key: cord-0742385-edinv5ou
authors: Liang, Shuobin; Li, Man; Yu, Xiaojuan; Jin, Hongwei; Zhang, Yongmin; Zhang, Lihe; Zhou, Demin; Xiao, Sulong
title: Synthesis and structure-activity relationship studies of water-soluble β-cyclodextrin-glycyrrhetinic acid conjugates as potential anti-influenza virus agents
date: 2019-03-15
journal: Eur J Med Chem
DOI: 10.1016/j.ejmech.2019.01.074
sha: dfd8a8d727848934c6196ac5764b13fe6649faa0
doc_id: 742385
cord_uid: edinv5ou

Glycyrrhetinic acid (GA) is a major constituent of the herb Glycyrrhiza glabra, and many of its derivatives demonstrate a broad spectrum of antiviral activities. In the current study, 18 water-soluble β-cyclodextrin (CD)-GA conjugates, in which GA was covalently coupled to the primary face of β-CD using 1,2,3-triazole moiety along with varying lengths of linker, were synthesized via copper-catalyzed azide-alkyl cycloaddition reaction. Benefited from the attached β-CD moiety, all these conjugates showed lower hydrophobicity (AlogP) compared with their parent compound GA. With the exception of per-O-methylated β-CD-GA conjugate (35), all other conjugates showed no significant cytotoxicity to MDCK cells, and these conjugates were then screened against A/WSN/33 (H1N1) virus using the cytopathic effect assay. The preliminary results indicated that six conjugates showed promising antiviral activity, and the C-3 and C-30 of GA could tolerate some modifications. Our findings suggested that GA could be used as a lead compound for the development of potential anti-influenza virus agents.

Licorice, the roots of the perennial herb Glycyrrhiza glabra which are endemic to Mediterranean and certain areas of Asia, has been one of the oldest and most extensively used medicinal plants [1] . Pharmacologically active components that have been most studied include triterpenoids (3e5%), with glycyrrhizic acid (also known as glycyrrhizin, 1) being present in the highest concentration, and flavonoids (1e1.5%) [2] . Glycyrrhizic acid (1), composed of one molecule of glycyrrhetinic acid (GA, 2) and two molecules of glucuronic acid (Fig. 1 ), can be hydrolyzed by b-glucuronidases in the intestinal bacteria [3] . The amount of 2 in licorice root is reported to be within the range of 0.1e1.6%, depending on species and growing region [4] . Compounds 1 and 2 have attracted considerable attention from chemists and pharmacologists because of their pharmacological and biological effects, such as anti-inflammatory, antitumor, antiviral and other activities [1, 5] .

A lot of studies have confirmed the antiviral activity of glycyrrhizic acid (1) . In Japan, compound 1 has been used in the treatment of chronic viral hepatitis for more than 40 years as the intravenous drug Stronger Neo-Minophagen C (SNMC). It has shown that the administration of SNMC to patients with hepatitis C virus infection lowers the serum transaminase activity, even in the patients resistant to the interferon therapy [6] . Pompei et al. have reported that compound 1 can inhibit many DNA and RNA viruses, including HBV, HIV and EBV in vitro [7] . The antiviral activities of compound 1 against SARS-associated corona virus and influenza virus have also been demonstrated [8, 9] . Recently, it has been noted that the application of compound 1 as a potential antiviral agent can be further improved by using certain drug delivery systems, e.g., mucoadhesive nanoparticles based on poly (methyl vinyl ether-comaleic anhydride) (PVM/MA) [10] .

Compared with glycyrrhizic acid (1) , studies of the antiviral activity of its aglycone 2 are limited, but have attracted increasing attention in recent years. Lin et al. have claimed that compound 2 is 7.5-fold more active against EBV (EC 50 ¼ 4 mM) than its parent compound 1 (EC 50 ¼ 30 mM) [11] . Compound 2 shows significant antiviral activity against rotavirus replication at a step or steps subsequent to virus entry [12] . The semi-synthetic derivatives of 2, such as 4-iodobenzyl ester (3), 4-nitrobenzyl ester (4) and 4-(trifluoromethyl) benzyl ester (5) , show potent inhibitory effects on HBV DNA replication activity with IC 50 s at the micromolar level [13] . A recent study has indicated that GA derivative (6) , with a 2-hydroxypropyl group at C-30 and an acetyl group at C-3, show remarkable antiviral activity against TK þ and TK À strains of HSV-1 with EC 50 of 4.95 mM [14] . Despite the recognized pharmacological roles as antiviral agents, the main disadvantage of compound 2 and its derivative for application in the food or pharmaceutical industry is their low aqueous solubility due to its non-polar structure (logP: 6.75 [15] ). It has reported that the solubility of compound 2 in water is only 10.6 mg/mL (37 C) , and the water/n-BuOH partition coefficient is 1.02 Â 10 À2 (37 C) [16] . This combination of strong lipophilicity, low solubility and partition coefficient indicates its low bioavailability.

Some strategies have been assessed to overcome the limitation. Cyclodextrins (CDs) are a class of highly water-soluble and biocompatible cyclic oligosaccharides, which can reversely form host-guest inclusion complexes with a variety of guest molecules (drugs), thus improving certain properties of drugs, such as solubility, stability and bioavailability [17, 18] . The CD-triterpene inclusion complexes have been also synthesized to increase the aqueous solubility of certain pentacyclic triterpenes [19e21] . Ishida et al. have reported that the complex of compound 2 and HP-g-CD can improve the oral bioavailability and reduce mRNA expressions of TNF-a, IL-1b and IL-6 [22] . However, such a noncovalent complex is disadvantageous when drug targeting is to be attempted because the complex dissociates before it reaches the organs or tissues to which it is to be delivered [23] . Therefore, direct covalent linkage with b-CD has been suggested, which has been widely used in other water insoluble bioactive molecules, such as fullerene (C 60 ), 5-FU, folic acid and artesunate [24e27]. In our recent studies, a series of water-soluble triazole-bridged b-CD-pentacyclic triterpene conjugates have been synthesized via click chemistry [28, 29] .

As part of our continued interest in the structurally modified pentacyclic triterpene derivatives as antiviral inhibitors [29e33], we thought it value to prepare a wide range of pentacyclic triterpene derivatives to better explore their antiviral structureactivity relationship (SAR). Herein, we reported the synthesis and anti-influenza A/WSN/33 virus activity of a series of 1:1 b-CD-GA conjugates, in which GA (2) was covalently coupled to the primary face of b-CD via C-3 hydroxyl or C-30 carboxylic acid.

Scheme 1 illustrates the synthesis of b-CD-GA conjugates 23e27.

The commercially available GA (2) was reacted with 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) in THF to give the stable intermediate 7 in good yield, which proceeded towards a coupling reaction with different terminal alkynylfunctionalized primary amines under basic condition to install a flexible oligo (ethylene glycol) linker (8e12) in 46e82% yield. Then, 8e12 underwent a "click chemistry" reaction with 6 A -azide-6 Adeoxy-per-O-acetylated b-CD (16) , which was prepared from the known b-CD (13) in three steps using the conventional method as previously described [34] , in THF/H 2 O in the presence of a catalytic amount of copper sulfate and sodium ascorbate as reducing agent to yield 18e22 with yields ranging from 45% to 61%. At last, the acetyl groups of conjugates 18e22 were removed under Zembl en conditions [35] to afford 23e27 in 80e98% yields.

To increase the rigidness of the linker, the benzene and piperazine ring were introduced, and Scheme 2 describes the synthesis route for conjugates 30e31 and 33e34. The intermediate 7 was reacted either with an excess of 1-(2-aminoethyl) piperazine, followed by N-alkylation with propargyl bromide or with an excess of 4-ethynylaniline to give alkynyl-functionalized amides 29 and 32 in moderate yields. Similarly, coupling of compounds 29 and 32 with azide-functionalized per-O-acetylated b-CD (16) was performed via click reaction, followed by de-O-acetylation under Zempl en conditions to give the corresponding conjugates 31 and 34 as the final products.

Unlike the b-CD-GA conjugates described above, two other conjugates (35 and 40) , in which the per-O-methylated-b-CD was linked to the carboxylic acid at C-30 of GA or b-CD was linked to the hydroxyl at C-3 of GA, were designed. The method used to prepare conjugate 35 was outlined in Scheme 3, and intermediate 8 was coupled with 6 A -azide-6 A -deoxy-per-O-methylated-b-CD (17) via click chemistry to furnish conjugate 35. Conjugate 40 was synthesized according to the procedure described in Scheme 4. In order to synthesize C-3 alkynyl-functionalized compound 37 required for click reaction, the carboxylic acid group at C-30 of GA (2) was first protected by treatment with benzyl bromide in DMF, followed by O-alkylation at C-3 with propargyl bromide in the presence of sodium hydride. Coupling of compound 16 with O-propargyl GA derivative 37 was carried out via click reaction, followed by de-Obenzylation and de-O-acetylation reactions to give the conjugate 40 in 41% yield over three steps. 

The logarithm of the n-octanol/water partition coefficient (logP) is a well-known measure of molecular lipophilicity [36] . It is used to provide invaluable information for the overall understanding of the uptake, distribution, biotransformation and elimination of a wide variety of chemicals. In our study, the calculated AlogP values were determined using Pipeline Pilot software, Vers. 7.5 (Accelrys Corporation, San Diego, USA) [37] . Due to the introduction of b-CD along with different linkers, all the conjugates showed increased hydrophilicity compared with their parent compound GA (2) ( Table 1) 

The in vitro cytotoxic activity was evaluated for all of the synthesized conjugates 18e27, 30e31, 33e35 and 38e40 using Cell-Titer-Glo ® Assay. The results showed that most conjugates had no cytotoxicity against uninfected Madin-Daby canine kidney (MDCK) cells at a concentration of 50 mM, except for compound 35 possessing cytotoxicity at the same concentration (Fig. 2 ). This finding, together with our previous observation that per-O-methylated-b-CD derivatives of other pentacyclic triterpenes show different cytotoxicity at a concentration of 5e50 mM [28] , indicated that per-O-methylated-b-CD might impart certain degree of cytotoxicity in vitro. The five conjugates (23e27) with the GA and b-CD groups held constant, but with varying of the oligoethylene glycol linker revealed that compound 25 had the highest antiviral activity to A/ WSN/33 (H1N1) virus, indicating 1,2,3-triazole moiety along with diethylene glycol linker could allow a better fit between GA and the proper target. Elongation or shortening of the diethylene glycol chain leads to some decrease of the antiviral activity. Similar results were also observed for conjugates 18e22, in which the b-CD was acetylated, and compound 20 showed the greatest antiviral activity. The diethylene glycol linker of compounds 20 and 25 was further modified by replacing one ethylene glycol moiety with piperazine ring to increase the rigidness of the linker, leading to greatly reduced activity (20 vs. 30, 25 vs. 31). However, the introduction of an aromatic linker (1,2,3-triazol-4-yl)phenyl between b-CD and GA still retained reasonable antiviral activity (23 vs. 34). To our surprise, the introduction of aromatic amino acids methyl esters at C-30 of glycyrrhizin also showed more potent anti-influenza activity and 38e40 against MDCK cells using CellTiter-Glo ® Assay. than their parent compound [9] , indicating an aromatic group at C-30 might be helpful for the binding of GA with its receptor. Evaluation of the three derivatives (18, 23 and 35) with the same linker of (1,2,3-triazol-4-yl)methyl at the C-30 of GA revealed that the sub- (1) (EC 50 ¼ 364.6 mM) [9] , the effect of b-CD on the antiviral activity of GA is obviously more potent than that of two molecules of glucuronic acid.

In summary, a series of GA derivatives, altered at position C 

To a solution of alkyne (0.10 mmol) and azide (0.10 mmol) in 1:1 THF-H 2 O (5 mL), CuSO 4 (15.7 mg, 0.10 mmol) and sodium L-ascorbate (40.9 mg, 0.20 mmol) were added. The resulting solution was vigorously stirred for 12 h at room temperature. The reaction mixture was extracted with CH 2 Cl 2 (10 mL Â 3). The combined organics were dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by column chromatography.

The per-O-acetylated-b-CD-GA conjugate was dissolved in dry methanol (~5 mL per 100 mg of compound), and a solution of sodium methoxide (30% in methanol, 0.1 eq per mol of acetate) was added. The solution was stirred at room temperature for 4e6 h. After completion (TLC), the reaction mixture was neutralized with Amberlite IR-120 (H þ ) ion exchange resin, filtered and concentrated. The crude product was purified by RP column chromatography (eluted by CH 3 OH).

To a solution of compound 7 (200 mg, 0.34 mmol) and terminal alkynyl substituted amine (0.43 mmol) in DMF (10 mL), Na 2 CO 3 (72 mg, 0.68 mmol) was added. The resulting solution was vigorously stirred for 24 h at 60 C. The solvent was removed by steaming. The residue was purified by column chromatography.

Prepared from 7 and 2-(propyn-1-yloxy)-ethanamine according to general procedure C, the residue was purified by flash chromatography (eluent: petroleum ether:acetone ¼ 4:1) to afford 9 as a white solid with a yield of 46%. R f ¼ 0.70 (petroleum ether:acetone N-(3,6,9 ,12-tetraoxapentadec-14-yn-1-yl)-3bhydroxy-11-oxo-olean-12-en-30-amide (11) Prepared from 7 to 3,6,9,12-tetraoxapentadec-14-yn-1-amine according to general procedure C, the residue was purified by flash chromatography (eluent: DCM: MeOH ¼ 20:1) to afford 11 as a white solid with a yield of 52%. R f ¼ 0. 40 (3,6,9,12,15,18- hexaoxaheneicos-20-yn-1-yl)-3b-hydroxy-11-oxo-olean-12-en-30-amide (12) Prepared from 7 to 3,6,9,12,15,18-hexaoxaheneicos-20-yn-1amine according to general procedure C, the residue was purified by flash chromatography (eluent: petroleum ether:acetone ¼ 4:1) to afford 12 as a yellow oil with a yield of 52%. R f ¼ 0. 35 

Prepared from 9 and 16 according to general procedure A, the residue was purified by flash chromatography (eluent: petroleum ether:acetone ¼ 1:1) to afford 19 as a white foam with a yield of 60%. R f ¼ 0.20 (petroleum ether:acetone ¼ 1:1); 1 05 (m, 14H) 4.1.14. Synthesis of N-(1-(6 A -deoxy-b-cyclodextrin-6-yl)-1H-1,2,3triazol-4-yl)methyl-3b-hydroxy-11-oxo-olean-12-en-30-amide (23) Prepared from 18 according to general procedure B, the residue was purified by RP flash chromatography (eluent: methanol) to afford 23 as a white foam with a yield of 86%. 1 -deoxy-b-cyclodextrin-6-yl)-1H-1,2,3-triazol-4-yl)methoxy))ethoxy]ethyl)-3b-hydroxy-11-oxoolean-12-en-30-amide (25) Prepared from 20 according to general procedure B, the residue was purified by RP flash chromatography (eluent: methanol) to afford 25 as a white foam with a yield of 82%. 1 -deoxy-b-cyclodextrin-6-yl)-1H-1,2,3-triazol-4-yl)-2,5,8,11-tetraoxatridecan-13-yl)-3b-hydroxy-11oxo-olean-12-en-30-amide (26) Prepared from 21 according to general procedure B, the residue was purified by RP flash chromatography (eluent: methanol) to afford 26 as a white foam with a yield of 98%. 1 Prepared from 22 according to general procedure B, the residue was purified by RP flash chromatography (eluent: methanol) to afford 27 as a white foam with a yield of 90%. 1 4.1.19. N-(2-(piperazin-1-yl)-ethyl)-3b-hydroxy-11-oxo-olean-12en-30-amide (28) Prepared from 7 and 2-(piperazin-1-yl)ethan-1-amine according to general procedure C, the residue was purified by flash chromatography (eluent: DCM:MeOH:NH 3 $H 2 O ¼ 20:1:0.2) to afford 28 as a white solid with a yield of 45%. R f ¼ 0. 35 4.1.20. Synthesis of N-(2-(4-(prop-2-yn-1-yl)piperzain-1-yl)ethyl)-3b-hydroxy-11-oxo-olean-12-en-30-amide (29) To a solution of 28 (90 mg, 0.16 mmol) and bromopropyne (21.2 mg, 0.18 mmol) in dried THF, K 2 CO 3 (40 mg, 0.29 mmol) was added. The resulting solution was vigorously stirred for 24 h at room temperature. The solvent was removed by steaming. The residue was purified by column chromatography to afford compound 29 as a yellow solid with a yield of 76%. R f ¼ 0.45 (DCM:MeOH:NH 3 $H 2 O ¼ 10:1:0.01); m.p. 121e123 C; 1 H NMR

H1N1 influenza virus A/WSN/33 (H1N1) was used in antiviral studies. It was propagated in MDCK cells in serum-free Eagle's minimum essential medium supplemented with 2 mg/mL trypsin and 1.2 mM bicarbonate. Titers of virus stocks were determined according to Reed and Muench (1938) in MDCK cells [41] .

All of the reported conjugates were evaluated for cytotoxicity in MDCK cells. The cells (1 Â 10 4 cells per well) were seeded into 96well tissue culture plates and incubated at 37 C for 24 h in an atmosphere of 5% CO 2 to allow the cells to adhere to the surface of the wells. Subsequently, the culture medium was replaced with fresh medium containing the compounds at the concentration of 50 mM in triplicate, and control wells contained the equivalent volume of the medium containing 1% DMSO. After 36 h of incubation at 37 C in an atmosphere of 5% CO 2 , CellTiter-Glo reagent was added, and the plates were read using a Tecan Infinite M2000 PRO™ plate reader.

The assay was performed as described by Noah et al. [38] with some modifications. MDCK cells were seeded into 96-well plates, incubated overnight and infected with influenza virus (MOI ¼ 0.1) suspended in DMEM supplemented with 1% FBS, test compound and 2 mg/mL TPCK-treated trypsin, with a final DMSO concentration of 1% in each well, followed by 40 h of incubation, CellTiter-Glo reagent was added, and the plates were read using a Tecan Infinite M2000 PRO™ plate reader.

11(s, 6H, 2 Â CH 3 ), 0.99 (s, 3H, CH 3 ), 0.93 (dd, 1H

6 Hz); 13 C NMR (100 MHz

Prepared from 29 and 16 according to general procedure A, the residue was purified by flash chromatography (eluent: petroleum ether: acetone ¼ 1:2) to afford 30 as a white foam with a yield of 42%. R f ¼ 0.10 (petroleum ether:acetone ¼ 1:2); 1 H NMR (600 MHz

3-triazol-4-yl)methyl)piperazin-1-yl)-ethyl)-3b-hydroxy-11-oxo-olean-12-en-30-amide (31) Prepared from 30 according to general procedure B, the residue was purified by RP flash chromatography (eluent: methanol) to afford 31 as a white foam with a yield of 90%. 1 H NMR (600 MHz, MeOD:CDCl 3 ¼ 2:1): d 7.97 (s, 1H), 5.67 (s, 1H), 5.08 (d, 1H

To a solution of 2 (669 mg, 1.42 mmol) and benzenamine (111 mg, 0.95 mmol) in DMF, DMAP (55 mg, 0.45 mmol) and EDC (362 mg, 1.90 mmol) were added. The resulting solution was vigorously stirred for 24 h at room temperature. The solvent was removed by steaming. The residue was purified by column chromatography to afford compound 32 as a white solid with a yield of 60%

34 (s, 1H), 2.22 (dd, 1H, J ¼ 13.8, 3.2 Hz), 2.10e1.59 (m, 11H), 1.50e0.85 (m, other aliphatic ring protons), 1.39, 1.24 (s, each 3H, 2 Â CH 3 ), 1.12 (s, 6H, 2 Â CH 3 ), 1.00, 0.82, 0.80 (s, each 3H, 3 Â CH 3 ), 0.70 (d, 1H, J ¼ 11.7 Hz); 13 C NMR (100 MHz

Hz), 3.76e3.65 (m, 6H), 3.22 (dd, 1H, J ¼ 11.0, 5.2 Hz), 2.83 (s, 1H), 2.79 (td, 1H, J ¼ 13.6, 3.5 Hz), 2.28e2.25 (m, 1H), 2.15e1.97(m, 61H), 1.92e1.20 (m, other aliphatic ring protons), 1.39, 1.26 (s, each 3H, 2 Â CH 3 ), 1.12 (s, 6H, 2 Â CH 3 ), 1.06e1.04 (m, 1H), 1.00 (s, 3H, CH 3 ), 0.97 (dt, 1H

) Prepared from 8 and 17 according to general procedure A, the residue was purified by flash chromatography (eluent: petroleum ether:acetone ¼ 1:1) to afford 35 as a white foam with a yield of 59%. R f ¼ 0.15 (petroleum ether:acetone ¼ 1:1); 1 H NMR (600 MHz, CDCl 3 ): d 7.62 (s, 1H), 6.34 (br s, 1H), 5.66 (s, 1H), 5.33 (d, 1H, J ¼ 3.2 Hz), 5.17 (d, 1H, J ¼ 3.4 Hz), 5.16 (d, 1H, J ¼ 3.5 Hz), 5.13e5.12 (m, 3H)

A solution of 36 (342 mg, 0.61 mmol) in dry THF (20 mL) was cooled to 0 C. Sodium hydride (96 mg, 2.4 mmol) was added, and the mixture was stirred for 1 h at 0 C. Then, 3-bromopropyne was added, and the solution was stirred for 24 h at room temperature. The solvent of THF was evaporated, and the residue was purified by column chromatography to afford compound 37 as a white solid with a yield of 60%

54 (s, 1H), 5.20 (d, 1H, J ¼ 12.2 Hz), 5.09 (d, 1H

1 Hz)

Prepared from 37 and 16 according to general procedure A, the residue was purified by flash chromatography (eluent: petroleum ether: acetone ¼ 1:1) to afford 38 as a white foam with a yield of 60%. R f ¼ 0.49 (petroleum ether:acetone ¼ 1:1); 1 H NMR (600 MHz

A -deoxy-per-O-acetylated-bcyclodextrin-6-yl)-1H-1,2,3-triazol-4-yl)methoxy)-11-oxo-olean-12-en-30-oic acid (39) A solution of compound 38 (50 mg, 0.019 mmol) in methanol ¼ 0

16.45; ESI-HRMS (m/z) Calcd for C 115 H 157 N 3 O 58 [MþH] þ : 2508.9501. Found 2508.9487. 4.1.30. Synthesis of 3b-((1-(6 A -deoxy-b-cyclodextrin-6-yl)-1H-1,2,3-triazol-4-yl)methoxy)-11-oxo-olean-12-en-30-oic acid (40) Prepared from 39 according to general procedure B, the residue was purified by RP flash chromatography (eluent: methanol) to afford 40 as a white foam with a yield of 81%. 1 H NMR (600 MHz

The pharmacological activities of Licorice

Ethosomes for skin delivery of ammonium glycyrrhizinate: In vitro percutaneous permeation through human skin and in vivo anti-inflammatory activity on human volunteers

Bioavailability study of glycyrrhetic acid after oral administration of glycyrrhizin in rats; Relevance to the intestinal bacterial hydrolysis

Separation and analysis of glycyrrhizin, 18b-glycyrrhetic acid and 18a-glycyrrhetic acid in liquorice roots by means of capillary zone electrophoresis

Therapeutic potential of glycyrrhetinic acids: a patent review

Pharmacokinetics of intravenous glycyrrhizin after single and multiple doses in patients with chronic hepatitis C infection

Glycyrrhizic acid inhibits virus growth and inactivates virus-particles

Glycyrrhizin, an active component of liquorice roots, and replication of SARSassociated coronavirus

Glycyrrhizic acid derivatives as influenza A/H1N1 virus inhibitors

Preparation and characterization of mucoadhesive nanoparticles of poly (methyl vinyl ether-co-maleic anhydride) containing glycyrrhizic acid intended for vaginal administration

Inhibitory effects of some derivatives of glycyrrhizic acid against Epstein-Barr virus infection: structure-activity relationships

18b-glycyrrhetinic acid inhibits rotavirus replication in culture

Synthesis, biological evaluation and structure-activity relationships of glycyrrhetinic acid derivatives as novel anti-hepatitis B virus agents

Chemoenzymatic synthesis of new derivatives of glycyrrhetinic acid with antiviral activity. Molecular docking study

Effect and mechanism of penetration enhancement of organic base and alcohol on Glycyrrhetinic acid in vitro

Studies of oligosaccharides .12. Hydrophilization of glycyrrhetinic acid by coupling to gentio oligosaccharides

Complexation of phytochemicals with cyclodextrin derivatives -an insight

Cyclodextrins in pharmaceutical formulations II: solubilization, binding constant, and complexation efficiency

A comparison investigation on the solubilization of betulin and betulinic acid in cyclodextrin derivatives

Complexation between oleanolic and maslinic acids with native and modified cyclodextrins

New improved drug delivery technologies for pentacyclic triterpenes: a review

Effect of 18 b-glycyrrhetinic acid and hydroxypropyl gamma cyclodextrin complex on indomethacin-induced small intestinal injury in mice

-biphenylyl)acetyl]-a-, -b-, and -g-cyclodextrins and 6 A -deoxy-6 A -[[(4-biphenylyl)acetyl]amino]-a-, -b-, and -g-cyclodextrins: potential prodrugs for colon-specific delivery

5-Fluorouracil acetic acid/b-cyclodextrin conjugates: drug release behavior in enzymatic and rat cecal media

Potential use of folate-appended methyl-b-cyclodextrin as an anticancer agent

Conjugation of cyclodextrin with fullerene as a new class of HCV entry inhibitors

Synthesis, characterization, and in vitro evaluation of artesunate-b-cyclodextrin conjugates as novel anti-cancer prodrugs

Synthesis and anti-HCV entry activity studies of bcyclodextrin-pentacyclic triterpene conjugates

Pentacyclic triterpenes grafted on CD cores to interfere with influenza virus entry: a dramatic multivalent effect

Development of oleanane-type triterpenes as a new class of HCV entry inhibitors

Discovery of pentacyclic triterpenoids as potential entry inhibitors of influenza viruses

Recent progress in the antiviral activity and mechanism study of pentacyclic triterpenoids and their derivatives

Synthesis and biological evaluation of ring A and/or C expansion and opening echinocystic acid derivatives for anti-HCV entry inhibitors

Synthesis of monofacially functionalized cyclodextrins bearing amino pendent groups

The saponification acetyl sugar and relative substances

Prediction of n-octanol/water partition coefficients from PHYSPROP database using artificial neural networks and Estate indices

Escape from Flatland: increasing saturation as an approach to improving clinical success

Amino derivatives of glycyrrhetinic acid as potential inhibitors of cholinesterases

Synthesis of glycyrrhetinic acid derivatives for the treatment of metabolic diseases

Synthesis and antitumor activity of ring A modified glycyrrhetinic acid derivatives

A simple method of estimating fifty percent endpoint

This work was supported by the National Natural Science