2
X. Zhao et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
Fig. 1. Structures of SGLT2 inhibitors.
Fig. 2. Structures of C-glucoside SGLT2 inhibitors with the dioxa-bicycle or spiroketal moiety.
in Japan in 2014,5 and ertugliflozin is currently under phase-III
clinical trial.15 All these motivated us to synthesize the novel
SGLT2 inhibitors by modifying the glucoside moiety, and a number
of 6-hydroxyl C-aryl glucosides (11a3–17a) and their intramolecu-
lar dehydrate derivatives (11b–17b) were then prepared (Fig. 3).
The preparation of C-glucoside derivatives 11a, 11b, 12a and
12b is outlined in Scheme 1. Lithiation of benzothiophene (20)
and 1-bromo-4-ethoxybenzene (25) followed by the addition of a
lithiated aromatic to MOM-protected 3-bromo-4-hydroxyben-
zaldehyde (19) yielded alcohols, which were then reduced by
treatment with Et3SiH and BF3ÁOEt2 to give aglycones 21 and 26.
Lithium halogen exchange of 21 and 26 followed by the addition
of a lithiated aromatic to 2,3,4,6-tetra-O-benzylgluconolactone
(22), respectively, yielded lactols, which were reduced by treat-
ment with Et3SiH and BF3ÁOEt2 to give compounds 23 and 27. Suc-
cessive removal of the methoxymethyl group and benzyl groups
with HCl and BCl3 generated compounds 11a and 12a. The dihy-
drofuran ring of compounds 11b and 12b were formed by the
intramolecular Mitsunobu reaction upon treatment of 11a and
12a with PPh3 and diethyl azodicarboxylate (DEAD).
The configuration at C-1 of glucose in compounds 11a and 12a
was determined as b-linkage by the coupling constant (J = 9.3 Hz, J
= 9.4 Hz, respectively) between anomeric hydrogen and adjacent
hydrogen in the 1H NMR spectra.12 The configuration at C-2 of glu-
cose in dihydrofuran derivatives, which were formed by Mit-
sunobu reaction, was determined by single-crystal X-ray
diffraction analysis, and the crystal structure of representative
compound 11b was shown in Fig. 4.
In order to construct the derivatives with structural diversity
more efficiently and conveniently, the synthetic route was then
modified as follows: the key intermediate 36 was synthesized as
shown in Scheme 2. Firstly, 2-chloro-4-hydroxybenzaldehyde
(29) was treated with pyridinium tribromide to give compound
30, and the phenolic hydroxyl group was then protected with ben-
zyl bromide to give compound 31. Subsequently, the aldehyde
group of compound 31 was reduced with NaBH4 and was protected
with a tert-butyldiphenylsilyl (TBDPS) group to give compound 33.
Lithium halogen exchange of 33 followed by the addition of a lithi-
ated aromatic to 2,3,4,6-tetra-O-benzylgluconolactone (22) yielded
lactols, which was reduced by treatment with Et3SiH and BF3ÁOEt2
to give compounds 34. The removal of the TBDPS group by tetra-
butylammonium fluoride (TBAF) followed by the oxidation of ben-
zylalcohol to benzaldehyde with MnO2 afforded the key
intermediate 36.
The synthesis of C-glucoside derivative 13a17–17a and 13b–17b
was shown in Scheme 3. The lithiation of thianaphthene (20), 1-
bromo-4-ethoxybenzene (25), 1-bromo-4-methoxybenzene (37),
1-bromo-4-ethylbenzene (38) and 1-bromo-4-methylbenzene
(39) followed by the addition of a lithiated aromatic to 36 yielded
lactols, which were reduced by treatment with Et3SiH and BF3ÁOEt2
to give compounds 13–17. The removal of benzyl groups with BCl3
generated compounds 13a–17a. The dihydrofuran rings of com-
pounds 13b–17b were formed by the intramolecular Mitsunobu
reaction upon treatment of 13a–17a with PPh3 and DEAD.
The cell-based SGLT2 inhibition assay was then performed to
evaluate the inhibitory effects of all synthesized compounds on
hSGLT2 activities, and used dapagliflozin as positive reference. As
shown in Table 1, compounds 12a, 14a–17a exhibited excellent
SGLT2 inhibitory activity, with IC50 values ranging from 0.63 nM
to 12.17 nM. In addition, compounds 16a and 17a were the most
potent compounds with IC50 values of 0.63 and 0.81 nM, respec-
tively, and comparable with the reference drug dapagliflozin
(IC50 = 1.05 nM). Compound 12a displayed moderate SGLT2 inhibi-
tory potency (IC50 = 12.17 nM), and the introduction of chlorine
atom at C-4 of arene B led to potent compound 14a, with IC50 value
of 1.03 nM, which was comparable to that of dapagliflozin. This
suggests the addition of chlorine atom at the 4-position of arene
B is critical for the improved SGLT2 inhibitory activity. When the
ethoxyl group of compound 14a was changed to methoxyl group,
the resulting compound 15a displayed a comparable SGLT2 inhibi-
tory activity to that of 14a. Surprisingly, introduction of the ethyl
or methyl group at C-4 of arene C result in the most potent com-
pounds 16a and 17a, respectively. Unexpectedly, all the dehydrate
derivatives lose the SGLT2 inhibitory activity, with inhibition per-
centage no more than 66.5% at the concentration of 0.5
lM, which
might because of the configuration inversion at C-2 of glucose.
Zhao, Xiaoyu
