N-Alkyl derivatives of diosgenyl 2-amino-2-deoxy-β-D-glucopyranoside; synthesis and antimicrobial activity

  1. Agata Walczewska1,
  2. Daria Grzywacz1,
  3. Dorota Bednarczyk1,
  4. Małgorzata Dawgul2,
  5. Andrzej Nowacki1,
  6. Wojciech Kamysz2,
  7. Beata Liberek1,§ and
  8. Henryk Myszka1

1Department of Chemistry, University of Gdańsk, Wita Stwosza 63, 80-308 Gdańsk, Poland
2Department of Pharmacy, Medical University of Gdańsk, Hallera 107, 80-416 Gdańsk, Poland

  1. Corresponding author email

§ Tel.: + 48 58 5235071; Fax: + 48-58-5235012

Associate Editor: N. Sewald
Beilstein J. Org. Chem. 2015, 11, 869–874. doi:10.3762/bjoc.11.97
Received 19 Dec 2014, Accepted 17 Apr 2015, Published 22 May 2015

Abstract

Diosgenyl 2-amino-2-deoxy-β-D-glucopyranoside is a synthetic saponin exhibiting attractive pharmacological properties. Different pathways tested by us to obtain this glycoside are summarized here. Moreover, the synthesis of N-alkyl and N,N-dialkyl derivatives of the glucopyranoside is presented. Evaluation of antibacterial and antifungal activities of these derivatives indicates that they have no inhibitory activity against Gram-negative bacteria, whereas many of the tested N-alkyl saponins were found to inhibit the growth of Gram-positive bacteria and human pathogenic fungi.

Keywords: antimicrobial activities; D-glucosamine; diosgenin glycosylation; N-alkylation

Introduction

Saponins are a group of steroid or triterpenoid glycosides, widely distributed in the plant kingdom [1]. Saponins are characteristic by their foaming properties in aqueous solution, causing them to be used as detergents, surfactants and emulsifiers. Moreover, they display a wide range of pharmacological activities, including antifungal, antiparasitic, antiinflammatory, antibacterial, and antitumor activities [2-5]. No wonder, saponins have been evaluated as vaccine adjuvants [6]. Despite the fact that thousands of homogeneous saponins have been characterized, new types of saponins are regularly isolated from nature and their biological activities are evaluated [7-11]. The yields of homogenous saponins isolated from natural sources are rather low. Therefore, chemical synthesis of saponins have been investigated [12-22] as well as the evaluation of their antitumor activities [23-27].

Naturally-occurring diosgenyl glycosides are the most abundant steroidal saponins. They have been continuously synthesized [28-32] and their cardiovascular, antifungal, anticancer [33-36] and antithrombotic activities [37] have been investigated. Gelation ability of the pentose derivatized diosgenyl saponins have also been reported [38]. In the family of diosgenyl β-glycosides D-glucopyranose is the first sugar attached to the diosgenin. Very often this D-glucopyranose is substituted with α-L-rhamnopyranose at 2-OH and other sugars at 4-OH. The change of D-glucopyranose into 2-amino-2-deoxy-D-glucopyranose provides diosgenyl 2-amino-2-deoxy-β-D-glucopyranoside (7), a synthetic saponin, first reported by us [39]. It was also demonstrated that diosgenyl 2-amino-2-deoxy-β-D-glucopyranoside hydrochloride increases the number of apoptotic B cells, in combination with cladribine (2-CdA), which were isolated from chronic lymphotic leukemia (B-CLL) patients [40]. The presence of the amine group in this promising antitumor compound creates the opportunity to synthesize new analogues with an enhanced activity. In this way, many of the N-acyl [41-43] as well as urea and thiosemicarbazone [44] analogues of 7 have been obtained and evaluated. Their characteristic feature is that their amine group is bound with the carbonyl or thiocarbonyl group. Such analogues are much more lipophilic, but also less basic than the parent saponin 7. In this paper, for the first time, the synthesis and antimicrobial activity of the N-alkyl derivatives of diosgenyl 2-amino-2-deoxy-β-D-glucopyranoside (7) are presented. From the chemical point of view, the alkyl group has quite different properties than the acyl group. First, alkylation does not change significantly the basicity of the parent amine group. Thus, the ability to bind protons by the parent compound and its analogue should be comparable. Second, the N-alkylamine group, similarly to the amine group, is able to work as a hydrogen bond acceptor. On the other hand, alkylation improves lipophilicity of the compound, which may be crucial for its biological activity.

At the beginning, our experiences concerning the synthesis of the parent diosgenyl 2-amino-2-deoxy-β-D-glucopyranoside (7) are summarized and presented. We have studied different glycosyl donors, different amine group protections, different solvents and promoters to find the best way to obtain 7. The presented compilation is informative for all those interested in the glycosidation of 2-amino-2-deoxy sugars.

Results and Discussion

Chemistry

To synthesize the parent diosgenyl 2-amino-2-deoxy-β-D-glucopyranoside (7), the O-acetylated bromides 2ad, chlorides 3ad and (N-phenyl)trifluoroacetimidates 5ad, α or β anomers, were examined (Scheme 1). These glycosyl donors were N-protected with trifluoroacetyl (TFA, a), 2,2,2-trichloroethoxycarbonyl (Troc, b), phthaloyl (Phth, c), and tetrachlorophthaloyl (TCP, d) groups, respectively. Applications of bromides 2a and 2d [40] and chlorides 3a–d [45] were previously reported. Here, applications of the two remaining bromides 2b and 2c as well as (N-phenyl)trifluoroacetimidates 5a–d are demonstrated. To synthesize bromide 2b we used a procedure described by Ellervik and Magnusson for other glycosylations [46]. However, the bromide obtained by them was a mixture of α and β anomers whereas 2b is a pure α anomer (J1,2 4,0 Hz). Bromide 2b, identified as the α anomer, was also synthesized by Higashi et al., but in a slightly different manner [47]. Bromide 2c (α + β) was synthesized analogously to 2b. Synthesis of (N-phenyl)trifluoroacetimidates 5a–d demands removal of the acetyl groups from the anomeric hydroxy groups in 1a–d. It was done with ethylenediamine in a mixture with acetic acid in THF, a procedure adopted from Zhang and Kováč [48]. This selective 1-O-deacetylation turned out to be very effective for 1a, 1b, and 1c (97%, 84%, and 90%, respectively). However, this was quite ineffective for 1d (36%). Therefore, 1-O-deacetylation of the latter was carried out via hydrolysis (Ag2CO3, acetone/H2O 2:1) of bromide 2d (73% yield) or chloride 3d (72% yield). (N-Phenyl)trifluoroacetimidates 5a–d were synthesized in reaction of the respective N-protected 3,4,6-tri-O-acetyl-D-glucosamines 4a–d with N-phenyltrifluoroacetimidoyl chloride, according to a procedure proposed by Yu and Tao for 1-hydroxy derivatives of D-glucose and L-rhamnose [49].

[1860-5397-11-97-i1]

Scheme 1: Reagents used for the synthesis of diosgenyl 2-amino-2-deoxy-β-D-glucopyranoside (7).

Glycosylation of diosgenin with twelve different derivatives of D-glucosamine (2a–d, 3a–d, and 5a–d), was examined using “normal” and “reverse” procedures [50] (Table 1). In the “normal” procedure, the promoter (silver triflate or trimethylsilyl triflate) was added to the solution of diosgenin and the respective glycosyl donor. In the “reverse” procedure, the respective glycosyl donor was added to the solution of diosgenin and the promoter. Diosgenin glycosylations were carried out in dichloromethane or/and in a mixture of dichloromethane and diethyl ether. The results summarized in Table 1 indicate that the “reverse” procedure is much more effective than the “normal” procedure. Running of the diosgenin glycosylation also depends on the kind of the solvent used. It is particularly important when bromide 2a is used as a glycosyl donor. Reaction of 2a with diosgenin conducted by the “reverse” procedure in the CH2Cl2/Et2O mixture leads to glycoside 6a in 77% yield. The same procedure applied in CH2Cl2 gives no glycoside. Similarly, reaction of 2b with diosgenin conducted by the “reverse” procedure in the CH2Cl2/Et2O mixture gives glycoside 6b in an excellent 98% yield. In turn, bromides with the phthaloyl protections of the amine group (2c and 2d) react more effectively with diosgenin when the reagents are dissolved solely in CH2Cl2. A comparison of the efficiency of the glycosyl donors indicates that the yields of diosgenin glycosylation with bromides 2a, 2b and 2d are higher than those with analogous chlorides 3a, 3b and 3d. However, reactivity of chloride 3c is stronger than that of analogous bromide 2c. (N-Phenyl)trifluoroacetimidates (5ad) seem to be quite effective glycosyl donors. However their comparison with halogens 2a–d and 3a–d is encumbered since the glycosylation conditions were different for 5a–d. The N-trifluoroacetyl-protected bromide 2a is the less reactive among the bromides 2a–d; the remaining bromides react similarly. The same refers to chlorides 3a–d. In the case of (N-phenyl)trifluoroacetimidates 4ad, the least efficient is 4d with the tetrachlorophthaloyl protection of the amine group; the remaining (N-phenyl)trifluoroacetimidates react similarly. In the experimental section (see Supporting Information File 1), the best procedures for each glycosyl donor are presented. Finally, diosgenyl 2-amino-2-deoxy-β-D-glucopyranose (7) was obtained by complete deprotections of 6a–d, as previously reported [45].

Table 1: Procedures and results concerning diosgenin glycosylation.

Entry Procedure Glycosyl donor Solvent Promoter Product Yield (%)
1 normal 2a (α) CH2Cl2/Et2O AgOTf 6a 30
2 reverse 2a (α) CH2Cl2/Et2O AgOTf 6a 77
3 reverse 2a (α) CH2Cl2 AgOTf
4 reverse 2b (α) CH2Cl2/Et2O AgOTf 6b 98
5 normal 2c (α + β) CH2Cl2/Et2O AgOTf 6c 51
6 reverse 2c (α + β) CH2Cl2/Et2O AgOTf 6c 55
7 reverse 2c (α + β) CH2Cl2 AgOTf 6c 90
8 normal 2d (α + β) CH2Cl2/Et2O AgOTf 6d 73
9 reverse 2d (α + β) CH2Cl2 AgOTf 6d 93
10 reverse 3a (α) CH2Cl2/Et2O AgOTf 6a 69
11 reverse 3b (α) CH2Cl2/Et2O AgOTf 6b 86
12 reverse 3c (β) CH2Cl2 AgOTf 6c 99
13 reverse 3d (β) CH2Cl2 AgOTf 6d 87
14 normal 5a (α + β) CH2Cl2 TMSOTf 6a 85
15 normal 5b (α + β) CH2Cl2 TMSOTf 6b 81
16 normal 5c (β) CH2Cl2 TMSOTf 6c 83
17 normal 5d (β) CH2Cl2 TMSOTf 6d 52

To obtain N-alkyl derivatives of diosgenyl 2-amino-2-deoxy-β-D-glucopyranoside (7), a method called “reductive alkylation of amines” was chosen. This method was previously successfully used to prepare N-alkyl derivatives of 1,3,4,6-tetra-O-acetyl-2-amino-2-deoxy-D-glucose [51,52]. Thus, reductive alkylation of 7 with a 1.2 molar excess of the appropriate aldehyde and a twofold molar excess of NaBH3CN provided mono- (9, 11, 15, 16) and dialkylated products (8, 10, 1214, 17), solely or as mixtures (Scheme 2). The respective mixtures of mono- and dialkylated products were separated. Structures of the N-alkylated derivatives of 7 were confirmed by the NMR (1H and 13C) spectroscopy and mass spectrometry (see Supporting Information File 1). All of them, similarly to the parent diosgenyl glycoside (7), adopt the 4C1 conformation, as demonstrated by the J1,2 ≈ 8 Hz, J2,3J3,4J4,5 ≈ 9–10 Hz coupling constants.

[1860-5397-11-97-i2]

Scheme 2: N-Alkylation of diosgenyl 2-amino-2-deoxy-β-D-glucopyranoside (7).

Evaluation of antimicrobial activity

The N-alkyl derivatives of diosgenyl 2-amino-2-deoxy-β-D-glucopyranosides 815 and 17 were tested for their antibacterial and antifungal in vitro activity against 5 strains of Gram-negative bacteria, 5 strains of Gram-positive bacteria, and 3 strains of human pathogenic fungi. Respective minimum inhibitory concentration (MIC) values determined by a serial dilution microplate method according to the guidelines of the Clinical and Laboratory Standards Institute (CLSI) for 815 and 17 as well as for 7 hydrochloride are summarized in Table 2 and Table 3. The latter was added as the reference since its high in vitro activities and in vivo efficacy were proved [53].

The determined MIC values indicate that compounds explored have rather poor if any inhibitory activity against the Gram-negative bacteria, such as Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris and Pseudomonas aeruginosa. In contrast, almost all the tested N-alkyl saponins were found to inhibit the growth of the Gram-positive bacteria (Table 2). Among the tested compounds the most active was diosgenyl 2-deoxy-2-ethylamino-β-D-glucopyranoside (9) with MIC of 0.5, 1, 2, and 8 μg/mL against Staphylococcus epidermidis, Enterococcus faecalis, Staphylococcus aureus, and Rhodococcus equi, respectively. Also the N-propyl derivative 11 was found to be active against Enterococcus faecalis, Staphylococcus epidermidis, and Staphylococcus aureus with MIC of 1, 1, and 8 μg/mL, respectively. Importantly, both 9 and 11 exhibit a stronger inhibitory effectivity than diosgenyl 2-deoxy-2-amino-β-D-glucopyranoside hydrochloride (7·HCl), which was found to be very active alone and in combination with daptomycin and vancomycin against Gram-positive cocci [53]. The N,N-dialkyl derivatives 12, 13 and 14 act against the Gram-positive bacteria more efficiently or similarly to 7 hydrochloride. In turn, N-pentyl (15) and N,N-dihexyl (17) compounds are completely inactive with respect to all the tested strains of the Gram-positive bacteria. The results presented indicate that both elongation of the alkyl group as well as addition of another alkyl group are rather ineffective from the standpoint of the inhibitory activity towards the Gram-positive bacteria. Such findings are probably due to the lower solubility of the compounds with longer N-alkyl groups or to the micelle formation.

Table 2: Minimum inhibitory concentration (MIC) [μg/mL] for 815 and 17 against the Gram-positive bacteria.

Comp. Bacillus subtilis Enterococcus faecalis Rhodococcus equi Staphylococcus aureus Staphylococcus epidermidis
HCl 8 16 16 16 16
8 8 32 64 32 64
9 64 1 8 2 0.5
10 32 32 16 32 32
11 64 1 32 8 1
12 16 8 16 8 32
13 16 8 16 8 8
14 32 4 8 16 32
15 >1024 >1024 512 1024 1024
17 64 64 512 128 256

Studies on the activity of the synthesized N-alkyl derivatives of diosgenyl 2-deoxy-2-amino-β-D-glucopyranoside (815 and 17) against 3 strains of the human pathogenic fungi (Table 3) indicate that the growth of Candida tropicalis is the most efficiently inhibited by the reference compound 7·HCl with MIC of 0.5 μg/mL. A slightly lower activity was exhibited by N,N-diethyl derivative 10 (MIC 1 μg/mL), N,N-dimethyl derivative 8 (MIC 2 μg/mL), and N,N-dipropyl derivative 12 (MIC 4 μg/mL). Compounds with the longer alkyl chains (1315, 17) show very weak inhibitory activity against Candida tropicalis.

Table 3: Minimum inhibitory concentration (MIC) [μg/mL] for 815 and 17 against human pathogenic fungi.

Comp. Candida tropicalis Candida albicans Aspergillus niger
7·HCl 0.5 2 64
8 2 2 64
9 a 16 8
10 1 2 128
11 a 8 8
12 4 4 64
13 128 8 16
14 32 16 256
15 64 128 128
17 128 64 128

aNot determined.

The results presented for Candida albicans resemble those obtained for Candida tropicalis. The growth of this strain of fungi is inhibited at the lowest concentrations by 7·HCl and equally well by 8, 10, and 12 (MIC 2 μg/mL for each compound mentioned). Evidently, short dialkyl derivatives (8, 10, 12) are more effective against the tested fungi than analogous monoalkyl derivatives (9, 11), longer monoalkyl (15) and dialkyl derivatives (13, 14, 17).

Among the tested strains of fungi, Aspergillus niger turned out to be the least susceptible to the N-alkyl derivatives of diosgenyl 2-deoxy-2-amino-β-D-glucopyranoside (815 and 17). It is worth notice that N-ethyl (9) and N-propyl (11) derivatives reveal much better activity than the reference 7·HCl (MIC 8, 8, and 64 μg/mL, respectively). Also N,N-dibutyl derivative (13) with MIC of 16 μg/mL inhibits the growth of Aspergillus niger at lower concentrations in comparison to that of 7·HCl.

Conclusion

Different pathways leading to diosgenyl 2-amino-2-deoxy-β-D-glucopyranoside and several N-alkyl derivatives are reported. Investigations of their antimicrobial activity indicate that N-ethyl and N-propyl derivatives exhibit stronger activity against Gram-positive bacteria than the parent diosgenyl 2-deoxy-2-amino-β-D-glucopyranoside hydrochloride.

Supporting Information

Supporting Information File 1: Experimental details for the preparation of compounds 2b, 2c, 4a–d, 5a–d, 6a–d, 817, corresponding characterization data and information on the way of determination of minimum inhibitory concentration.
Format: PDF Size: 402.8 KB Download

Acknowledgements

This research was financed by the European Union within the European Regional Development Fund - Grant UDA-POIG.01.01.02-14-102/09 and by the Ministry of Science and Higher Education - grant DS/530-8457-D603-15.

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