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Bioorganic & Medicinal Chemistry Letters 22 (2012) 3168–3171
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Bioorganic & Medicinal Chemistry Letters
Glucose–aspirin: Synthesis and in vitro anti-cancer activity studies
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James N. Jacob , Makio J. Tazawa
Organomed Corporation, 11 Grandview St., Unit 8, Coventry, RI 02816, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Glucose–aspirin (GA) was synthesized by conjugating aspirin (ASA) to glucose. The water solubility and
biological activity of GA was studied in comparison to aspirin. The human serum protease activity on the
ester showed a slower hydrolysis rate, compared to ASA. Glucose–aspirin was sevenfold more water sol-
uble than aspirin and it was about 8- to 9-fold more active in inhibiting cell growth than aspirin in their
anti-cancer cell culture activity on breast (SKBR3), pancreatic (PANC-1), and prostate (PC3) cell lines,
whereas the activity was similar on a benign non-cancerous cell line (WI 38). In conclusion, GA is a highly
water soluble derivative of aspirin. Although the serum hydrolysis for GA was slower, there was signif-
icant anti-cancer activity at the doses studied under the experimental conditions.
Received 6 January 2012
Revised 8 March 2012
Accepted 13 March 2012
Available online 23 March 2012
Keywords:
Aspirin
Glucose–aspirin
Water soluble aspirin
Serum hydrolysis
Anti-cancer activity
Ó 2012 Elsevier Ltd. All rights reserved.
Aspirin is a widely used and relatively safe non-steroidal anti-
inflammatory drug (NSAID) that has been used for over 100 years.
The main uses of aspirin can be summarized as an analgesic, anti-
pyretic, anti-rheumatic, and anti-inflammatory agent. It may be
used to prevent stroke, heart attack, and cancer.1 The use of aspirin
is increasing as new benefits are discovered on a regular basis.
Aspirin has positive effects on Alzheimer’s disease and Parkinson’s
disease.2,3 It is a non-selective cyclooxygenase inhibitor, and cyclo-
oxygenase-derived prostaglandins are involved in inflammatory
activity. Prostaglandins also are involved in gastrointestinal pro-
tection and vascular homeostasis. Aspirin acetylates the Ser530 hy-
droxyl group in the COX binding site of COX-1 and COX-2, and is a
much stronger inhibitor of COX-1 than of COX-2.4,5 Aspirin has
been known for its cancer prevention ability. Clinical based study
showed that aspirin use is associated with significantly decreased
risk of pancreatic cancer and colorectal cancer.6,7
molecule at a specified carbon of glucose. When aspirin is conju-
gated to C-1 of glucose to provide 1-O-(20-acetyloxy) benzoyl-
-2-glucopyranose, the compound is prone to rapid hydrolysis of
the acetyl group.9 A glucose conjugate of aspirin at C-3 of glucose
forms 3-O-(20-acetoxy) benzoyl-
-2-glucopyranose, also called
a-
D
a-D
glucose–aspirin (GA) was first reported in a German patent,10 how-
ever very little studies have been done using this compound even
though it has great potential as injectable form of aspirin. We re-
port the synthesis of this compound using mild conditions includ-
ing its spectral and analytical data as well as serum hydrolysis
studies. As a first step towards developing it as a cancer prevention
agent we evaluated the in vitro anticancer activity of this highly
water soluble aspirin-drug and compared it with aspirin. Further
studies involving in vivo are needed to learn its effect in animals.
Synthesis of 1,2:5,6-di-O-isopropylidende-3-(20-acetyloxybenzoyl)-
D-glucose or glucose–aspirin: Synthesis of GA was reported in a Ger-
Long term use of aspirin is a concern because of its side effects
particularly in low risk populations.5 Aspirin is taken orally
because it is not very water soluble. Some of the undesirable side
effects of aspirin result from undissolved particles in the gastroin-
testinal mucosa, causing ulcers and bleeding. Therefore, a water
soluble form of aspirin could be used to develop an injectable for-
mulation, while avoiding the gastrointestinal track. Lysine aspirin
(lysine acetylsalicylate) is used as an injectable form of aspirin
with some analgesic effects.8 Although aspirin may be made water
soluble through salt formation, the solutions are unstable and have
high Na+ or Ca++ ion concentrations. Solubility can be increased
considerably, however, by conjugating aspirin to the glucose
man patent by acylating protected glucose using acetyl salicyloyl
chloride10. We used dicyclohexyl carbodiimide (DCC) as a coupling
agent for the ester synthesis11 as described below. This method
uses mild conditions and avoids the use of toxic solvents such as
pyridine, dioxane etc. and strong reagents such as thionyl chloride
as was previously used.10 Acetylsalicylic acid (1, 12 g, 0.07 mol)
was dissolved in 300 mL of ethyl acetate in a 1 l round bottom flask
fitted with an anhydrous calcium chloride guard tube. Dicyclohex-
ylcarbodiimide (8.24 g, 0.04 mol) was added, resulting in the
formation of a white precipitate. Diacetone-D-glucose (2, 10 g,
0.04 mol) was then added, along with dimethylaminopyridine
(4.88 g, 0.04 mol). The mixture was stirred for 3 h at room temper-
ature. The solid byproduct, dicyclohexyl urea, was removed by
filtration. The filtrate was washed with 10% potassium carbonate
(2 ꢀ 300 mL), 10% HCl (2 ꢀ 300 mL) and with brine (300 mL). The
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0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.