Fluorine-Directed Glycosylation Enables the Stereocontrolled Synthesis of Selective SGLT2 Inhibitors for Type II Diabetes

Article abstract of DOI:10.1002/chem.201705373

Inhibition of the sodium-glucose co-transporters (SGLT1 and SGLT2) is a validated strategy to address the increasing prevalence of type II diabetes mellitus. However, achieving selective inhibition of human SGLT1 or SGLT2 remains challenging. Orally available small molecule drugs based on the d-glucose core of the natural product Gliflozin have proven to be clinically effective in this regard, effectively impeding glucose reabsorption. Herein, we disclose the influence of molecular editing with fluorine at the C2 position of the pyranose ring of Phlorizin analogues Remogliflozin Etabonate and Dapagliflozin (Farxiga) to concurrently direct β-selective glycosylation, as is required for biological efficacy, and enhance aspects of the physicochemical profile. Given the abundance of glycosylated pharmaceuticals in diabetes therapy that contain a β-configured d-glucose nucleus, it is envisaged that this strategy may prove to be expansive.

Full text of DOI:10.1002/chem.201705373

DOI: 10.1002/chem.201705373
Communication
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Biological Chemistry |Hot Paper|
Fluorine-Directed Glycosylation Enables the Stereocontrolled
Synthesis of Selective SGLT2 Inhibitors for Type II Diabetes
Anna Sadurní,[a] Gerald Kehr,[a] Marie Ahlqvist,[b] Johan Wernevik,[c] Helena Peilot Sjçgren,[c]
Cecilia Kankkonen,[c] Laurent Knerr,*[d] and Ryan Gilmour*[a, e]
mately 90% of all cases.[2] Characterised by a growing resist-
Abstract: Inhibition of the sodium-glucose co-transporters
(SGLT1 and SGLT2) is a validated strategy to address the
ance of the body to insulin, patients with Type II diabetes
cannot regulate cellular glucose metabolism leading to an in-
increasing prevalence of type II diabetes mellitus. However,
crease in blood-glucose concentration and subsequent pathol-
achieving selective inhibition of human SGLT1 or SGLT2 re-
ogies.[1] Contemporary treatments focus on disease manage-
mains challenging. Orally available small molecule drugs
ment via insulin injections and oral hypoglycemic drugs,[1,3]
based on the d-glucose core of the natural product Gliflo-
zin have proven to be clinically effective in this regard, ef-
thereby addressing the symptoms and not the disorder.
Contemporary strategies for the design of small molecule
fectively impeding glucose reabsorption. Herein, we dis-
Type II diabetes drugs have focused on the selective inhibition
close the influence of molecular editing with fluorine at
of the Type II sodium-glucose co-transporter (SGLT2), located
the C2 position of the pyranose ring of Phlorizin analogues
Remogliflozin Etabonate and Dapagliflozin (Farxigaꢀ) to
in the proximal tubule.[4,5] This transporter consists of a large
transmembrane protein, and is responsible for reabsorbing
concurrently direct b-selective glycosylation, as is required
90% of the glucose that would otherwise be eliminated in
for biological efficacy, and enhance aspects of the physi-
urine.[6,7] Logically, the selective inhibition of SGLT2 decreases
cochemical profile. Given the abundance of glycosylated
glucose reabsorption, allowing a greater proportion to be elim-
pharmaceuticals in diabetes therapy that contain a b-con-
inated from the body: This reduces the blood-glucose concen-
figured d-glucose nucleus, it is envisaged that this strat-
egy may prove to be expansive.
tration.[8] Investigations by a number of laboratories have fo-
cused on structurally modifying the natural product Phlorizin,[9]
a derivative of d-glucose first isolated in 1835 from the bark of
apple trees (Figure 1). From a therapeutic perspective, a major
An estimated 422 million people suffer from diabetes mellitus
according to the World Health Organization (WHO). This consti-
tutes a 400% increase in cases between 1980 and 2014, with
incidence rates maintaining a steep trajectory.[1] The clinical
sub-categorisation of the disease into Type I and II diabetes is
strikingly asymmetric, with the latter accounting for approxi-
shortcoming of b-Phlorizin (1) is that it is a potent inhibitor of
[a] A. Sadurní, Dr. G. Kehr, Prof. Dr. R. Gilmour
Organisch-Chemisches Institut
Westfälische Wilhelms-Universität Münster
Corrensstraße 40, 48149 (Germany)
E-mail: ryan.gilmour@uni-muenster.de
Homepage: http://www.uni-muenster.de/Chemie.oc/gilmour/index.html
[b] Dr. M. Ahlqvist
DMPK, Drug Safety and Metabolism, IMED Biotech Unit
Astrazeneca, Gothenburg (Sweden)
[c] J. Wernevik, Dr. H. P. Sjçgren, Dr. C. Kankkonen
Discovery Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg (Sweden)
[d] Dr. L. Knerr
Medicinal Chemistry, Cardiovascular and Metabolic Diseases
IMED Biotech Unit, Astrazeneca, Gothenburg (Sweden)
E-mail: Laurent.Knerr@astrazeneca.com
[e] Prof. Dr. R. Gilmour
Excellence Cluster EXC 1003, Cells in Motion
Westfälische Wilhelms-Universität Münster
Münster (Germany)
Supporting information and the ORCID identification number(s) for the au-
thor(s) of this article can be found under
https://doi.org/10.1002/chem.201705373.
Figure 1. Selected C- and O-linked SGLT-2 inhibitors for the treatment of
TypeII diabetes mellitus.
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both SGLT channels, and not just SGLT2.[9] This lack of selectivi-
ty is problematic, since significant inhibition of SGLT1 can
cause glucose-galactose malabsorption; a process that is
linked to a number of adverse side effects.[10,11] This lack of spe-
cificity, coupled with its compromised hydrolytic stability, ren-
ders b-Phlorizin itself a poor drug candidate. Consequently, a
plenum of analogs have been developed in recent years with
improved SGLT2:SGLT1 selectivity (>2000:1) and glycosidase
resistance.[12,13] Key design features include (i) the administra-
tion of a prodrug [C6 carbonates; Sergliflozin etabonate (2) and
Remogliflozin Etabonate (3)] to reduce hydrolysis in the gastro-
intestinal tract; and (ii) the introduction of C-glycosides to link
the monosaccharide core with the aromatic unit (examples in-
clude Ipragliflozin (4, Suglatꢀ), Dapagliflozin (5, Farxigaꢀ), Cana-
gliflozin (6, Invokanaꢀ) and Empagliflozin (7, Jardianceꢀ),
Figure 1).[13–16]
fluoro substituent could be harnessed as a directing group for
b-selective chemical glycosylation;[18] this would build on previ-
ous studies from this laboratory invoking nucleophilic addition
to the transient oxocarbenium ion via a modified Felkin–Anh–
Eisenstein induction model proceeding via a tentative SN1
paradigm (Figure 2).[23] Cumulatively, the potential to influence
reactivity/selectivity in synthesis, augment metabolic stability
and address the timely issue of SGLT specificity rendered the
study of fluorinated Phlorizin derivatives appealing.
In all cases, the d-glucose unit is preserved together with
the b-configured anomeric linkage, with only the C6-hydroxyl
group having been functionalised in the pro-drug. The remain-
ing stereotriad is conserved, presumably to ensure that the
molecular recognition events that underpin the subsequent
glycolysis pathway are not disrupted. With a view to contribu-
ting to the identification of novel selective SGLT2 inhibitors
with diminished side effects and increased efficacy, the effect
of fluorination at C2 of Remogliflozin Etabonate (3) and Dapagli-
flozin (5) was explored. These scaffolds would serve as models
for the O-glycosylated and C-glycosylated drugs, respectively. It
was envisaged that this subtle structural modification would
serve several purposes: The fluorine substituent at C2 would
likely influence the stereoselectivity of the glycosylation event,
whilst simultaneously enhancing the hydrolytic stability of the
product glycoside towards enzymatic degradation.[17] The
effect of the OH!F substitution, which in this context serves
as both a steering group for chemical glycosylation[18] and a
hydroxyl bioisostere,[19] would ultimately be determined by
SGLT2 inhibition assays and physicochemical profiling.
Figure 2. Felkin–Anh–Eisenstein induction model invoked to account for the
b-selectivity observed in fluorine-directed glycosylation.[18,24]
To explore the influence of fluorine insertion at C2 of the d-
glucose core in key SGLT2 inhibitor candidates, the synthesis
of two, representative analogues was envisaged: (i) Remogliflo-
zin Etabonate, an O-linked prodrug, and (ii) the C-glycoside Da-
pagliflozin (Farxigaꢀ, Figure 3, upper). For control experiments,
the analogous 2-hydroxy (OH) and 2-deoxy (H) systems would
also be required. This would allow the implications of fluorina-
tion on both glycosylation selectivity and SGLT inhibition to be
placed on a structural foundation.
Retrosynthetic analysis of the target analogues of Remogliflo-
zin Etabonate and Dapagliflozin centered upon three common
intermediates (A, B and C) derived from disconnection of the
glycosidic linkage (Figure 3, lower). Since it was desirable to
Molecular editing with fluorine: As a classic bioisostere of the
hydroxyl functionality, fluorine is inimitable amongst the halo-
gen series. Whilst this substitution mitigates significant steric
alterations to the systems, it is a powerful strategy to modulate
physicochemical parameters such as lipophilicity, metabolic
stability, and the pKa values of neighboring groups.[20,21] More-
over, the strategic introduction of fluorine can be harnessed to
induce conformational changes arising from stabilising stereo-
electronic and/or electrostatic interactions when positioned vi-
cinal to an electron-withdrawing group.[22] Cumulatively, these
factors render fluorination attractive from the perspective of
modulating structure and reactivity.[18,23]
Ensuring b-stereoselectivity: Pertinent to this study is the
strategic replacement of the d-glucose core by 2-deoxy-2-
fluoro-d-glucose. In the course of their mechanistic enzymolo-
gy program, Withers and co-workers have elegantly demon-
strated the destabilising effect of the 2-fluoro substituent on
the formation of the oxocarbenium ion in enzymatic process-
es.[17] This study led to the finding that fluorine introduction at
C2 of glucose derivatives enhances stability towards b-glycosi-
dases.[24] Bearing this in mind, it was envisaged that the 2-
Figure 3. The target analogues of Remogliflozin Etabonate [3 (X=OH), 8
(X=F), 10 (X=H)] and Dapagliflozin [5 (X=OH), 9 (X=F), 11 (X=H)].
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generate a series differing only in the modification at C2 (X=F,
OH, H), triacetyl-d-glucal 12 constitutes a versatile, commercial-
ly available building block for the unnatural sugars. Conven-
iently, the aromatic fragments B and C required for the synthe-
sis of the Remogliflozin Etabonate and Dapagliflozin have previ-
ously been described.[13,25] The six carbohydrate fragments (X=
F, OH, H) required to access both target scaffolds were pre-
pared according to the procedures described in Scheme 1 (Full
experimental details in the Supporting Information).[21,26–28]
Scheme 2. Syntheses of Remogliflozin Etabonate analogues 3 (X=OH), 8
(X=F), 10 (X=H)]. [a] Reagents and conditions: [yield] i) TMSOTf, CH2Cl2,
À788C to RT [19a 52%, 19b 30%, 19c 52%]; ii) H2, Pd/C, MeOH, RT [20a
98%, 20b 50%, 20c 70%]; iii) DEPC, Sc(OTf)3, Tol/EtOH 4:1, 558C [8 65%, 10
35%, 3 70%]. [b] Reported as the ratio of a:b (DEPC=diethyl pyrocarbon-
ate).
Having successfully prepared the O-linked analogue, atten-
tion was focused on the synthesis of the C-linked aromatic
fragment required for the Dapagliflozin surrogates (Scheme 3).
Key to success was the activation of 21 by halogen-lithium ex-
change, and subsequent addition to the donor lactones 17a–c
to generate lactols 22a–c. Importantly, only the fluorinated lac-
tone 17a generated the desired a-anomer exclusively (assign-
Scheme 1. Syntheses of the glycosyl donors 16a–c and 17a–c [C2 substitu-
ent: a (F), b (H) and c (OBn)]. [a] Reagents and conditions: [yield] i) Cl3CCN,
DBU, RT [16a 97%, 16b (97%), 16c (92%)]; ii) DMSO, Ac2O, RT [17a 81%,
17b 77%, 17c 75%].
Having prepared the three trichloroacetimidate donors (16a–c)
and the aromatic acceptor (18) required for the synthesis of
Remogliflozin Etabonate analoguess 3, 8, 10, glycosylation con-
ditions were explored (Scheme 2). Based on previous experi-
ence,[18] CH2Cl2 was selected as the solvent of choice to miti-
gate the risk of solvent participation, and catalytic TMSOTf was
chosen as the activator. Comparison of glycosylation selectivi-
ties using the three glycosyl donors revealed an increased b-
selectivity with 16a!19a (a:b 1:2, X=F), limited or no selec-
tivity for 16b!19b (a:b 1:1.4, X=H), and a-selectivity for
16c!19c (a:b 2.7:1, X=OBn).
This finding is in line with previous observations that per-
benzylated, gluco-configured 2-deoxy-2-fluoro donors preferen-
tially favor formation of the b-glycoside (1,2-trans).[18a] In the
subsequent synthetic steps only the b-anomer was employed.
Finally, benzyl-deprotection (20a–c) and selective formation of
the primary carbamate furnished the three Remogliflozin Eta-
bonate surrogates (3, 8, 10) in good yields and with high
purity for biological evaluation.
Scheme 3. Syntheses of Dapagliflozin analogues [5 (X=OH), 9 (X=F), 11
(X=H)]. [a] Reagents and conditions: [yield] i) n-BuLi (2.5m in hexanes), THF/
Tol (1:2), À788C [22a 73%, 22b 78%, 22c 88%]; ii) Et3SiH, BF3·Et2O, CH2Cl2,
À108C to 08C [23a 62%, 23b 51%, 20c 80%]; iii) H2, Pd/C, EtOAc, RT [9
73%, 11 63%, 5 93%]. [b] Reported as the ratio of a:b.
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ment as a- due to the higher priority of oxygen over carbon).
Reaction of the 2-deoxy-lactone 17b gave a complex and un-
stable a:b mixture of 22b that was used directly in the subse-
quent reduction step.
bryonic kidney (HEK) 293 cells transiently expressing the
mouse or human SGLT1 or SGLT2 transporters using Methyl-d-
[U-14C]glucopyranoside as the radiotracer. In the case of the 2-
deoxy-2-fluoro compounds (X=F), introduction of fluorine was
detrimental, but biological activity could still be observed. Al-
though less active than the parent scaffold 5, the fluorinated
Dapagliflozin analogue 9 selectively inhibited human and
mouse SGLT2 over SGLT1. Interestingly, deletion of the 2-OH
group (11) furnished an inactive compound thereby confirm-
ing the bioisosteric aptitude of fluorine in this class of com-
pounds.
For completeness, the 2-OBn lactone 17c was processed to
22c, delivering the a-product; this observation is in good
agreement with previous studies from Suzuki and co-work-
ers.[29] The stereochemistry at C1 was established by detailed
nOe analysis (full details are provided in the Supporting Infor-
mation). Independent reduction of the lactols with triethylsi-
lane and BF3·Et2O furnished compounds 23a–c in good to
high yields. Notably, for the fluorinated system 23a the stereo-
chemical integrity of the anomeric center was retained deliver-
ing exclusively the b-anomer (the a:b ratio was assigned due
to the higher priority of carbon over hydrogen, with the same
anti-relationship to F as stated above), whilst for the 2-deoxy
23b the a:b ratio was improved (a:b 1:25) and for the 2-OBn
23c a loss in selectivity was observed (a:b 1:4).[29] For the re-
mainder of the synthetic sequence, only the b-anomer was uti-
lized, with final benzyl-deprotection affording the Dapagliflozin
surrogates 5, 9, and 11.
Similarly, evaluation of the Remogliflozin analogues 20a (X=
F) and 20c (X=OH), as well as the Remogliflozin Etabonate sys-
tems 3 (X=OH) and 8 (X=F) confirmed the 2-OH group to be
essential for activity.
In accordance with previous reports regarding the effect of
glucose modification in SGLT2 inhibitors[30,31] the 2-deoxy deriv-
atives (10, 11) completely lost their capacity to inhibit glucose
uptake in our assay in both the Dapagliflozin (11) and Remogli-
flozin Etabonate series (10).
Physicochemical analyses: Having explored the effect of mo-
lecular editing at C2 of the pyranose ring, a range of physico-
chemical parameters such as solubility and metabolic stability
were determined for the compound set (Table 2). The metabol-
ic stability of the F and OH matched pairs in the Dapagliflozin
and Remogliflozin series were studied in human hepatocytes
(hHeps) and human liver micrososomes (HLM). The Dapagliflo-
zin scaffolds 5 (X=OH) and 9 (X=F) were shown to be reason-
ably stable, and to possess very similar intrinsic clearances in
both HLM and hHeps. However, the Remogliflozin derivatives
20a (X=F) and 20c (X=OH) demonstrated different behav-
iours. Indeed whilst 20c proved to be stable in the hHeps and
demonstrated only limited metabolism upon incubation with
HLM, 20a proved to be significantly less stable in both assays.
Whilst the clearance of 20a remained limited in hepatocytes, it
was only moderately stable in the microsomes assay with Clint
reaching 21.6. The significantly higher lipophilicity of 20a com-
pared to 20c (DlogD7.4: 0.9) could potentially explain the in-
creased sensitivity to metabolising enzymes.
In vitro analysis: The ability of the target compounds to selec-
tively inhibit human and mouse SGLT1 and SGLT2 was ex-
plored (Table 1). This investigation was complemented by a
physicochemical analysis to establish the effect of molecular
editing of the C2-position (Table 2). Initially, the SGLT-depen-
dent glucose uptake inhibition was measured in human em-
Table 1. SGLT dependant glucose uptake inhibition measured in human
embryonic kidney (HEK) 293 cells transiently expressing the SGLTs using
methyl-d-[U-14C]glucopyranoside as tracer.[a]
Structure
X
SGLT1 Hu SGLT2 Hu SGLT1 Mouse SGLT2 Mouse
[IC50 mm]
[IC50 mm]
[IC50 mm]
[IC50 mm]
5
9
11
20a
20c
3
OH 1.39[13]
0.0011[13]
1.26
>30
>30
0.0124[32]
1.95[32]
>30
2.65
>30
>30
>30
–
–
>30
>30
0.0029
0.62
>30
>30
–
–
>30
>30
F
H
F
>30
>30
>30
OH 4.25[32]
OH >30
8
10
F
H
>30
>30
To further elucidate the impact of fluorine introduction, if
any, on the observed difference in the metabolic stabilities be-
tween 20a and 20c we performed a metabolite identification
study in human hepatocytes (see Supporting Information).
After 120 minutes incubation the parent hydroxyl derivative
20c was 97% intact with several metabolites having been
formed, including trace amounts (<0.2%) of O-dealkylated
aglycone compounds (two unidentified isomers). Metabolism
of the glycosyl part was observed in the form of O-glucuroni-
dation (0.55%), oxidation of the primary alcohol to carboxylic
acid (1.1%) and loss of the aglycone unit (0.96%). Metabolism
of the fluorinated derivative 20a under the same conditions
was more pronounced with 84% of the parent compound re-
maining. Although O-dealkylation of the aglycone was also ob-
served (again as a pair of isomers) as the main metabolism
pathway (6.1 and 3.1%), a novel metabolite resulting from hy-
droxylation of the aglycone core was identified (4.6%). Inter-
estingly, metabolism of the glycosyl unit was more limited in
>30
[a] SGLT1: sodium–glucose transporter 1; SGLT2: sodium–glucose trans-
porter 2; Hu, Human; IC50: half maximal inhibitory concentration, report-
ed as average value of a minimum of 2 replicates; mm, micromolar.
Table 2. Physicochemical analyses of the target structures.
Structure
X
Human Hepato-
cytes Clint
[mL/min/10À6
cells][a]
Human Micro-
somes Clint
[mL/min/mg][a]
Log
D7.4
PBS Solu-
bility
(pH 7.4)
[mm][a]
[a]
5
9
20a
20c
OH 3.0
10.1
7.4
21.6
8.25
1.9
3.1
2.4
1.5
>1000
450
864
F
F
5.4
8.4
OH <1
>1000
Clint: intrinsic clearance values; LogD7.4: distribution coefficient at pH 7.4;
[a] See Supporting Information for assays details.
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impact of fluorination on the biotransformation pathway of
these derivatives. The measured solubilities at pH 7.4 of the
fluorinated derivatives 9 and 20a remain very good for biolog-
ical application but proved to be significantly attenuated com-
pared to their hydroxylated matched pairs. Again, these dis-
crepancies may be a consequence of differences in lipophilicity
profiles.
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In conclusion, fluorine-directed glycosylation has been ex-
ploited for the stereocontrolled synthesis of SGLT2 inhibitors
for type II diabetes. For the first time, this strategy has been
exploited for the generation of C-glycosides, with the expected
1,2-trans stereochemical preference predominating. A single
site [OH!F] substitution at C2 in a Dapagliflozin model com-
pound has been shown to preserve the selective inhibition of
human/mouse SGLT2 over human/mouse SGLT1. Whilst this
target selectivity is accompanied by a loss in efficacy, it should
be noted that the drug scaffolds are structurally unoptimised.
Moreover, deletion of F or OH at C2 renders the compound
completely inactive and demonstrates the importance of
single atom changes at the chemistry–biology interface.[33]
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to optimize the fluorine containing core of the Dapagliflozin
candidate will be the focus of future efforts.
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Experimental Section
Full experimental details are provided in the Supporting Informa-
tion.
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This work was supported by the WWU Münster, the Deutsche
Forschungsgemeinschaft (DFG): “Cells in Motion, Cluster of Ex-
cellence”(CiM, FF-2013-10); and the European Research Council
(ERC-2013-StG Starter Grant to RG–Project number 336376-
ChMiFluorS); Initial Training Network, FLUOR21 (AS), funded by
the FP7 Marie Curie Actions of the European Commission (FP7-
PEOPLE-2013-ITN-607787).
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The authors declare no conflict of interest.
Keywords: bioiosteres · carbohydrates · diabetes · fluorine ·
selective glycosylation
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Manuscript received: November 13, 2017
Accepted manuscript online: December 6, 2017
Version of record online: December 20, 2017
Chem. Eur. J. 2018, 24, 2832 –2836
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