Dammarane triterpenoids for pharmaceutical use: a patent review (2005 - 2014).

Review

Expert Opin. Ther. Patents Downloaded from informahealthcare.com by Nyu Medical Center on 05/05/15 For personal use only.

Dammarane triterpenoids for pharmaceutical use: a patent review (2005 -- 2014) 1.

Introduction

2.

Patent review

3.

Conclusion

4.

Expert opinion

Jiaqing Cao, Xiaoshu Zhang, Fanzhi Qu, Zhenghong Guo & Yuqing Zhao† †

Shenyang Pharmaceutical University, School of Traditional Chinese Materia Medica, Shenyang, People’ s Republic of China

Introduction: Dammarane triterpenoids, the main secondary metabolites of Panax ginseng, are very important natural compounds with remarkable biological activity. They could be isolated from the plants of Panax or other genus, as well as through the modifications of certain natural products. This review is a collection of a number of patents (2005 -- 2014) that describe the dammarane triterpenoids for therapeutic or preventive uses on numerous common diseases. Areas covered: In this review, patents from 2005 to 2014 on chemical structures and treatment of different diseases by dammarane triterpenoids have been summarized. The SciFinder and the World Intellectual Property Organisation databases have been used as main sources for the search. Expert opinion: In the last decade, over 90 patents concerning dammarane derivatives for pharmaceutical have been published. These types of compounds could be used as agents for prevention and treatment of various kinds of diseases, such as cancer, diabetes mellitus and metabolic syndrome, hyperlipidemia, cardiovascular and cerebrovascular disease, aging, neurodegenerative disease, bone disease, liver disease, kidney disease, gastrointestinal disease, depression-type mental illness and skin aging. Rare plants, except for Panax genus, which contain dammarane triterpenoids should be studied extensively. In addition, more dammarane triterpenoids with good biological activity, especially the aglycones possessing novel side chain, should be prepared using chemical modification. Finally, pharmacological effects of dammarane triterpenoids should be further studied. Keywords: dammarane, Panax, side chain, triterpenoid Expert Opin. Ther. Patents [Early Online]

1.

Introduction

Dammarane triterpenoids have been gaining worldwide attention for a long time because of their potent bioactivities. Dammarane triterpenoids have been confirmed to be the main bioactive ingredients of Panax ginseng (Araliaceae) [1,2], the oldest and best-known traditional Chinese medicinal plant. Aside from Panax, dammarane triterpenoids are also distributed in other genera, such as Gynostemma (Cucurbitaceae), Aralia (Araliaceae), Aglaia (Meliaceae), Bacopa (Scrophulariaceae), Ceriops (Rhizophoraceae), Copernicia (Arecaceae), Celastrus (Celastraceae), Forsythia (Oleaceae), Kageneckia, Myrica (Myrica), Rhus (Anacardiaceae), Polyscias (Araliaceae) and Sapindus (Sapindus) [3-6]. The basic molecular skeleton of dammarane triterpenoids comprises tetracyclic moiety and side chain moiety (Figure 1). The structures of the tetracyclic part show the following remarkable features: C-3 is hydroxylation, or glycosylation, or carbonylation; C-6 is hydroxylation or glycosylation; C-12 is hydroxylation or carbonylation, C-2 and C-7 are hydroxylation occasionally; carbon-carbon double 10.1517/13543776.2015.1038239 © 2015 Informa UK, Ltd. ISSN 1354-3776, e-ISSN 1744-7674 All rights reserved: reproduction in whole or in part not permitted

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Dammarane triterpenoids, the active ingredients of Panax ginseng, have played an important role in the development of natural drugs, and the skeleton of them has two parts: tetracyclic moiety and side chain moiety. Dammarane triterpenoids could be used to prevent and treat various diseases, such as cancer, diabetes, hyperlipidemia, cardiovascular and cerebrovascular disease, aging and neurodegenerative disease. The diversity and novelty of dammarane structures, resulting from the differences of bioactivities, mainly depend on the varieties of the side chain of the aglycones. In this review, 53 varieties of side chain of dammarane structures were listed; however, only 27 types applied for patents on their pharmaceutical uses. Future patents and pharmaceutical research on natural dammarane triterpenoids should focus on the other plants containing this type of compounds, aside from the Panax genus. Effective methods to obtain more dammarane triterpenoids with bioactivities include isolation from plants, as well as chemical modification of known leading compounds. Further pharmaceutical studies on dammarane triterpenoids should focus on the detailed mechanisms of action and the structure--activity relationships.

This box summarizes key points contained in the article.

side chain

H; β-OH; =O 12

H; OH 2 β-OH; β-O-sugar; =O

3

5

7

tetracyclic moiety H; β-OH

6

28

C6-C7; C6=C7

H;OH C5-C6; C5=C6

H; α-OH; α-O-sugar

Figure 1. Basic structure of dammarane triterpenoid.

bonds are always positioned at C5=C6 or C6=C7 (Figure 1). Furthermore, according to the modification of side chain [3-5], dammarane-type compounds have many origins (Figure 2), such as the compounds without carbon-carbon double bonds (Figure 2A-1 to A-16), containing one carbon-carbon double bond (Figure 2B-1 to B-29), and containing two carbon-carbon double bonds (Figure 2C-1 to C-8). The bioactivities and chemical properties of dammarane triterpenes have been investigated, and several pharmacological effects have been disclosed, including antifatigue, antihyperglycemic, antiobesity, anticancer, anti-HIV, antioxidant, antiaging, immunostimulatory, antiatherosclerotic and antihypertensive effects [7-9]. 2

The patent databases of SciFinder and the website of the World Intellectual Property Organisation were used as the main sources to locate patent applications containing dammarane triterpenoids with pharmaceutical uses. After eliminating the duplicates and rejected applications, nearly > 90 patents have been analyzed and cited in this paper. The various pharmacological effects of dammarane triterpenoids have undoubtedly attributed to their resemblance in chemical structure. Therefore, in this review, we focus on the chemical structures of dammarane triterpenoids with significant biological activity in some patents and treatment of different diseases. 2.

Patent review

In this paper, we have reviewed recent studies on the effects of ginsenosides on various diseases, particularly on cancer, diabetes mellitus and metabolic syndrome, hyperlipidemia, cardiovascular and cerebrovascular disease, aging, neurodegenerative disease, bone disease, liver disease, kidney disease, gastrointestinal disease, depression-type mental illness and skin aging. Cancer Studies on the anticancer effects of dammarane triterpenoids have become increasingly popular in recent years; some have shown that various ginsenosides, especially Rg3 and Rh2, possess antineoplastic effects [7-9]. Rg3 has been used as an antineoplastic drug in China, called ‘Shen-Yi Capsule’ for > 10 years, because of its excellent anticancer activities. In addition, Rh2 showed significant inhibition effects on tumor growth in nude mice bearing human ovarian cancer cells and remarkable increase in survival. Ginsenosides Rh2 and Rg3 inhibit the activities of CYP enzymes (CYP3A4, CYP2D6, CYP2C9, CYP2C19 and CYP2B6) [10]. According to the records from some patents, the main anticancer active ingredients of the standard extract or ginsenoside mixtures from Panax plants include ginsenosides Rg3 and Rh2 and their analogs [11]. For example, mixtures composed of Rh2, protopanaxadiol (PPD) and protopanaxatriol (PPT) exhibit stronger antitumor activities on U87, B16, MCF-7, BXCP-3 and CAPAN-1 cancer cells compared with each individual component alone [12]. Ginsenosides, which is one kind or some kinds of Rh2, Rg3, Rb1, Rb2, Rc, Rd, Rg1 and Rg2, could be combined with cantharidin safely to treat tumors because ginsenoside could reduce the toxic adverse effect. The main compounds of P. notoginseng with anticancer activity [13] include ginsenosides Rh1 and Rh4 and notoginsenoside T5, among others. Both ginsenoside Rg6 and ginsenoside F4 could inhibit lymphoma tumor cell significantly [14,15]. At the same time, ginsenoside F4 significantly inhibits tumor cells through the CCK-8 assay. Compared with Rg3, pseudo-ginsenoside RT6 showed better anticancer activities in different concentrations (0 -- 45 µg/ml) against the tumor cells, such as MCF-7, PC3M and NCI-H 446 [16]. 2.1

Expert Opin. Ther. Patents (2015) 25(7)

Dammarane triterpenoids for pharmaceutical use: a patent review (2005 -- 2014)

OH HO

OH

A-1 OH

OH

OH OH

HO

A-11

O

B-1 HO

HO

B-5

O

B-11

B-12

OH OH

HO B-20

B-25

O

B-19

B-18

OH

OCH 3

OH

HO H 3CO B-23

B-22

B-21

O

B-26

OOH OH C-2

OH B-24

OH

OH

O

OCH 3 B-27

O

OH C-1

HO OH

OCH 3

OH

OH

HO

OH

HO

B-14

B-13

B-17

B-16

OOH

HO

OH

OC 2H 5

B-9

HO

HO B-15

OOH HO

HO B-8

HO

OCH 3 HO

HO

OH

OH

B-10

B-4

HO O B-7

HO

HO

HO B-3

O

B-6

OOH

OH

HO HO B-2

HO

A-15

A-14

OH

HO

O

O

A-13

HO

A-10

OH

A-12

A-16

O A-9

O

HO

OH

A-5

O

A-8

O O

OH HO

A-4

O

A-7

O

OCH 3

OH

A-3

O

A-6


OCH 3

HO

A-2

O

HO

OH

OH

OH B-28

B-29

C-4

C-5

HO

C-3 OOH

C-6

C-8

C-7

Figure 2. Various types of side chain.

Dammarane aglycones have effective anticancer activity than their corresponding glycosides. PPD, a common aglycone, exhibits better anticancer activity than Rh2 and Rg3 [17]. A promising derivative from PPD with cancerpreventive effects, 25-methoxy-dammarane-3b, 12b and 20-triol (25-OCH3-PPD) [18,19], showed better anticancer activities than PPD, Rh2 and Rg3, and could treat various

malignant tumor diseases, such as human melanoma, cervical carcinoma and liver cancer. The anticancer mechanism of 25-OCH3-PPD could induce apoptosis and arrest the cells in the G1 phase to inhibit the growth and proliferation of human tumor cells, as well as the expression of the MDM2 oncogene [20]. Moreover, 25-OCH3-PPD could decrease the growth of tumors in a lung cancer mouse model


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without any apparent toxicity. The effective dosage of a pair of ginsenoside sapogenins is 20(R)-25-OCH3-PPD and 20 (S)-25-OCH3-PPD, or their mixture is 1 -- 100 mg/kg/day [21]. In addition, another dammarane compound, 20(R or S)25-hydroxyl-PPD [22], which could be prepared successfully from total ginseng saponins [23] or panaxadiol (PD) [24] through either acidic or basic hydrolysis, acid or alkali under ultrasonic or microwave condition, could also prevent malignant tumors, inhibit tumor angiogenesis, induce tumor cell apoptosis, inhibit tumor invasion and metastasis, enhance body immunity and lower the side effect of chemotherapeutic medicine. Furthermore, 25-hydroxyl-PPD, combined with at least one chemotherapeutic drug, could treat tumors, such as prostate cancer, lung cancer, glioma, pancreatic cancer and/or breast cancer [25]. (20S,22S)-dammar-22, 25-epoxy-3b,12b,20-triol [26], 20 (S)-3-methoxy-PD [27], 20(S)-3b,20,21-trihydroxydammaran24-ene [28] and other novel degradation products of ginsenosides could revert tumor multidrug resistance and increase the sensitivity of multidrug-resistant cells on antitumor drugs. In particular, 20(S)-3-methoxy-PD has strong anticancer activity against MCF-7, HeLa and HepG2 cancer cells, with IC50 of 22.6 ± 2.49 µM, 25.81 ± 6.9 µM and 27 ± 5.76 µM, respectively. A group of dammarane sapogenins, including PAM-120, PBM-110, PBM-100, PAN-20 [29], (20S)-25OH-PPD, (20S)-3b,12b,20,26-tetrahydroxy-dammarane-24Zene, (20S)-3b, 12b,20,26-tetrahydroxy-dammarane-24E-ene, (20S)-3b,6a,12b, 20-tetrahydroxy-25-hydroperoxy-dammarane-23-ene (20S,24R)-3b,6a,12b,20, 24-pentahydroxydammar-25-ene and (20S)-6a,12b,20-trihydroxy-dammar24-ene-3-one [30], have shown surprising antitumor activities. PPD analogs have been widely used as a template for development of new chemical entities with potential antitumor activity. Studies on the structure--activity relationship (SAR) among ginsenosides and their anticancer effects have shown that PPD-type saponins are more effective than PPT-type saponins. A Chinese patent [31] introduced a preparation method for PPD peroxide derivatives, (20S)-25-hydroperoxy-3,12,20trihydroxyl-dammar-23-ene, (20S,24R)-24-hydroperoxy-3, 12,20-trihydroxyl-dammar-25(26)-ene, (20S,24S)-24-hydroperoxy-3 and 12,20-trihydroxyl-dammar-25(26)-ene, which could be applied to produce antineoplastic drugs. It was patented that the C-3, 12-ester derivatives or salts of 20(S)PPD showed better antitumor activities and could enhance the activities of other antiviral and antitumor agents and decrease the toxicity of chlormethine, cyclophosphamide, 5-fluorouracil, amantadin, mercaptopurine, aciclovir and lamifudine [32]. A series of dicarboxylic acid ester derivatives of compound K, such as succinate and glutarate [33], could be used to form salts with better water solubility, thereby retaining their anticancer activities. Compared with ginsenoside Rg3, dammarane derivatives (e.g., 3-O-[b-D-glucopyranosyl(1!2)-b-D-glucopyranosyl] dammarane-3b,12b-diol and 3-O-b-D-glucopyranosyl dammarane-3b,12b-diol), through hydrogenation of the double bond in C-20, showed 2 -- 3 times more improved anticancer activities in A549, 4

SK-OV-3, SK-MEL-2, XF498 and HCT15 [34]. Some Rh2 derivatives [35] could treat lung cancer, liver cancer, gastric cancer, colon cancer, prostate gland cancer, glioma, laryngeal carcinoma or esophageal cancer. However, Rh2 was dealt with microorganism [36] and the derivatives were obtained, (20S)-25-ethyoxyl-3,12,20-trihydroxyl-dammar-23-ene could be used as antitumor agent for treating cervical cancer, leukemia, neuroblastoma, prostatic cancer, liver cancer and breast cancer. The modification of the end of the side chain (C25-C27) appeared in an up-to-date patent [37], which disclosed the preparation progress of PPD derivatives, including: i) ozonation and reductive amination reaction or ii) ozonation, condensation, reduction and acylation reaction. The derivatives showed strong antitumor activities against several kinds of cancer cells. Aside from P. ginseng, Glycosmis pentaphylla is another natural source of anticancer dammarane triterpenoids [38]. A patent declared that the four new compounds from G. pentaphylla, namely, damulin A, damulin B, gypenoside L and gypenoside LI [39], exhibited better anticancer activities on A549, MKN45, SMMC-7721 and HL60 cells, respectively than Rg3. Diabetes mellitus and metabolic syndrome In recent years, diabetes mellitus and metabolic syndrome disease have affected hundreds of millions of men and women around the world. Increasing number of clinical trials and animal experiments have proven that dammarane triterpenoids, especially ginsenosides; for example, the mixture [40] comprising Rg3, Rg5 and Rk1, may be used for the prevention and treatment of diabetes by lowering the blood glucose, increasing insulin sensitivity, regulating lipid metabolism and even reducing body weight. Another patent [41] reported ginsenosides Rf2, Rh1 and so on, and their fatty acid ester derivatives could be used to improve hyperglycemia, glucose tolerance and polydipsia, and treat other metabolic diseases. A series of 20(S)- or 20(R)-3,20,25-trihydroxyl dammarane-12-one derivatives (3-O: H, aliph. acyl, aryloxy and so on; 20-O: pentosyl, 6-deoxyhexosyl, hexosyl or oligosaccharidyl; 25-O: H, alkyl, halo substituted alkyl and so on) was synthesized and screened in vivo with antidiabetic effects as compared with the standard drugs [42]. 2.2

Hyperlipidemia, cardiovascular and cerebrovascular diseases

2.3

Hyperlipidemia has increasingly gained attention because of the associated risks for diabetes mellitus and cardiovascular diseases. The data from some patents suggested that PPD, PPT, PD and panaxatriol (PT) [43] could be used in producing blood lipid-lowering drugs with wide clinical application prospects. According to the animal model assay, ocotillol R1 isolated from P. quinquefolius stems and leaves could lower the regulation level of total cholesterol [44]. Some patents indicated that the antihyperlipidemia effect of




dammarane triterpenoids depends on both the content and the type of chemical structure. P. ginseng extracts with the ratio of ginsenosides (Rg3 + Rg5 + Rk1)/(Rb1 + Rb2 + Rc + Rd) (w/w) over 1.0 reduced the weight of rat suffering from obesity because of the estrogen deficiency caused by ovary removal. In addition, this mixture could also reduce blood cholesterol, low-density lipoprotein and triglyceride content, and increase high-density lipoprotein content [45]. Meanwhile, specific components, namely, ginsenoside Rg3, Rg2 and Rh2, as well as at least one saponin metabolite selected from 20(S)-PPD, 20(S)-PPT and compound K, could enhance antiobesity activity, energy improving activity or blood circulation improving effect. In the past few decades, people have suffered commonly from cardiovascular and cerebrovascular diseases regardless of race, age and gender. Current studies have shown that dammarane triterpenoids have a protective effect on these diseases [46]. The ginsenosides from plants of the Panax genus are often used to treat thrombotic diseases [47,48], ischemic cardiomyopathy, myocardial damage caused by myocardial infarction and other cardiovascular-related diseases. Among the multitudinous dammarane triterpenoids, ginsenoside Rb2, ginsenoside Rg1 and notoginsenoside R1 have been mentioned frequently for the treatment of cardiovascular and cerebrovascular diseases. Ginsenoside Rb2 could be used to prevent and treat myocardial remodelling [49]. The mixture containing ginsenoside Rg1 and notoginsenoside R1, with ginsenoside Rg1 content of 95 -- 98%, could effectively treat coronary heart disease and angina pectoris [50]. Furthermore, medicine extracts [51] with 45 -- 95% notoginsenoside R1, ginsenoside Rg1, Rb1, Re and Rd, may be used to prepare medicaments for alleviating the toxicity of anthracene ring antitumor drugs to the heart. However, ginsenoside Rb1 and Re effectively reduce blood pressure to better control the systolic blood pressure of spontaneously hypertensive rats [52,53]. The composition from Panax containing ginsenosides Rg3, Rg5 and Rk1 is beneficial to angiostenosis and restenosis, inhibiting 50% of muscle cell growth at the concentration of 5 µg/ml by ELISA assay [54]. Moreover, the significant foam cell formation-inhibiting effects and vascular smooth muscle proliferation-inhibiting effects were measured by the expression of TNF-a, inducible nitric oxide synthase, ABCA1, CD36, PPAR-g and MMP-9 [55]. Pseudoginsenosides F11 and RT5 [56-58] from P. quinquefolius are also useful for the treatment of myocardial ischemia, cerebral ischemia and apoplexia. Hence, the animal model results showed that 20(R)-pseudoginsenoside F11 at 5 -- 15 mg/kg could be used to treat arrhythmia [59]. In addition, majonoside R2 [60] as an active component may be used to prepare drugs or functional foods to treat myocardial ischemia, whereas notoginsenoside Fc [61] could prevent and treat thrombotic diseases induced by platelet aggregation function, hyperfunction and blood coagulation increase, such as myocardial ischemia and myocardial infarction. Another plant, Aralia elita, which contains dammarane triterpenoids,

has been studied recently. A novel dammar-12-one saponin [62] that could be used to treat ischemic cardiomyopathy, myocardial damage caused by myocardial infarction and other cardiovascular-related diseases has been found. Aging, neurodegenerative disease Today, in most countries, neurodegenerative diseases represent one of the greatest challenges of our aging society; aging could cause a series of neurodegenerative disease, which has been commonly accepted. Dammarane triterpenoids play an important role in the CNS [63]. The compound K is an effective ingredient for antiaging agent because of its ability to increase in the expression of hyaluronic acid synthase gene in human cell [64]. According to another patent [65], low-polar ginsenoside, which consists of one or more: i) PPT; ii) PT, dammar-3b,6a,12b-trihydroxyl-20(21),24 (25)-diene and dammar-3b,6a,12b-trihydroxyl-20(22),24 (25)-diene; iii) 20-(R)-Rg2, 20-(S)-Rg2, 20-(R)-Rh1 and 20-(S)-Rh1; iv) dammar-3b,6a,12b-trihydroxyl-20(21),24 (25)-diene, Rg6, Pk3 and Rs7 and dammar-3b,6a,12b-trihydroxyl-20(22),24(25)-diene, F4, Rh4 and Rs6; v) PPD; vi) PD, dammar-3b,12b-dihydroxyl-20(21), 24-diene and dammar-3b,12b-dihydroxyl-20(22),24-diene and vii) ginsenoside Rg3 and Rh2, could be used as antiaging medicine. A number of dammaranes, such as ginsenoside Rg1, notoginsenoside R1 and pseudoginsenoside F11, also contribute to the treatment of neurodegenerative disease (Alzheimer’s and Parkinson’s disease). A patent [66] exhibited that the mixture of ginsenoside Rg1 and notoginsenoside R1, containing 95 -- 98% ginsenoside Rg1 and 0.1 -- 3% notoginsenoside R1, had synergic effect on senile dementia; the unit dose of the mixture was 2.5 -- 50 mg. At the same time, Rg1 protects cytochondriome and reduces neuron apoptosis by relieving oligo-Ab1-42-induced neuron stress injury, relieving the inhibiting effect of Ab1-42 on PKA-CREB signal passage [67]. Notoginsenoside R1 could be used to improve the cognition, learning and memory capabilities of an APP/PS1 transgenic AD mouse, restore the intracerebral choline acetyltransferase level of the mouse and reduce the intracerebral malondialdehyde level. In addition, notoginsenoside R1 increases the insulin degrading enzyme level and inhibits the accumulation of the Ab [68]. Moreover, 5 -- 400 mg of pseudo-ginsenoside F11 could improve the learning and memory of patients with senile dementia or brain function disorders, and could be used as an inhibitory for Alzheimer’s disease and vascular dementia [69]. Aside from the dammaranes described above, other compounds, for example, 20S-24S-epoxy-3b, 12b and 25-triol [70], could prevent or treat degenerative diseases of the CNS. These compounds showed strong antioxidant protection and improved rat space exploration and orientation capabilities by vascular dementia models. Other natural compounds, namely, (20S)-notoginseng saponin A4, (20S)-notoginseng saponin A6 or Notoginseng saponin B [71], could effectively prevent and treat diseases induced by mitochondrial disorder, 2.4


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including Parkinson’s disease and Alzheimer’s disease. A number of researchers [72,73] have synthesized a series of ginsenoside compounds (Rg5, Rk1, Rg3 and so on), which could be used to treat or prevent a pathological condition, particularly neurodegeneration diseases, by inhibiting b-amyloid peptide (including Ab42) production accessed by incubating the CHO-APP cells. Bone, liver, kidney and gastrointestinal disease In a previous patent, a set of 20-O-glycosyl-20(S)-PPD derivatives (some changes in C-3, 12, which were replaced with acyl groups) [74] were synthesized to develop novel rheumatic arthritis and osteoarthritis inhibitors. The other patent applications [75,76] reported that when the content of ginsenoside Rg3, Rk1 and Rg5 was higher than the total of ginsenoside Rb1, Rb2, Rc and Rd in the ginseng extractive, it could inhibit RANKL-induced osteoclast differentiation and bone resorption-related gene, generation of TRAP (+) coenocyte and expression of osteoclast-related factor, such as TRAP, NFATc1 and JNK and be used to treat and prevent bone metabolic disease and bone disease. Ginsenosides Rd, Rg3 and Rg5 could be used to treat liver injury and diseases. The combination between the ginsenoside Rd and the cell factor fibroblast growth factor-4 may induce the mesenchymal stem cells to be differentiated to the hepatic cell [77]. Ginsenoside Rg5, in combination with other ginsenosides, could be used to treat hepatitis, and the ratio of ginsenoside Rg5 and other constituents was 1/(0.1 -- 10) (w/w) [78]. Similarly, other patents [79,80] illustrated that the mixture of ginsenosides could protect the liver effectively by controlling nitric oxide generation and lactate dehydrogenase, glutamate oxaloacetate transaminase and glutamate-pyruvate transaminase activities when they contain the ginsenoside ratio (Rg3 + Rg5)/(Rc + Rd + Rb1 + Rb2) (w/w) that is > 1.0. Moreover, the dammarane triterpene derivatives from Gynostemma pentaphyllum [81], (20S,23R)-3b,20-dihydro-xydammar-24-en-21-oic acid 21,23-lactone, (20R,23R)3b,20-dihydro-xydammar-24-en-21-oic acid 21,23-lactone can treat hepatic fibrosis because of the effects on the inducing apoptosis of hepatic stellate LX2 cells. Furthermore, the mixture containing ginsenoside PD, PT, PPD, PPT, Re, Rk3 and Rh4 could be used in preventing, improving or treating renal diseases [82,83]. Ginsenoside Re could be used for prevention or treatment of gastrointestinal diseases [84], while ginsenoside Rd could treat ulcerative colitis and non-bacterial chronic colitis [85]. The other patent [86] reported that the extracts of ginseng and lactobacillus-fermented ginseng, containing at least one ginseng saponin derivative, such as ginsenoside Rb1, Rb2, Rc, Rd, Rg1, Rg3 and Rh2, could treat ulcerative colitis and Crohn’s disease without side effects. Several dammarane derivatives, for example, (20S,24R)-3,12-dihydroxy 20,24-epoxy-dammar-25-ene, (20S,24S)-3,12-dihydroxy20,24-epoxy-dammar-25-ene, exhibited strong inhibition towards Gram-positive and Gram-negative bacteria, with


2.5

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MIC of 4 -- 128 µg/ml and from 64 to 128 µg/ml, respectively, and could prevent and treat bacterial infection diseases, enteritis and diarrhea [87]. Depression-type mental illness Proven by tests, some dammarane derivatives, for example, ginsenosides Rd and Rg1, have favorable antidepression effect and could be used as an active ingredient in preparing the medicine to prevent or treat depression-type mental illness. Ginsenoside Rd could remarkably shorten the immobility time in a mouse tail suspension test, force mouse swimming test and reduce the escape failure number of the mouse in an acquired helplessness test under a test dosage [88]. Ginsenoside Rg1 had significant antidepressive effect in a dosedependent manner, and the daily dose is 5 -- 11 mg/kg, and the antidepressant may be in dosage forms of tablet, capsule, granule, pill, drops, juice, syrup, sublingual tablet, liquid injection, injection powder or freeze-dried powder for injection [89]. In addition, 20(S)-PPT derivatives [90,91], prepared according to the synthesis routes: 20(S)-PPT was replaced with OH, -NOH- or NH2 on C-3 and OH, -NOH- or NH2 on C-12, were described that they could shorten mouse immobility time in tail suspension test and motionless time in forced swimming test. 2.6

Skin aging Several dammarane triterpenoids could resist skin aging, such as Rg2, Rg4, Rg6, Rh1, Rh4 and Rk3 [92]. Ginsenoside F1and compound K showed the ability to prevent skin aging by inhibiting the decomposition of epidermal--dermal junction [93]. The nanoemulsion obtained by emulsifying the main metabolites of dammarane-type ginseng saponins could enhance skin penetration and promote proliferation of fibroblast and biosynthesis of collagen [94]. It was found [95-100] that the extracts from P. ginseng, containing mainly ginsenosides Rg3, Rg5 and Rk1, increased cell propagation in a dermal fibroblast directly, increasing the synthesis of collagen and tissue inhibitor of MMP-1, increasing the expression of procollagen in a dermal cell decreased by UV radiation and decreasing expression of MMP-1. These extracts could inhibit TRAP (+) apocyte formation and gene expression of osteoclast-related factors (TRAP, NFATc1, JNK and so on) of osteoclast differentiated with RANKL, and furthermore may be used to treat skin aging diseases. P. pseudoginseng Wall can also prevent and improve wrinkles. Ginsenosides or saponins, mixed with oil and fat, hydrocarbon and fatty acids could effectively prevent aging because they can improve skin elasticity and provide UV protection [101]. Both of the following mixture in the patent applications [102,103], ginsenoside RK3 and Rh4; Rh4, Rk3, Rg6 and F4, were cited in preventing skin aging caused by UV exposure, or treating skin wrinkle by inhibiting fibroblast collagenase activity induced by UV exposure [104]. 2.7



Types of diseases

Number of patents


1. Cancer 2. Diabetes mellitus and metabolic syndrome 3. Hyperlipidemia 4. Aging 5. Neurodegeneative disease 6. Cardiovascular and cerebrovascular disease 7. Bone disease 8. Liver disease 9. Kidney disease 10. Gastrointestinal disease 11. Depression-type mental illness 12. Skin aging

30 3 3 2 8 17 3 5 2 4 4 13

11 4% 10 4% 9 2% 8 5% 7 3%

12 14% 1 33%

2 3% 6 18%

5 9%

3 3% 4 2%

Figure 3. The number of patents about different diseases in this text.

3.

Conclusion

In the patents of this review, most of dammarane triterpenoids were isolated from the leaves, stems, berries, and roots of different plants, namely, P. ginseng, P. quinquefolius, P. notoginseng, P. vietnamensis, P. pseudo-ginseng Wall. var. pseudo-ginseng and G. pentaphylla. The other dammarane derivatives were prepared by semi-synthesis methods of the natural compounds. Several patents have indicated that dammarane triterpenes have a huge number of activities in both laboratory and clinical medicine regarding different diseases. Figure 3 shows that dammarane triterpenes could be used to prevent and treat cancer (30 correlated patents), cardiovascular and cerebrovascular diseases (17 correlated patents). Some patents have indicated that the biological activities of dammarane triterpenes are primarily dependent on the type of chemical structure. In this paper, dozens of compounds for pharmaceutical use were mentioned (Table 1). Table 1 shows the types of side chain of dammarane triterpenes in the patents of this review (A-1, A-2, A-3, A-4, A-6, A-7, A-9, A-10, A-11, A-12, A-13, A-14, A-16; B-1, B-2, B-3, B-5, B-6, B-9, B-10, B-11, B-14, B-16; C-2, C-5, C-6, and C-7). Therefore, only 27 types of side chains were applied for patents on their pharmaceutical uses (as summarized in Figure 2). Furthermore, the rest of the side chains were new natural products from several plants, and had not been studied extensively and patented in time. PPD or PPT analogs, possessing B-1 side chain, were reported by most of the patents because these compounds are rich in nature and their concentration in plants is higher than the others. Rg3 was described in patents to have high frequency, which can be used to treat cancer, bone disease, diabetes, hyperlipidemia, cardiovascular disease, neurodegenerative disease, gastrointestinal diseases, liver diseases, skin aging, and so on, whereas ginsenoside Rb1 was described in > 10 patents.

However, as shown in Figure 4 and Table 1, even if the series of compounds having two C=C in side chain were mentioned by fewer patents, ginsenoside Rg5 with C-7 side chain as well as ginsenoside Rk1 (C-5 type side chain) are reported frequently, and studies on their use for treating neurodegenerative diseases and skin aging are growing steadily in recent years. The applicability of dammarane semi-synthesis derivatives expand to pharmaceutical industry because of their good bioactivity. Most of the patents dealt with modifications of dammarane triterpenes at positions C-3, 6, 12 and 20, and the esterification, etherification, reduction methods of currently known ginsenosides or aglycones were applied as the effective strategy for more bioactive derivatives. In this review, all new fatty acid ester, aromatic esters and new dammaranes possessing double-bond on 20 (21) or 20 (22) were prepared using the above-mentioned semi-synthesis methods. Up to now, the SAR between dammarane triterpenes and all kinds of diseases has not been illuminated clearly, although numerous compounds of this type have been reported for the prevention and treatment of various diseases. Previous studies of the SAR of dammaranes by our group and others suggested that the activity against cancer was affected generally by the following factors: the number of sugar moieties, structural type of dammarane, the substituent groups in the side chain, different modifying groups and so on. Specifically, the presence of the sugar moieties reduced the anticancer activity [105]; PPD-type compounds were more effective than PPT-type ones [105]; as the substituent groups in the side chain, methoxy groups and hydroxyl groups enhanced anticancer activities normally [105,106]; the anticancer activity was reduced when C-3 and/or C-12 were substituted with long-chain fatty acids [107]; the cytotoxic activity was increased when dammaranes were esterified with the protected amino acids at C-3, while decreased when substituted at C-12 [108].


7

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Table 1. Dammarane triterpenoids in patents of this review. No.

R1

R2

R3

R4

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

H H H H H H H H H H H H H H H H H H H H H H H H H

OH OH OH OH OH OCH3 OH OH O-glc(2!1) Glc O-glc OH OH OH OH OH =O =O OH OH OH OH O-glc(2!1) glc OH OH OH

H H H H H H H OH H H H O-glc(2!1) Rha H H O-glc(2!1) xyl OH O-glc O-glc(2!1) rha H O-glc H OH O-glc(2!1) xyl O-Ara O-Glc(2!1)xyl

OH OH OH OH OH OH OH OH OH OH OH =O OH OH OH

A-1 A-10 A-11 A-12 A-13 A-14 A-14 A-14 A-16 A-16 A-2 A-2 A-3 A-4 A-6 A-6 A-6 A-6 or A-7 A-7 A-7 A-9 B-1 B-1 B-1 B-1

26 27 28 29 30 31 32 33 34 35 36 37

H H H H H H H H H H H H

O-glc(2!1) glc =O OH O-glc (2!1) glc O-glc (2!1) glc O-glc (2!1) arap O-glc (2!1) glc O-glc(2!1) glc OH OH OH O-glc(2!1) glc

OH OH H H H H H H O-glc(2!1) rha O-glc O-glc(2!1) rha H

=O OH O-Glc OH OH OH OH OH OH OH OH OH

B-1 B-1 B-1 B-1 B-1 B-1 B-1 B-1 B-1 B-1 B-1 B-1

38 39 40

H H OH

OH O-glc O-glc(2!1) glc

O-glc H

OH OH OH

B-1 B-1 B-1

OH OH H H OH OH OH OH OH

Side chain

Glycosylation on side chain

[21-24,30] [87] [81] [81] [26] [27] [43,82] [43,65,82] [34] [34] [21-24] [41] [18-24] [21,23] [36,60] [44] [16] [56,59] [70] [57,58] [87] [62] [50,51,66,68] [71] [71]

C20-O-glc C20-O-glc C20-O-glc (6!1) Glc

C20-O-glc C20-O-glc C20-O-glc C20-O-glc C20-O-glc C20-O-glc C20-O-glc

Ref.

(6!1) (6!1) (6!1) (6!1)

glc arap arap araf

[62] [30] [33] [45,51-53,75,76,79,80,86] [45,46,75,76,79,80,86] [46] [45,75,76,79,80,86] [45,51,75-77,79,80,85,86,88] [51-53,83,84] [42,50,51,66,67,86,89] [92] [16,39,40,45,54,55,72,73, 75,76,79,80,86,95-100] [13,41,65] [12,35,86] [39]

1. 20(S)-25-OH-PPD; 2. (20S,24R)-3,12-Dihydroxy-20,24-epoxy-dammar-25-ene; 3. (20R,23R)-3b,20-Dihydro-xydammar-24-en-21-oic acid 21,23-lactone; 4. (20S,23R)-3b,20-Dihydroxydammar-24-en-21-oic acid 21,23-lactone; 5. (20S,22S)-Dammar-22,25-epoxy-3b,12b,20-triol; 6. 20(S)-3-Methoxy-panaxadiol; 7. Panaxadiol; 8. Panaxatriol; 9. 3-O-[b-D-Glucopyranosyl(1!2)-b-D-glucopyranosyl] dammarane-3b,12b-diol; 10. 3-O-b-D-Glucopyranosyl dammarane-3b,12b-diol; 11. 20(R)-25-OH-PPD; 12. Ginsenoside Rf2; 13. 20(S)-25-Methoxy -PPD; 14. 20(R)-25-Methoxy-PPD; 15. Majonoside R2; 16. Ocotillol R1; 17. Pseudoginsenoside RT6; 18. Pseudoginsenoside F11; 19. (20S,24S)-Epoxy-3b,12b,25-triol; 20. Pseudoginsenoside RT5; 21. (20S,24S)-3,12-Dihydroxy-20,24-epoxy-dammar-25-ene; 22. A new compound from Aralia elita (CN 103804455A); 23. Notoginsenoside R1; 24. (20S)-Notoginseng saponin A4; 25. (20S)-Notoginseng saponin A6; 26. (20S)-3b,6a,20-Trihydroxydammar-24-ene-12-one 3-O-b-D-pyranosyl(1!2)-b-D-glucopyranoside; 27. (20S)-6a,2b,20-Trihydroxy-dammar-24-ene-3-one; 28. Compound K; 29. Ginsenoside Rb1; 30. Ginsenoside Rb2; 31. Ginsenoside Rb3; 32. Ginsenoside Rc; 33. Ginsenoside Rd; 34. Ginsenoside Re; 35. Ginsenoside Rg1; 36. Ginsenoside Rg2; 37. Ginsenoside Rg3; 38. Ginsenoside Rh1; 39. Ginsenoside Rh2; 40. Gypenoside L; 41. Notoginsenoside Fc; 42. 20(S)- or 20(R)-PPD; 43. 20(S)- or 20(R)-PPT; 44. 20(S)- or 20(R)-3,20,25-Trihydroxyl dammarane-12-one; 45. (20R)-Ginsenoside Rg2; 46. (20R)-Ginsenoside Rh2; 47. Gypenoside LI; 48. 20(S)-3,20,21-Trihydroxydammaran-24-ene; 49. (20S)-3b,12b,20,26-Tetrahydroxy-dammarane-24E-ene; 50. (20S)-3b,12b,20,26-Tetrahydroxy-dammarane-24Zene; 51. (20S,24S)-24-Hydroperoxy-3,12,20-trihydroxyl-dammar-25-ene; 52. (20S,24R)-24-Hydroperoxy-3,12,20-trihydroxyl-dammar-25-ene; 53. (20S,24R)3b,6a,12b,20,24-Pentahydroxy-dammar-25-ene; 54. (20S)-25-Hydroperoxy-3b,12b,20-trihydroxyl-dammar-23-ene; 55. (20S)-3b,6a,12b,20-Tetrahydroxy25-hydroperoxy-dammarane-23-ene; 56. (20S)-25-Ethyoxyl-3b,12b,20-trihydroxyl-dammar-23-ene; 57. PBM-100; 58. Notoginsenoside T5; 59. Dammar-3b,12bdihydroxyl-20(21),24-diene; 60. Dammar-3b,6a,12b-trihydroxyl-20(21),24-diene; 61. Ginsenoside Rg6; 62. Ginsenoside Rh4; 63. Ginsenoside Rk1; 64. Ginsenoside Rk3; 65. Notoginsenoside T5; 66. PAM-120; 67. PAN-20; 68. PAN-30; 69. Ginsenoside Pk3; 70. Ginsenoside Rs7; 71. Dammar-3b,6a,12b-trihydroxyl-20 (22),24-diene; 72. Ginsenoside Rh3; 73. Damulin A; 74. Amulin B; 75. Ginsenoside F4; 76. Ginsenoside Rg5; 77. Notoginseng saponin B; 78. PBM-110. PPD: Protopanaxadiol; PPT: Protopanaxatriol.

8




Table 1. Dammarane triterpenoids in patents of this review (continued). No.

R1

41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63

H H H H H H OH H H H H H H H H H H H H H

R2

R3 O-glc(6!1) xyl H OH H O-glc(2!1) rha H

H H

O-glc(2!1) xyl OH OH OH OH O-glc O-glc(2!1) glc OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH O-glc(4!1) glc

64 65 66 67 68 69 70 71 72 73 74 75 76

H H H H H H H H H OH OH H H

OH OH OH O-glc O-glc(2!1) OH OH OH O-glc O-glc(2!1) O-glc(2!1) OH O-glc(2!1)

O-glc O-glc(3!1) xyl H H H O-glc O-glc-6-Ac OH H

77 78

H H

OH OH

glc

Side chain

OH OH OH =O OH OH OH H OH OH OH OH OH OH OH OH OH OH OH OH OH OH OH

B-1 B-1 or B-2 B-1 or B-2 B-1 or B-2 B-2 B-2 B-2 B-3 B-5 B-6 B-9 B-10 B-11 B-14 B-14 B-16 C-2 C-5 C-5 C-5 C-5 C-5 C-5

O-Glc(2!1)Rha H

OH OH OH OH OH OH OH OH OH OH OH OH OH

C-5 C-5 C-5 C-5 C-5 C-5 C-5 C-6 C-6 C-7 C-7 C-7 C-7

O-Glc OH

O-Glc OH

C-7 C-7

H H H H H OH H OH H H O-glc(3!1) xyl H OH O-glc(2!1) rha O-glc H

glc glc glc

R4

Glycosylation on side chain

Ref. [61] [12,41,43,48,56,70,72,82] [12,30,41,43,70,82] [42] [65] [65] [39] [28] [30] [30] [31] [31] [30] [31] [30] [36] [29] [13] [65] [65] [14,47,62] [13,27,82] [40,45,47,54,55,72,73, 75,76,96-100] [47,82] [13] [29] [29] [29] [65] [65] [65] [10,47] [39] [39] [15,47] [40,45,54,55,72,73, 75,76,79,80,95-100] [71] [29]

1. 20(S)-25-OH-PPD; 2. (20S,24R)-3,12-Dihydroxy-20,24-epoxy-dammar-25-ene; 3. (20R,23R)-3b,20-Dihydro-xydammar-24-en-21-oic acid 21,23-lactone; 4. (20S,23R)-3b,20-Dihydroxydammar-24-en-21-oic acid 21,23-lactone; 5. (20S,22S)-Dammar-22,25-epoxy-3b,12b,20-triol; 6. 20(S)-3-Methoxy-panaxadiol; 7. Panaxadiol; 8. Panaxatriol; 9. 3-O-[b-D-Glucopyranosyl(1!2)-b-D-glucopyranosyl] dammarane-3b,12b-diol; 10. 3-O-b-D-Glucopyranosyl dammarane-3b,12b-diol; 11. 20(R)-25-OH-PPD; 12. Ginsenoside Rf2; 13. 20(S)-25-Methoxy -PPD; 14. 20(R)-25-Methoxy-PPD; 15. Majonoside R2; 16. Ocotillol R1; 17. Pseudoginsenoside RT6; 18. Pseudoginsenoside F11; 19. (20S,24S)-Epoxy-3b,12b,25-triol; 20. Pseudoginsenoside RT5; 21. (20S,24S)-3,12-Dihydroxy-20,24-epoxy-dammar-25-ene; 22. A new compound from Aralia elita (CN 103804455A); 23. Notoginsenoside R1; 24. (20S)-Notoginseng saponin A4; 25. (20S)-Notoginseng saponin A6; 26. (20S)-3b,6a,20-Trihydroxydammar-24-ene-12-one 3-O-b-D-pyranosyl(1!2)-b-D-glucopyranoside; 27. (20S)-6a,2b,20-Trihydroxy-dammar-24-ene-3-one; 28. Compound K; 29. Ginsenoside Rb1; 30. Ginsenoside Rb2; 31. Ginsenoside Rb3; 32. Ginsenoside Rc; 33. Ginsenoside Rd; 34. Ginsenoside Re; 35. Ginsenoside Rg1; 36. Ginsenoside Rg2; 37. Ginsenoside Rg3; 38. Ginsenoside Rh1; 39. Ginsenoside Rh2; 40. Gypenoside L; 41. Notoginsenoside Fc; 42. 20(S)- or 20(R)-PPD; 43. 20(S)- or 20(R)-PPT; 44. 20(S)- or 20(R)-3,20,25-Trihydroxyl dammarane-12-one; 45. (20R)-Ginsenoside Rg2; 46. (20R)-Ginsenoside Rh2; 47. Gypenoside LI; 48. 20(S)-3,20,21-Trihydroxydammaran-24-ene; 49. (20S)-3b,12b,20,26-Tetrahydroxy-dammarane-24E-ene; 50. (20S)-3b,12b,20,26-Tetrahydroxy-dammarane-24Zene; 51. (20S,24S)-24-Hydroperoxy-3,12,20-trihydroxyl-dammar-25-ene; 52. (20S,24R)-24-Hydroperoxy-3,12,20-trihydroxyl-dammar-25-ene; 53. (20S,24R)3b,6a,12b,20,24-Pentahydroxy-dammar-25-ene; 54. (20S)-25-Hydroperoxy-3b,12b,20-trihydroxyl-dammar-23-ene; 55. (20S)-3b,6a,12b,20-Tetrahydroxy25-hydroperoxy-dammarane-23-ene; 56. (20S)-25-Ethyoxyl-3b,12b,20-trihydroxyl-dammar-23-ene; 57. PBM-100; 58. Notoginsenoside T5; 59. Dammar-3b,12bdihydroxyl-20(21),24-diene; 60. Dammar-3b,6a,12b-trihydroxyl-20(21),24-diene; 61. Ginsenoside Rg6; 62. Ginsenoside Rh4; 63. Ginsenoside Rk1; 64. Ginsenoside Rk3; 65. Notoginsenoside T5; 66. PAM-120; 67. PAN-20; 68. PAN-30; 69. Ginsenoside Pk3; 70. Ginsenoside Rs7; 71. Dammar-3b,6a,12b-trihydroxyl-20 (22),24-diene; 72. Ginsenoside Rh3; 73. Damulin A; 74. Amulin B; 75. Ginsenoside F4; 76. Ginsenoside Rg5; 77. Notoginseng saponin B; 78. PBM-110. PPD: Protopanaxadiol; PPT: Protopanaxatriol.


9

J. Cao et al.

Side Chain R4

R1

R2


R3

Figure 4. Structures of dammarane triterpenoids (1 -- 78 in Table 1).

4.

Expert opinion

In the past 10 years, over 90 patents on dammarane triterpenoids have been reported for the prevention and treatment of a lot of diseases, such as cancer, diabetes mellitus and metabolic syndrome, hyperlipidemia, cardiovascular and cerebrovascular disease, neurodegenerative disease and so on. The medicinal dammarane triterpenoids in the present patents mostly come from P. ginseng and other species of the same genus. Nowadays, pharmaceutical researchers usually prefer the individual compound with bioactivities instead of the crude extracts of plants because of the dominant role played by natural monomeric compounds in the discovery of leads for the development of drugs. Thus, it is reasonable that future patents about dammarane-type natural medicines will be focused on the plants not only in Panax genus, but also in G. cardiospermum, G. pentaphyllum, A. elita, Aglaia odorata, Aglaia lawii, Bacopa monniera, Ceriops tagal, Copernicia cerifera, Celastrus rosthornianus, Forsythia suspensa, Kageneckia angustifolia, Myrica rubra, Rhus javanica, Polyscias fulva and Sapindus mukorossi, which are confirmed to contain dammarane compounds. We concluded that compounds of PPD or PPT type were extensively studied on their biological activities and clinical application. Nevertheless, pharmaceutical chemists should increase efforts and focus on further research on rare dammarane triterpenes, especially those having novel type of side

10

chain apart from PPD- or PPT-type derivatives in order to get surprising novel structures. Moreover, the researchers also should exert all their energies on structural modification about the hydroxyl or double bonds. In most cases, the aglycones play a more important role than its relevant saponins because of its more effective bioactivities. However, few aglycone compounds can meet the needs of sufficient water solubility. Therefore, it is a good choice to introduce hydrophilic groups, for example, amino, carboxylic or sulfonic groups rather than saccharide groups because amination or sulfation methods may change the bioactivity of compounds conspicuously. Certainly, it is more important to know clearly the target-based chemical modification and semi-synthesis by the aid of computer-aided drug design used in the field of dammarane pharmaceutical chemistry. Besides chemical modification, we were also delighted to find that the dammarane triterpenoids with novel side chains could be prepared by microbial conversion methods in some patents. Therefore, biotransformation of dammarane triterpenes should be put into use on a large scale for producing new alternative derivatives. At the same time, researchers should do their utmost to study systematically the SARs between the structures of dammarane triterpenoids and their bioactivities in order to indicate the direction of the structure modification and optimization. Even though more and more dammarane triterpenoids have been studied for the prevention and treatment of various diseases, the effects and pharmacological mechanisms of action are still not yet entirely understood. Further studies on pharmacological effects of dammarane triterpenoids should be conducted regarding the detailed mode of action and mechanisms both in vitro and in vivo.

Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.



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Affiliation Jiaqing Cao1, Xiaoshu Zhang1, Fanzhi Qu1, Zhenghong Guo1 & Yuqing Zhao†1,2 † Author for correspondence 1 Shenyang Pharmaceutical University, School of Traditional Chinese Materia Medica, Shenyang 110016, People’s Republic of China Tel: +86 24 23986521; Fax: +86 24 23986522; E-mail: [email protected] 2 Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, Shenyang 110016, People’s Republic of China

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