesized from 9-demethylberberine which could be used as acetylcholine esterase inhibitor for treating Alzheimer’s disease, vascular dementia, and cognitive dysfunction [156]. 7. BERBERINE DERIVATIVES ATHEROSCLEROSIS

FOR

ANTI-

The development of atherosclerosis is particularly related to the metabolism of cholesterol. Atherosclerosis leads to the development of various cardiovascular diseases, the most threatening of which are myocardial infarction and stroke [157]. Cholesterol mainly occurs within low density lipoproteins (LDLs). Reducing the blood cholesterol level is an effective method to treat atherosclerosis. A high LDL level causes the formation of cholesterol deposits on blood-vessel walls and development of atherosclerotic plaque [158]. Increased hepatic LDLR expression improves the clearance of blood LDL-c through a receptor-mediated endocytosis [159, 160]. An additional mechanism that berberine inhibited cholesterol and triglycerides synthesis in hepatic cells through activation of AMPK was reported [161].

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Xiao et al.

In recent years, berberine has been reported to possess up-regulatory activity on the low-density-lipoprotein receptor (LDLR) expression. Yang et al. synthesized berberine analogues with substituents on the benzene ring D as a novel class of low-density-lipoprotein receptor up-regulators and evaluated for their activity [46]. The analysis of SAR indicated that the two methoxyl groups in an ortho-distribution on D ring afforded a good activity. Among the analogues, compound 50 (Fig. 8) bearing a methoxyl at both 10- and 11position showed an increased LDLR up-regulatory activity. Twenty-nine derivatives of berberine or pseudoberberine (50) were designed, semisynthesized, and evaluated for their up-regulatory activity on the low-density-lipoprotein receptor (LDLR) expression by Li et al [102]. A series of aromatic and reduced berberine derivatives were synthesized to study their influence on increased LDLR gene expression levels and hypocholesterolemic activity in vitro and in vivo using the Triton WR1339-induced hypercholesterolemia mode, and to analyze the structure-activity relationship. As a result, berberine derivatives containing a reduced ring C were more capable of increasing the LDL receptor gene expression than the corresponding aromatic derivatives and 9-O-tosyltetrahydroberberine 51 (Fig. 8) and 12-bromotetrahydroberberine 52 (Fig. 8) possessed pronounced hypocholesterolemic activity and reduced the total cholesterol level by 33 and 27%; the triglyceride level, by 25 and 26% [162], respectively. Berberine derivatives 53 (Fig. 8) were prepared for therapeutic use of controlling blood lipid levels, which increased hepatic expression of LDLR (stability of LDLR mRNA and LDLR gene transcription) and the phosphorylation of acetyl CoA carboxylase via the activation of AMPK to enhance the oxidation of fatty acid and reduced hepatic triglyceride accumulation by releasing it in the form of very low density lipoprotein [163]. O

O

O

O H

O N+

O

N

O O

50

S

51

O O

Br

H

O N+

O

O

N

O O

O

O R S O

53 52

R=alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl

Fig. (8). Structures of berberine derivatives 50-53 for atherosclerosis.

8. BERBERINE DERIVATIVES MALARIAL ACTIVITY

FOR

ANTI-

It had been reported that berberine in vitro inhibited both nucleic acid and protein synthesis in human malaria Plasmodium falciparum FCR-3 [164]. Berberine protected host spleen tissue from injuries induced by P. chabaudi [165]. In addition, the inhibitor activity against telomerase of human malaria P. falciparum was covered [166]. Ten protoberberine derivatives were tested in vitro against two clones of human malaria, P. falciparum D-6 (Sierra Leone clone) and W-2 (Indochina clone). In the in vitro screen, compounds with a dihydro or quaternary protoberberine structure possessed potency against P. falciparum. However, none of them was active in vivo against P. berghei. An alkyl-substituted 2,3catechol function as part of either a quaternary protoberberine structure or a dihydroprotoberberine structure with a neutral nitrogen atom was required to maintain potency in vitro against P. falciparum [167]. Berberine chloride and ten synthetic analogues were tested by using chloroquine-sensitive and -resistant strains for antimalarial activity assessed by measurement of proliferation inhibition of P. falciparum in vitro. Results suggested that DNA was not the only site of a positive effect on the activity of these analogues [168]. Iwasa et al. assessed antimalarial activity of the protoberberine alkaloids in vitro against P. falciparum and structure-activity relationships are proposed [107]. The results demonstrated that the activity of the quaternary protoberberinium with salts an aromatic ring C was higher than that of quaternary salts such as the N-metho salts or N-oxides of tetrahydro and dihydro derivatives as well as tertiary tetrahydroprotoberberines. Meanwhile, the type of the quaternary nitrogen atom, the nature and size of the substituents at the C-13 position and the type of O-alkyl substituents on rings A and D influenced antimalarial activity of the protoberberine alkaloids. The introduction of a hydrophilic function into the C-13 position of the protoberberinium salts might have a positive effect on the antimalarial activity. The 13-Hydroxyberberine 54 (Fig. 9) presented the same level of activity as berberine, while 13-butylberberine 55b (Fig. 9) and 13-propylpalmatine 55a (Fig. 9) were the most active compounds in antimalarial activity against P. falciparum in vitro among the 13-alkylberberines and 13-alkylpalmatines respectively but less active than berberine [107]. Further study on SAR of the protoberberine alkaloids was done by Iwasa et al. to find out the influence of the type of oxygen substituents on ring A, C and D and the position of the oxygen functions on ring D [119]. Shifting the oxygen functions at C-9 and C-10 to C-10 and C-11 would significantly increase the activity. Derivatives bearing a methylenedioxy function at C-2 and C-3 or C-9 and C-10 showed higher activity than those methoxy groups at the same positions. Introduction of a methoxy group into the C-1 position, replacement of a hydroxy group at C-2 or C-3 with a methoxy group or displacement of a hydroxy function at C-13 by the oxygen substituents led to a decrease in the activity. The combination therapy of berberine and artemisinin for malaria and several other diseases had been patented [169]. This patent mentioned that a single unit or pill containing both berberine and artemisinin was used for the treatment and prevention of chloroquine-resistant and anti-malarial drug-

Berberine Derivatives with Different Pharmacological Activities

Mini-Reviews in Medicinal Chemistry, 2017, Vol. 17, No. 0

resistant strains of the malaria parasite in humans and animals. O OH N+

O

O O

O

R

O

N O 55a-b

O 54

55a: R=CH2CH2CH3 55b: R=CH2CH2CH2CH3

Fig. (9). Structures of berberine derivatives 54-55 for antimalarial activity.

9. SUMMARY AND FUTURE DIRECTIONS Multiple pharmacological activities of berberine against cancer, diabetes, inflammation, atherosclerosis, Alzheimer’s disease, microorganism and malaria have been investigated in recent years. With the anti-cancer and anti-diabetic activities revealed by berberine, and the increasing need of researches on cancer and diabetes diseases, researchers mainly payed their attention on these two activities of berberine now. How to modification of berberine with function groups to enable it with the ability to target to multiple therapeutic moleculars would be a new direction to enhance its therapeutic efficiency. The majority modifications of berberine are focused on altering the peripheral functional groups. Future work should be done on the modification of central tetracycles of berberine, thus to achieve a new understanding and discovery on the biological activities of berberine derivatives, and the actual mechanisms underlying these pharmacological properties need to be determined. Berberine derivatives can also result in toxic effects. Hence, how to modification of berberine with enhanced therapeutic activities, meanwhile to improve its selectivity and safety is needed. Clinical application of berberine is limited because of its poor bioavailability, which could be attributed its poor absorption (56%) and the first-pass effect in the intestine (43.5%) and liver (0.14%) [170]. The poor absorption may be attributed to its self-aggregation, poor permeability, Pglycoprotein-mediated eflux, and hepatobiliary re-excretion [170, 171]. Furthermore, berberine has low permeability [172].Therefore, bioavailability of berberine might be improved by increasing its permeability, reducing its selfaggregation and inhibiting P-glycoprotein with the suitable modification in the future studies. With the increasing researches on berberine derivatives, enhanced biological activities and bioavailability could be obtained and finally enable it to be applied for clinical utilization. CONCLUSION The structural modification of berberine for multiple activities, including anti-hyperglycemic, anti-tumor, antimicrobial, anti-inflammatory, anti-alzheimer, anti-atherosclerosis and anti-malarial activities and their structure-activity relationship have been discussed in this paper, which indicates that the modification of the functional groups to berberine can changes its biological activities, and the activities are

13

closely related to the groups. By modification of the structure of berberine using modern medicinal chemistry-based molecular modification, berberine derivatives with better biological activity and enhanced bioavailability could be obtained and showed promising potential for clinical application. LIST OF ABBREVIATIONS ACh AChE AD AMPK

= = = =

BuChE DMF DNA FBG GSK HAS HepG2 HRAR LDLR MAPK MDR MIC MMP PBG RLAR ROS SAR

= = = = = = = = = = = = = = = = =

Acetylcholine Acetylcholinesterase Alzheimer’s disease Adenosine monophosphate-activated protein kinase Butyrylcholinesterase Dimethyl formamide Deoxyribonucleic acid Fasting blood glucose Glycogen synthase kinase Human serum albumin Human hepatoma cell lines Human recombinant aldose reductase Low-density-lipoprotein receptor Mitogen-activated protein kinase Multiple drug resistance Minimum inhibitory concentration Matrix metalloproteinase Postprandial blood glucose Rat lens aldose reductase Reactive oxygen species Structure activity relationships

CONSENT FOR PUBLICATION Not applicable. CONFLICT OF INTEREST The authors confirm that this article content has no conflict of interest. ACKNOWLEDGEMENTS This work was founded by National Natural Science Foundation of China (81301258), Hunan Provincial Natural Science Foundation of China (2016JJ2161), Specialized Research Fund for the Doctoral Program of Higher Education of China (20130162120078), the Fundamental Research Funds for the Central Universities of Central South University and Shenghua Yuying Project of Central South University. REFERENCES [1]

[2]

Huang, Z.; Zeng, Y.; Lan, P.; Sun, P.H.; Chen, W. M. Advances in structural modifications and biological activities of berberine: an active compound in traditional Chinese medicine. Mini. Rev. Med. Chem., 2011, 11 (13), 1122-1129. Watt, G., A Dictionary of the Economic Products of India. reprinted edition ed.; Periodical Expert: Delhi, 1972; Vol. VI (Pt. IV), p 83.

14 [3] [4] [5] [6] [7]

[8]

[9]

[10]

[11]

[12]

[13] [14]

[15] [16]

[17]

[18]

[19] [20]

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PMID: 28325147

Graphical Abstract

Mini-Reviews in Medicinal Chemistry, 2017, Vol. 17, No. 00

Graphical Abstract Mini-Reviews in Medicinal Chemistry, 2017, Vol. 17, No. 00 000

Berberine Derivatives with Different Pharmacological Activities via Structural Modifications Daipeng Xiao, Zhenbao Liu, Shanshan Zhang, Mi Zhou, Fen He, Ming Zou, Junying Peng, Xiong xie, Yanfei Liu* and Dongming Peng# *

Department of Pharmaceutical Engineering, School of Chemistry and Chemical Engineering, Central South University, Changsha 410083, PR China; #Department of Medicinal Chemistry, School of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, PR China

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D 10 12 O 11 Structures of berberine.

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