DOI: 10.1002/cmdc.201000282
Dansyl C-Glucoside as a Novel Agent Against Endotoxic Shock
Barbara La Ferla,[a] Valerio Spinosa,[a] Giuseppe D’Orazio,[a] Marco Palazzo,[b] Andrea Balsari,[c]
Anastasia A. Foppoli,[d] Cristiano Rumio,[b] and Francesco Nicotra*[a]
Dedicated to Prof. Saverio Florio on the occasion of his 70th birthday.
The biological role of carbohydrates in a variety of recognition
processes of pharmacological relevance has stimulated interest
in glycomimetics as potential drugs.[1] Relenza, Tamiflu, and
Glyset are some successful examples of approved drugs be-
longing to this class of compounds. In the field of C-glycosides,
which are glycomimetics where the anomeric oxygen is re-
placed with a carbon atom to give improved chemical and
metabolic stability at the anomeric centre, no relevant bioac-
tivity has been reported until now. We have found that the
dansyl C-glucoside 5 is a novel and potent agent against endo-
toxic shock, fully protecting mice from sepsis.
glyco-drugs arises from the need for protection/deprotection
steps and the control of stereochemistry. An orthogonal func-
tional group suitable for chemoselective derivatisation of a
polyhydroxylated compound like a sugar is the primary amino
group.
We identified 2-(a-d-glucopyranosyl)ethanamine 3 (Scheme
1) as a key C-glycosyl intermediate, and generated this com-
pound by stereoselective C-allylation[7] of methyl a-d-glucopyr-
anoside, followed by ozonolysis and reductive amination of
the obtained aldehyde (present as hemiacetal 1).[8]
Some of us found that, in a murine model of endotoxic
shock induced by LPS, oral administration of glucose
(2.5 gkgꢀ1) protects all mice tested from sepsis.[2] This protec-
tion is mediated by the activation of the sodium-dependent
glucose transporter-1 (SGLT-1). A major drawback of this treat-
ment is that a high concentration of glucose, which impacts
metabolism, must be used. Therefore, our goal was to identify
glucomimetics that, at pharmacological concentrations, were
able to achieve protection against LPS-induced damage while
avoiding the side effects associated with the administration of
a high concentration of glucose.
Very little is known about the structure of SGLT-1 and its
mechanism of action,[3–6] although some aryl b-glucosides have
been patented as SGLT-1 inhibitors. Therefore, the only infor-
mation available for the rational design of SGLT-1 ligands is
based on the structure of d-glucose (or d-galactose, which is
also transported) and an aromatic aglycon. In order to gener-
ate compounds that would mimic glucose but could not be
metabolised, a C-glucoside is the key intermediate of choice.
We also looked for a procedure that allows the stereoselective
generation of this C-glucosidic key intermediate, and then its
derivatisation to generate a library, avoiding protection and
deprotection steps. A strong limitation in the development of
Scheme 1. Reagents and conditions: a) BSTFA, CH3CN, 808C, 1h; then,
TMSOTf, Me3Si(allyl), RT, 12h; then O3, MeOH/H2O (1:1), ꢀ788C, 75 min; then
Me2S, 5 min;[8] b) AcONH4, NaCNBH3, MeOH, RT, 1h, (3) 55%, (4) 57% (two
steps); c) MeOH, THF, K2CO3, dansyl-Cl, RT, 2h, (5) 50%, (6) 58%; d) MeOH,
THF, K2CO3, naphthylsulphonyl-Cl, RT, 2h, 52%; e) MeOH, THF, K2CO3, naph-
thylcarboxy-Cl, RT, 2h, 46%.
The amino group of compound 3 was chemoselectively
functionalised in different ways in the presence of the free
sugar hydroxy groups. The choice of pharmacophores to be
linked to the amine in 3 was essentially based on the limited
data reported in the literature on molecules able to interact
with SGLT-1, such as phloridzin, a natural b-glucoside with an
aromatic aglycon.[9] We started to derivatise compound 3 by
reaction with fluorescent dansyl chloride, and luckily dansyl
C-glucoside 5 displayed a very interesting anti-inflammatory
activity in vitro (see below, Figures 1 and 2).
[a] Dr. B. La Ferla, V. Spinosa, G. D’Orazio, Prof. F. Nicotra
Department of Biotechnology and Bioscience & CINMPIS, Universitꢀ degli
studi di Milano Bicocca, Piazza della Scienza 2, 20126 Milano (Italy)
Fax: (+39)026-448-3565
[b] Dr. M. Palazzo, Prof. C. Rumio
Department of Human Morphology, Universitꢀ degli studi di Milano, Via
Mangiagalli 31, 20133 Milano (Italy)
[c] Prof. A. Balsari
Institute of Pathology, Universitꢀ degli studi di Milano, Via Mangiagalli 31,
20133 Milano (Italy)
[d] Dr. A. A. Foppoli
Encouraged by this result, and to identify some structural re-
quirements for biological activity, we made a number of signifi-
cant changes in the structure of compound 5. We generated
naphthyl sulphonamide 7, which lacks a dimethylamino group,
Department of Pharmaceutical Sciences “P. Pratesi”, Universitꢀ degli studi di
Milano, Via Mangiagalli 25, 20133 Milano (Italy)
Supporting information for this article is available on the WWW under
ChemMedChem 2010, 5, 1677 – 1680
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1677