New water soluble glycosides of 11-keto-β-boswellic acid: A paradigm

Article abstract of DOI:10.1080/14786419.2017.1342084

Though several glycosides of various triterpenes are known, but surprisingly no boswellic acid glycosides are reported so far. With a view to make water soluble boswellic acids, prepared glycosides of 11-keto boswellic acid for the first time. Naturally occurring boswellic acids which are anti-inflammatory agents are lipophylic in nature and thus, become a limiting factor in terms of their bioavailability. Among boswellic acids, 11-keto-β-boswellic acid is found to exhibit superior biological activity and hence successfully prepared its glucosyl and maltosyl derivatives viz., 11-keto-β-boswellic acid-24-O-β-D-glucopyranoside (9) and 11-keto-β-boswellic acid-24-O-α-D-glucopyranosyl-(1?→?4)-β-D-glucopyranoside (15) which are water soluble. Both these compounds are soluble in water to the extent of 10% (w/w) which is very significant.

Full text of DOI:10.1080/14786419.2017.1342084

Natural Product Research
Formerly Natural Product Letters
ISSN: 1478-6419 (Print) 1478-6427 (Online) Journal homepage: http://www.tandfonline.com/loi/gnpl20
New water soluble glycosides of 11-keto-β-
boswellic acid: A paradigm
B. N. Manjunath, Suvarna Shenvi, A. Raja & G. Chandrasekara Reddy
To cite this article: B. N. Manjunath, Suvarna Shenvi, A. Raja & G. Chandrasekara Reddy (2017):
New water soluble glycosides of 11-keto-β-boswellic acid: A paradigm, Natural Product Research,
DOI: 10.1080/14786419.2017.1342084
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Date: 27 June 2017, At: 02:53

Natural Product research, 2017
https://doi.org/10.1080/14786419.2017.1342084
New water soluble glycosides of 11-keto-β-boswellic acid: A
paradigm
B. N. Manjunath, Suvarna Shenvi, A. Raja and G. Chandrasekara Reddy
chemical sciences division, Vittal Mallya scientific research Foundation, Bangalore, India
ABSTRACT
ARTICLE HISTORY
received 20 March 2017
accepted 18 May 2017
Though several glycosides of various triterpenes are known, but
surprisingly no boswellic acid glycosides are reported so far. With a
view to make water soluble boswellic acids, prepared glycosides of
11-keto boswellic acid for the first time. Naturally occurring boswellic
acids which are anti-inflammatory agents are lipophylic in nature
and thus, become a limiting factor in terms of their bioavailability.
Among boswellic acids, 11-keto-β-boswellic acid is found to exhibit
superior biological activity and hence successfully prepared its
glucosyl and maltosyl derivatives viz., 11-keto-β-boswellic acid-24-
O-β-D-glucopyranoside (9) and 11-keto-β-boswellic acid-24-O-α-D-
glucopyranosyl-(1 → 4)-β-D-glucopyranoside (15) which are water
soluble. Both these compounds are soluble in water to the extent of
10% (w/w) which is very significant.
KEYWORDS
Boswellia seratta; boswellic
acids; glycosylation;
bioavailability
1. Introduction
The gum resin of Boswellia serrata is well known in Ayurveda, the ancient Indian system of
medicine, as dhup or salai guggal. Triterpenoids present in Boswellia serrata Roxb.
(Burseraceae) oleo gum resin have been shown to be effective against rheumatoid arthitis,
chronic colitis, ulcerative colitis, skin allergies and ulcers, peritumoural brain edema, osteo-
arthitis and inflammation (Shenvi et al. 2014). Boswellic acids are pentacyclic triterpenic
CONTACT G. chandrasekara reddy
gcreddy@vmsrf.org
supplemental data for this article can be accessed at https://doi.org/10.1080/14786419.2017.1342084.
© 2017 Informa uK limited, trading as taylor & Francis Group

2
B. N. MANJUNATH ET AL.
acids (Figure 1) obtained from the gum resin exudate of Boswellia serrata (Pardhy &
Bhattacharya 1978).
Studies proved that among the various boswellic acids 11-keto-β-boswellic acid (β-KBA)
and 3-acetyl-11-keto-β-boswellic acid (β-AKBA) have been observed to be more active
(Ammon 2010). Although boswellic acids have been well studied and associated with
immense therapeutic values such as anti-inflammatory, anticancer, antibacterial, (Safayhi
et al.1992; Sailer et al. 1996) but their applications have been limited due to their poor
bioavailability. The lipophilic molecules are reluctantly absorbed in the biological systems.
Administration of high dose of boswellic acids is undesirable as it will burden liver and can
become hepatotoxic. Hence, it is necessary to achieve by some way, an increase in absorp-
tion of boswellic acids into biological systems so that their potentials can be exploited safely
at required dosage. One approach to increase the bioavailability of the lipophilic boswellic
acids has been to administer them along with fibre rich or high fat containing food (Singh
et al. 1996). But this approach is not desirable as it would alter the taste and not easily pal-
atable. A second approach would be to make their glycosides - prodrug model. Prodrugs
are often designed to improve bioavailabilty when a drug is poorly absorbed from gastro-
intestinal tract (Hacker et al. 2009). Many herbal extracts used in medicine contain glycosides
of active agent, which are hydrolysed in the intestines to release the active aglycone. In case
of salicin which is a β-d-glucopyranoside is cleaved by esterases to release salicylic acid
(Sneader 2000). Though several triterpenoid glycosides are known (Uvarova et al. 1973;
Gauthier et al. 2009; James & Dubery 2009; Sheng & Sun 2011; Schwarz et al. 2014), but so
far boswellic acid glycosylation is not reported. Since 11-keto-β-boswellic acid exhibits
superior bioactivity over other naturally occurring boswellic acids, we have prepared suc-
cessfully for the first time its water soluble glucosyl and maltosyl derivatives.
2. Results and discussion
Peracetyl bromo-α-d-glucose (6) was prepared by peracetylation of glucose by the procedure
adopted earlier in our laboratory (Shenvi et al. 2016). Glycosyl bromide thus, prepared was
treated with 3-acetyl-11-keto-β-boswellic acid (4) in presence of silver carbonate using ace-
tonitrile as a solvent to obtain boswellic acid glycoside (Figure 2) with about 50% yield.
Further, yields of glycosides of boswellic acids were improved up to 80–85% by altering the
solvent media to anhydrous dichloromethane and anhydrous toluene. The results are tab-
ulated (Table S1).
Figure 1. Prominent boswellic acids obtained from gum resin of Boswellia serrata.

NATURAL PRODUCT RESEARCH
3
Figure 2. Glucoconjugate of 3- acetyl-11-keto-β-boswellic acid.
Note: Conditions and reagents: (i) hBr/acoh; (ii) ag2co3/sovents (table s1) or K2co3/toluene at 100 °c; (iii) For compound
8, Na2co3/Meoh/chcl3; For compound 9, Na2co3/Meoh.
Figure 3. Peracetylated maltosyl bromide and maltosyl chloride.
Note: Reagents and conditions: (i) hBr/acoh, 6 h; (ii) ch3cocl, Zn(oac)2.2h2o.
Figure 4 Maltoconjugate of 3-acetyl-11-keto-β-boswellic acid.
Note: Reagents and conditions: (i) K2co3/toluene at 100οc (ii) For compound 14, Na2co3/Meoh/chcl3; For compound
15, Na2co3/Meoh.
Glycosylation of boswellic acid with disaccharide would definitely lead to higher hydro-
philic conjugates of boswellic acids. Hence, we tried glycosylation of boswellic acid using
maltose. Maltose was peracetylated [Ac2O, Et3 N/DMAP (catalytic amount), DMF, rt, 12 h]
followed by anomeric bromination using HBr/AcOH at ice cold temperature to get maltosyl
bromide (11) or chlorination using acetyl chloride and catylatic amount of zinc acetate to
get maltosyl chloride (12) (Figure 3). The maltosyl bromide/chloride thus, obtained was used
for glycosylation of 3-acetyl-11-keto-β-boswellic acid to obtain the corresponding maltoside
13 in 70% yield (Figure 4). Maltoside (13) was then deacetylated using sodium carbonate in
methanol/chloroform and in methanol alone at room temperature to obtain partially
deacetylated (14) and completely deacetylated (15) products, respectively. The decetylated
glycoside and maltoside of 11-keto-β-boswellic acid i.e. compounds 9 and 15 are easily
soluble in water to the extent of 10% (w/w) which is a very significant observation. We plan
to study their bio-efficacy and report the results elsewhere.

4
B. N. MANJUNATH ET AL.
3. Experimental
3.1. General
Melting points were recorded on an Acro melting point apparatus using a calibrated ther-
mometer. Thin layer chromatography (TLC) and column chromatography (CC) were per-
formed with TLC silica gel 60 F254, Merck and silica gel (200–400 mesh), respectively. Thin
layer chromatograms were developed using hexane: EtOAc (8:2, v/v) and compounds were
detected by H2SO4 spray (10%) with subsequent heating at 100–120 °C for 4–5 min. IR
spectra were recorded on Thermo-Nicolet instrument in KBr discs. NMR spectra were
recorded with TMS as internal standard on a Bruker and Jeol 400 MHz NMR spectrometers.
The chemical shifts are expressed in δ (ppm) units and the coupling constants (J) are given
in Hz.
4. Plant material
Boswellia Serratta gum resin was obtained from Natural Remedies; Plot No. 5B, Veerasandra
Industrial Area, 19th K.M.Stone, Hosur Road; Electronic city (Post); Bangalore-560100;
India
4.1. Isolation of boswellic acids (1–4)
The Boswellia serrata gum resin lumps (1 kg) were crushed and treated with methanol
(2 L × 2) in a percolator. Combined methanolic extracts were evaporated under reduced
pressure at 45 °C to obtain thick brown residue (450 g). Details of isolation of all four boswellic
acids are provided in the supplement (Experiment S1).
4.2. General procedure for preparation of glucose and maltose peracetate
To a solution of glucose (5, 5 g, 27.7 mmol), TEA (16.85 g, 166.6 mmol), DMF (150 mL) and
catalytic amount of DMAP was added AC2O (16.99 g, 166.6 mmol) drop wise maintaining
the temperature at 0 °C for 5–6 h. Completion of reaction was monitored by TLC, then added
aqueous solution of sodium hydrogen sulphate drop wise to the reaction mixture under
stirring till it attained pH~8.Then reaction mixture was extracted with EtOAc (2 × 50 mL) and
combined organic layer was washed with water (2 × 50 mL), dried over Na2SO4 and evapo-
rated to dryness under vacuum. Likewise maltosyl peracetate was prepared using twice the
quantity of reagents.
4.3. General procedure for preparation of glucosyl bromide (6) and maltosyl
bromide (11)
To glucose/maltose peracetate (3 g) was added 15 mL of 33% HBr in AcOH at 0 °C, slowly
allowed the reaction to come to room temperature under stirring and maintained for 45 min.
DCM (80 mL) was added to the reaction mixture and the solution was dropped into ice-cold
water. Separated the organic layer and then washed with solution of NaHCO3, water and
dried over Na2SO4. Organic layer was evaporated under vacuum to obtain required com-
pounds, which were stored in refrigerator.

NATURAL PRODUCT RESEARCH
5
4.4. General preparation of maltosyl chloride (12)
To a solution of maltose (10, 3 g, 8.765 mmol) in DMF (10 mL) was added TEA (8.42 g,
83.36 mmol) and acetyl chloride (6.49 g, 82.47 mmol) by maintaining the temperature at
0 °C. Stirred the reaction mixture at that temperature for 6–7 h and then added Zn (OAc)2.2H2O
(0.1 mmol) for completion of the reaction. To the reaction mass added EtOAc (2 × 50 mL)
and collected ethyl acetate layer, then washed the organic layer with 5% NaHCO3 (2 × 25 mL)
solution, then with water and dried over Na2SO4 .The organic layer on evaporation under
vacuum gave the required product.
4.5. Synthesis of 11-keto- β-boswellic acid-24-O-β-D-tetraacetylglucopyranoside
(7)
To a solution of 3-acetyl-11-keto-β-boswellic acid (4, 900 mg, 1.75 mmol) in toluene (30 mL),
added tetraacetyl-α-d-glucopyranosyl bromide (6, 1.45 g, 3.54 mmol) in presence of K2CO3
(122 mg, 0.885 mmol) along with 4 Å molecular sieves and heated to 100 °C for 4 h.
Completion of the reaction was monitored by TLC. Concentrated the toluene layer, then
added the EtOAc (30 ml), washed the EtOAc layer with water twice and concentrated ethyl
acetate layer to dryness to get crude product (2.03 g). The crude product was subjected to
silica column chromatography and eluted with hexane; EtOAc mixture (increasing polarity)
and isolated the pure product 7 (86% yield).
White crystalline solid, C46H66O14, mp: 170–172 °C, +13.39° (c = 1, MeOH).
IR (KBr, νmax): 3484, 2979, 2928, 1755, 1660, 1618, 1457, 1436, 1373, 1224, 1076, 1039 cm−1.
1H NMR (CDCl3, 400 Hz); δ 0.80 (3H, d, J = 6.4 Hz, –HC– CH3), 0.83 (3H, s, CH3), 0.95 (3H, bs,
CH3), 1.06 (3H, s, CH3), 1.12 (3H, s, CH3), 1.17 (3H, s, CH3), 1.31 (3H, s, CH3), 1.20–1.60 (17H),
2.00 (3H, s, OAc), 2.01 (3H, s, OAc), 2.02 (3H, s, OAc), 2.03 (3H, s, OAc), 2.08 (3H, s. OAc),
2.12–2.18 (2H, m), 2.39 (1H, s), 2.53 (1H, m), 3.80–3.84 (1H, m), 4.04–4.08 (1H, m), 4.20–4.25
(1H, m), 5.09–5.13 (1H, m), 5.23 (1H, d, J = 3.2 Hz), 5.26 (1H, s), 5.28 (1H, bs), 5.54 (1H, s,
C = CH–CO), 5.76 (1H, d, J = 8.0 Hz, α-H).
13C NMR (CDCl3, 100 MHz): δ 13.10, 17.41, 18.11, 18.76, 20.54 (4 × C), 21.12, 21.28, 22.88,
23.43, 27.18, 27.52, 28.84, 29.12, 29.68, 30.91, 32.81, 33.97, 34.53, 37.39, 39.33, 40.91, 43.75,
45.05, 46.82, 50.65, 59.05, 60.31, 61.57, 68.12, 70.08, 72.52, 72.72 (2 × C), 91.33, 130.49 (vinylic),
164.90 (vinylic), 169.22 (COOR), 169.42 (COOR), 170.01 (COOR), 170.06 (COOR), 170.45 (COOR),
174.05 (COOR), 199.12 (C=O).
HRMS-ESI: m/z [M + Na]+ for C46H66O14Na; calculated 865.4350; observed 865.4352.
4.6. Synthesis of 3-acetyl-11-keto-β-boswellic acid-24-O-β-D-glucopyranoside (8)
Details are provided in supplement (Experiment S2).
4.7. Synthesis of 11-keto-β-boswellic acid-24-O-β-D-glucopyranoside (9)
Added acetyl glycoside of 3-acetyl-11-keto-β-boswellic acid (7, 200 mg, 0.31 mmol) and
Na2CO3 (73.8 mg, 0.70 mmol) to methanol (5 mL), maintained at ambient temperature for
2 days and completion of the reaction was monitored byTLC (CHCl3: MeOH, 10%), evaporated
methanol and added water (2 mL) to the reaction mass and extracted with EtOAc (2 × 20 mL).

6
B. N. MANJUNATH ET AL.
Combined ethyl acetate layer was dried over Na2SO4 and concentrated under vacuum to
get the product 9 (95% yield).
White solid, C36H56O9, mp: 160–162 °C, +13.28° (c = 1, MeOH).
IR (KBr, νmax,): 3420, 2974, 2924, 2268, 2861, 1740, 1729, 1654, 1618, 1457, 1436, 1384,
1261, 1205, 1075, 1031 cm−1.
1H NMR (DMSO-d6, 400 Hz); δ 0.75 (3H, d, J = 5.2 Hz, –HC–CH3), 0.79 (3H, s, CH3), 0.93 (3H, bs,
CH3), 0.98 (3H, bs, CH3), 1.09 (3H, s, CH3), 1.18 (3H, s, CH3), 1.29 (3H,s, CH3), 1.36–2.26 (16H, m),
3.14–3.22 (5H, m), 3.45 (1H, m), 3.61 (1H, m), 3.83 (1H, m), 4.38 (1H, m), 4.55 (1H, bs), 4.96 (1H,
bs), 5.03 (1H, s), 5.17 (1H, d, J = 6.0 Hz), 5.31 (1H, d, J = 8.0 Hz, α-H), 5.42 (1H, s, C=CH–CO).
13C-NMR (DMSO-d6, 100 MHz): δ 13.43, 17.09, 17.95, 18.39, 20.08, 20.92, 24.38, 25.94, 26.61,
26.91, 28.42, 30.38, 32.41, 33.53, 37.05, 38.44, 38.67, 43.39, 43.30, 44,57, 47.25, 48.09, 48.58,
58.15, 59.80, 60.71, 68.32, 69.59, 72.63, 76.74, 77.71, 93.94,129.71 (vinylic), 164.20 (vinylic),
175.12 (COOR), 198.38 (C=O).
HRMS-ESI: m/z [M + Na]+ for C36H56O9Na; calculated 655.3822; observed 655.3823.
4.8. Synthesis of 3-acetyl-11-keto-β-boswellic acid-24-O-α-D-tetraacetyl
glucopyranosyl-(1 → 4)-β-D-triacetylglucopyranoside (13)
To a solution of 3-acetyl-11-keto-β-boswellic acid (4, 0.5 g, 0.976 mmol) in toluene (30 mL),
added maltosyl bromide (1.26 g, 1.76 mmol) in presence of K2CO3 (0.20 mg, 1.44 mmol) along
with 4 Å molecular sieves heated at 100 °C for 4 h. Completion of the reaction was monitored
by TLC. The toluene layer was concentrated, then EtOAc (30 mL) was added and the EtOAc
layer was washed with water twice, dried over anhydrous Na2SO4 and concentrated to dry-
ness to get crude product (2.03 g). Purified the crude product through silica column using
hexane; EtOAc mixture with increasing polarity and isolated the pure product (13) in 70%
yield. When reaction was carried out with maltosyl chloride 13 was obtained in 89% yield.
White crystalline solid, C58H82O22, mp: 218–220 °C, +20.12° (c = 1, MeOH).
IR (KBr, νmax): 3484, 2980, 2928, 1756, 1660, 1618, 1457, 1436, 1373, 1224, 1076, 1039 cm−1.
1H NMR (CDCl3, 400 Hz); δ 0.80 (3H, d, J = 6.4 Hz, –HC–CH3), 0.82 (3H, s, CH3), 0.95 (3H, bs,
CH3), 1.05 (3H, s, CH3), 1.12 (3H, s, CH3), 1.16 (3H, s, CH3), 1.20–1.31 (12H, m), 1.33 (3H, s, CH3),
1.99 (3H, s, OAc), 2.00 (3H, s, OAc), 2.02 (3H, s, OAc), 2.04 (3H, s, OAc), 2.05 (3H, s, OAc), 2.08
(6H, s, 2xOAc), 2.09 (3H, s, OAc), 2.11- 2.54 (7H, m), 3.81–3.83 (2H, m), 3.92–9.94 (2H, m), 4.03
(1H, t, J = 8.8 Hz), 4.06 (1H, m), 4.19–4.25 (2H, m), 4.42 (1H, dd, J = 2.4 Hz and 12.0 Hz), 4.85
(1H, dd, J = 4.0 Hz and 10.4 Hz), 5.02–5.07 (2H, m), 5.28–5.37 (3H, m), 5.41 (1H, d, J = 4.0 Hz,
β-H), 5.53 (1H, s, C = CH–CO), 5.78 (1H, d, J = 8.4 Hz, α-H).
13C NMR (CDCl3, 100 MHz): δ 13.20, 14.11, 17.42, 18.18, 18.76, 20.49, 20.58, 20.67, 20.86,
21.13, 21.29, 22.69, 23.09, 23.46, 27.21, 27.55, 28.85, 29.36, 29.70, 30.93, 31.93, 32.82, 33.99,
34.52, 37.40, 39.30, 40.93, 43.76, 45.05, 46.83, 50.58, 59.06, 60.29, 61.52, 62.36, 68.03, 68.61,
69.36, 70.06, 70.90, 72.60, 72.92 (2 × C), 75.29, 90.99, 95.73, 130.53 (Vinylic), 164.83 (vinylic),
169.45 (COOR), 169.84 (COOR), 170.05 (COOR), 170.20 (2 × COOR), 170.50 (COOR), 170.58
(COOR), 173.81 (2 × COOR), 199.02 (C=O).
4.9. Synthesis of 3-acetyl-11-keto-β-boswellic acid-24-O-α-D-glucopyranosyl-
(1 → 4)-β-D-glucopyranoside (14)
The details are provided in supplement (Experiment S3).

NATURAL PRODUCT RESEARCH
7
4.10. Synthesis of 11-keto-β-boswellic acid-24-O-α-D-glucopyranosy-(1 → 4)-β-D-
glucopyranoside (15)
Added acetyl maltoside of 3-acetyl-11-keto-β-boswellic acid (13, 200 mg, 0.174 mmol) and
Na2CO3 (73.8 mg, 0.70 mmol) to methanol (5 mL) and maintained at ambient temperature
for 3 days. Completion of the reaction was monitored byTLC (CHCl3: MeOH, 10%), evaporated
methanol and added water (2 mL) to the reaction mass and extracted with EtOAc (2 × 20 mL).
Combined ethyl acetate layer was dried over Na2SO4 and concentrated under vacuum to
get the product 15 (yield 95%).
White solid, C42H66O14, mp: 206–208 °C, +23.18° (c = 1, MeOH).
IR (KBr, νmax,): 3401, 2924, 2855, 1735, 1657, 1618 1457, 1436, 1384, 1262, 1221, 1050,
1031 cm−1.
1H NMR (DMSO-d6, 400 Hz); δ 0.77 (3H, d, J = 6.4 Hz, –HC–CH3), 0.85 (3H, s,CH3), 0.92 (3H,
brs, CH3), 0.98 (3H, s, CH3), 1.08 (3H, s, CH3), 1.18 (3H, s, CH3), 1.24 (3H, s,CH3), 1.40–2.25 (21H),
3.40–3.43 (3H,m), 3.48–3.50 (2H,m), 3.83 (1H, brs), 4.37 (1H, t, J = 5.6 Hz), 4.56 (2H, m), 4.91(2H,
m), 5.04 (1H, brs), 5.31(1H, d, J = 3.6 Hz, β-H), 5.36 (1H, d, J = 7.6 Hz, α-H), 5.43 (1H, brs), 5.51
(1H, brs), 5.57 (1H, brs).
13C NMR (DMSO-d6, 100 MHz): δ 13.44, 17.09, 17.95, 18.38, 20.07, 20.92, 24.36, 25.93, 26.61,
26.90, 28.42, 28.98, 30.37, 32.39, 33.53, 37.04, 38.43, 38.66, 40.38, 43.31, 44.56, 47.26, 48.07,
48.38, 58.15, 59.79, 60.28, 60.77, 68.31, 69.88, 72.18, 72.39, 73.44, 75.94, 76.33, 79.10, 93.69,
100.80, 129.69 (vinylic), 164.26 (vinylic), 175.09 (COOR), 198.40 (C=O).
HRMS-ESI: m/z [M + Na]+ for C42H66O14Na; calculated 817.4350; observed 817.4351.
5. Conclusion
Though 11-keto-β-boswellic acid is found to exhibit superior biological activity among
boswellic acids its usage is constrained because of its liphophilicity. In order to overcome
this, successfully prepared for the first time its glucosyl and maltosyl derivatives viz., 11-keto-
β-boswellic acid-24-O-β-D-glucopyranoside (9) and 11-keto-β-boswellic acid-24-O-α-D-glu-
copyranosyl-(1 → 4)-β-D-glucopyranoside (15) which are water soluble. Both these
compounds are soluble in water to the extent of 10% (w/w) which is very significant.
Supplementary material
Copies of the 1H NMR, 13C NMR, HRMS of compounds 7, 8, 9, 13, 14 and 15 are separately attached.
Acknowledgements
The authors express sincere thanks to Dr. Anil Kush, CEO, Vittal Mallya Scientific Research Foundation,
for his interest and encouragement, to DST, Govt. of India for the financial support (grant number:
SB/FT/CS-066/2012).
Disclosure statement
No potential conflict of interest was reported by the authors.

8
B. N. MANJUNATH ET AL.
Funding
This work was supported by the DST, Govt. of India [grant number SB/FT/CS-066/2012].
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