Amino acid ester prodrugs of the antiviral agent 2-bromo-5,6-dichloro-1- (β-D-ribofuranosyl)benzimidazole as potential substrates of hPEPT1 transporter

Article abstract of DOI:10.1021/jm049450i

Amino acid ester prodrugs of 2-bromo-5,6-dichloro-1-(βD-ribofuranosyl) benzimidazole (BDCRB) were synthesized and evaluated for their affinity for hPEPT1, an intestinal oligopeptide transporter. Assays of competitive inhibition of [³H]glycylsar

Full text of DOI:10.1021/jm049450i

1274
J. Med. Chem. 2005, 48, 1274-1277
Amino Acid Ester Prodrugs of the Antiviral Agent
2-Bromo-5,6-dichloro-1-(â-D-ribofuranosyl)benzimidazole as Potential Substrates
of hPEPT1 Transporter
Xueqin Song,† Balvinder S. Vig,†,§ Philip L. Lorenzi,† John C. Drach,‡,$ Leroy B. Townsend,| and
Gordon L. Amidon†,*
Department of Pharmaceutical Sciences, College of Pharmacy; Department of Biological and Materials Sciences,
School of Dentistry; and Department of Medicinal Chemistry, College of Pharmacy; University of Michigan,
Ann Arbor, Michigan 48109-1065
Received July 12, 2004
Amino acid ester prodrugs of 2-bromo-5,6-dichloro-1-(â-D-ribofuranosyl)benzimidazole (BDCRB)
were synthesized and evaluated for their affinity for hPEPT1, an intestinal oligopeptide
transporter. Assays of competitive inhibition of [3H]glycylsarcosine (Gly-Sar) uptake in HeLa/
hPEPT1 cells by the amino acid ester prodrugs of BDCRB suggested their 2- to 4-fold higher
affinity for hPEPT1 compared to BDCRB. Further, promoieties with hydrophobic side chains
and L-configuration were preferred by the hPEPT1 transporter.
Introduction
potent inhibitors of human cytomegalovirus (HCMV)
replication with low cellular toxicity at concentrations
inhibiting viral growth.20,21 The antiviral mechanism of
action of BDCRB is unique and involves inhibition of
viral DNA processing and virus assembly.22 However,
BDCRB like certain other nucleoside agents exhibits
modest oral bioavailability mainly due to extensive first-
pass effects.23 The oral bioavailability of an L-riboside
structural analogue, 2-isopropylamino-5,6-dichloro-1-(â-
L-ribofuranosyl)benzimidazole (maribavir), was found to
be high, indicating the inherent stabilization of the
glycosidic bond in vivo.24,25 Such stabilization of the
glycosidic bond via structural alterations of the riboside
moiety suggested that modulation of the free hydroxyl
groups may result in glycosidic bond stabilization as
well. Further, on the basis of recent reports on the
potential of amino acid ester prodrugs of floxuridine as
substrates of hPEPT1,26,27 it was hypothesized that
amino acid ester prodrugs of BDCRB could also be
potential substrates of the hPEPT1 transporter. The
syntheses of amino acid ester prodrugs of BDCRB were
therefore undertaken in order to (a) investigate their
affinity for and transport by the intestinal oligopeptide
transporters, and (b) determine if the promoiety affords
stabilization of the glycosidic bond of BDCRB.
In this report, we describe the synthesis of a variety
of amino acid ester prodrugs of BDCRB and their
affinities for the hPEPT1 transporter. The amino acids
that were used as promoieties included the aliphatic
amino acids L-valine, D-valine, and L-isoleucine; the
aromatic amino acids L-phenylalanine, its analogues
p-chloro-L-phenylalanine, p-methoxy-L-phenylalanine,
and p-ethoxy-L-phenylalanine, as well as D-phenylala-
nine; the secondary amino acid L-proline; and the polar
amino acids L-aspartic acid, D-aspartic acid, and
L-lysine. The amino acid promoieties selected in this
study represent a broad range of physicochemical and
structural properties. BDCRB prodrugs were evaluated
for their affinity for hPEPT1 by determination of their
Nucleoside analogues are one of the most important
classes of antiviral drugs.1,2 However, their clinical
utility is often hampered by poor biopharmaceutical
properties.3 Several nucleoside drugs exhibit poor oral
bioavailability and are highly toxic due to their inability
to distinguish between normal cells and target cells.1,2,4
Thus, strategies that can alleviate these effects will be
of immense benefit. In this regard, prodrug approaches
have been extensively adopted to improve pharmaceuti-
cal properties of drugs.5,6 Prodrugs targeted to nutrient
transporters have been developed in order to improve
oral bioavailability, since nutrient transporters are
expressed in the gastrointestinal (GI) tract and shown
to be vital in the transport of nutrients and various
therapeutically important drugs.7-11 Of these, oligopep-
tide transporters such as hPEPT1 are promising targets
since they are highly expressed in the GI tract and are
known to transport a wide variety of di- and tripeptides
as well as â-lactam antibiotics, ACE inhibitors, and
other peptidomimetic agents.12-16 It has been demon-
strated a posteriori that the 3- to 5-fold higher oral
bioavailability of valacyclovir and valganciclovir com-
pared to acyclovir and ganciclovir, respectively, is at-
tributable to their transport by oligopeptide trans-
porters.7-9 Recently, prodrug approaches termed “pro-
nucleotides” have been designed for intracellular deliv-
ery of nucleoside monophosphates in order to obviate
drug resistance arising from decreased nucleoside ki-
nase activity.17-19
The antiviral agent 2-bromo-5,6-dichloro-1-(â-D-ribo-
furanosyl)benzimidazole (BDCRB) is a member of a
novel class of benzimidazole ribonucleosides that are
* To whom correspondence should be addressed. Tel: 734-764-2464;
Fax: 734-763-6423; e-mail: glamidon@umich.edu.
† Department of Pharmaceutical Sciences.
‡ Department of Biological and Materials Sciences.
§ Department of Medicinal Chemistry.
| Current address: Exploratory Biopharmaceutics and Stability,
Pharmaceutical Research Institute, Bristol-Myers Squibb Company,
New Brunswick, NJ 08903-0191.
10.1021/jm049450i CCC: $30.25 © 2005 American Chemical Society
Published on Web 02/01/2005

Brief Articles
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 4 1275
Table 1. Inhibition of [3H]Gly-Sar Uptake in HeLa/hPEPT1
Cells and Calculated LogP of BDCRB and Various Amino Acid
Ester Prodrugs of BDCRB
IC50 (µM),
IC50
prodrugs
average ( SEMa ratiob CLogPc
BDCRB, 1
447 ( 35.4
166 ( 8.8
342 ( 18.0
121 ( 2.4
218 ( 22.4
282 ( 10.2
142 ( 16.8
300 ( 13.2
96 ( 0.7
260 ( 24.0
421 ( 38.4
537 ( 25.2
477 ( 35.5
431 ( 12.7
nad
2.7
1.3
3.7
2.1
1.6
3.1
1.5
4.7
1.7
1.1
0.8
0.9
na
2.04
2.59
L-Val-BDCRB, 4a
D-Val-BDCRB, 4b
L-Ile-BDCRB, 4c
2.59
3.12
L-Phe-BDCRB, 4d
D-Phe-BDCRB, 4e
p-chloro-L-Phe-BDCRB, 4f
p-methoxy-L-Phe-BDCRB, 4g
p-ethoxy-L-Phe-BDCRB, 4h
L-Asp-BDCRB, 4i
3.08
3.08
3.79
3.01
3.53
-1.35
-1.35
2.37
D-Asp-BDCRB, 4j
Figure 1. Correlation between IC50 and CLogP for BDCRB
and its amino acid ester prodrugs. IC50 expressed as mean (
SEM (n g 3). CLogP estimated using ChemDraw Ultra 7.0
and CLogP program (version 3.0) from BioByte Corp. (Clar-
emont, CA).
L-Pro-BDCRB, 4k
L-Lys-BDCRB, 4l
1.36
-1.21
Valacyclovir
a Mean and standard error of the mean derived from three
separate experiments. b Parent/prodrug. c Calculated using Chem-
Draw Ultra 7.0. d na: not applicable.
Thus, L-amino acids exhibited 1.3- to 2-fold higher
affinity for hPEPT1 than their D-counterparts. These
results are similar to those reported for L- and D-amino
acid ester prodrugs of acyclovir, AZT, and floxuridine
prodrugs9,26 and are also consistent with the stereo-
chemical preferences observed with di- and tripep-
tides.29,30
In conclusion, the novel amino acid ester prodrugs of
BDCRB synthesized exhibited increased affinity for
hPEPT1 transporter. The metabolism of BDCRB and
its prodrugs in various biological systems are currently
being investigated in order to determine direct hPEPT1-
mediated transport of the prodrugs and the extent of
glycosidic bond stabilization afforded by the amino acid
promoiety.
ability to inhibit [3H]Gly-Sar uptake in HeLa cells
overexpressing hPEPT1.
Results and Discussion
Uptake Inhibition Assays. IC50 values calculated
from the inhibition data using nonlinear regression
analysis for BDCRB and its amino acid ester prodrugs
are listed in Table 1. In our assay system, valacyclovir,
a known substrate of hPEPT19 that was used as a
positive control, exhibited high affinity (IC50 ) 431 µM)
for hPEPT1 transporter (Table 1). All amino acid ester
prodrugs of BDCRB tested also exhibited high affinity
(96-476 µM) for hPEPT1 transporter. Except for D-Val,
L-Pro, L-Lys, and D-Asp prodrugs, all amino acid ester
prodrugs of BDCRB exhibited significantly higher af-
finity for hPEPT1 than BDCRB (p < 0.01). Interestingly,
BDCRB, which has no structural similarities to known
hPEPT1 substrates, also exhibited affinity that was
similar to valacyclovir (IC50 ) 447 µM). None of the
other nucleoside agents tested to date (acyclovir, gan-
ciclovir, AZT, and floxuridine) exhibited any affinity for
hPEPT1 transporter.9,10,26,27 The high affinity of BDCRB
compared to the other nucleoside agents may in part
be due to its highly hydrophobic heterocycle.
Experimental Section
Synthesis of 2′,3′-O-Isopropylidene-BDCRB, 2. To a
stirred solution of BDCRB (100 mg, 0.25 mmol) in dry acetone
(15 mL) was added p-toluenesulfonic acid monohydrate (477
mg, 2.5 mmol). The mixture was stirred for 1 h at room
temperature and poured into ice-cold 10% Na2CO3 solution (20
mL). The mixture was evaporated to a small volume under
reduced pressure. The residue was extracted with ethyl
acetate, washed with water and brine, and dried over MgSO4.
2′,3′-O-Isopropylidene-BDCRB was purified by column chro-
matography.
The structure of the promoiety influenced the affinity
of BDCRB prodrugs for hPEPT1. Generally, amino acid
prodrugs of BDCRB with aliphatic (4a, 4c), aromatic
(4d, 4f-h), or acidic (4i) side chains showed higher
affinity than those with basic (L-Lys, 4l) or constrained
(L-Pro, 4k) side chains. A modest inverse linear correla-
tion of IC50 values and CLogP for BDCRB and its
prodrugs was evident (r2 ) 0.65, Figure 1; Asp prodrugs
which were distinct outliers were excluded), suggesting
that hydrophobicity of the promoiety plays a significant
role in the affinity of the prodrug for hPEPT1 trans-
porter. For BDCRB and its Phe-analogue prodrugs only,
this inverse linear correlation was substantially higher;
r2 ) 0.89. These results are consistent with earlier
literature studies with hPEPT1.26,28 These findings
corroborate our hypothesis that amino acid ester pro-
drugs in general would exhibit enhanced affinity for
hPEPT1.9,10,26,27
Synthesis of Amino Acid Ester Prodrugs of BDCRB,
4a-l. Amino acid ester prodrugs of BDCRB were synthesized
as described in Scheme 1. Boc-protected amino acids (Boc-L-
Asp, Boc-D-Asp, Boc-L-Ile, Boc-L-Lys, Boc-L-Phe, Boc-D-Phe,
Boc-p-chloro-L-Phe, Boc-p-methoxy-L-Phe, Boc-p-ethoxy-L-Phe,
Boc-L-Pro, Boc-L-Val, and Boc-D-Val; 5 mmol), DCC (5 mmol),
and DMAP (0.5 mmol) were allowed to react with 2′,3′-O-
isopropylidene-BDCRB (2) (1 mmol) in 10 mL of dry N,N-
dimethylformamide (DMF). The reaction mixture was stirred
at room temperature for 24 h. The progress of the reaction
was monitored by TLC. After 24 h, the reaction mixture was
filtered and DMF was removed in vacuo. The residue was
dissolved in ethyl acetate (30 mL) and washed with water (2
× 20 mL), saturated NaHCO3 (2 × 20 mL), and brine (1 × 20
mL). The organic layer was dried over MgSO4 and concen-
trated in vacuo. The intermediates (3a-l) were purified using
column chromatography. Pure intermediates were then treated
with 4 mL of TFA:DCM (1:1). After 4 h, the solvents were
removed in vacuo and the residues reconstituted with water
and lyophilized. The TFA salts of amino acid prodrugs of
BDCRB were obtained as white fluffy solids. All BDCRB
prodrugs were obtained in reasonable yields (∼40-50% over-
all) and purity (more than 95% pure). The observed molecular
The stereochemistry of the amino acid promoiety also
influenced the affinity of the prodrugs for hPEPT1.

1276 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 4
Brief Articles
Scheme 1. Synthetic Scheme and Structures of Amino Acid Ester Prodrugs of BDCRBa
a Reagents: (i) TsOH, acetone; (ii) N-tBoc-protected amino acids, DCC, DMAP; (iii) TFA, CH2Cl2.
weights (ESI-MS) of the prodrugs and proton nuclear magnetic
resonance (1H NMR) spectra were identical to that required
by their structures. (See Supporting Information for details).
Cell Culture. HeLa cells (passage 100-120) from American
Type Culture Collection (Rockville, MD) were routinely main-
tained in Dulbecco’s modified Eagle’s medium (DMEM) con-
taining 10% fetal bovine serum (FBS), 1% nonessential amino
acids, 1 mM sodium pyruvate, and 1% l-glutamine. Cells were
grown in an atmosphere of 5% CO2 and 90% relative humidity
at 37 °C.
software. Statistical significance was evaluated using Graph-
Pad Prism V.3.0 by performing one-way analysis of variance
with posthoc Tukey’s test to compare means.
Acknowledgment. This work was supported by
grant NIGMD-1R01GM 37188.
Supporting Information Available: Materials and meth-
1
ods; percent yield, HPLC purity, H NMR, and ESI-MS data
Uptake Inhibition of [3H]Gly-Sar in HeLa/hPEPT1
Cells. The affinity of BDCRB and its amino acid ester
prodrugs for hPEPT1 transporter was evaluated by measuring
their ability to inhibit the uptake of [3H]Gly-Sar, a standard
hPEPT1 substrate, in HeLa cells overexpressing hPEPT1 as
described previously.31,32 Briefly, HeLa cells were infected with
adenovirus containing hPEPT1 to obtain HeLa cells overex-
pressing hPEPT1, and at 2 days postinfection, cells were
washed twice with uptake buffer (pH 6.0, 145 mM NaCl, 3
mM KCl, 1 mM NaH2PO4, 1 mM CaC12, 0.5 mM MgCl2, 5 mM
D-glucose, and 5 mM MES) and incubated with 10 µmol/L Gly-
Sar (9.94 µmol/L Gly-Sar and 0.06 µmol/L [3H]Gly-Sar) and
various concentrations (0.1-2 mM) of BDCRB or its amino acid
ester prodrugs in 0.3 mL uptake buffer for 30 min at room
temperature. After 30 min, the drug solutions were aspirated
and the cells were washed three times with ice-cold uptake
buffer and solubilized with 0.1% Triton X-100/0.1 N NaOH.
Aliquots of the suspensions were then used for scintillation
counting (Beckman LS-9000, Beckman Instruments, Fullerton,
CA) and for protein assays.
for intermediate 2 and compounds 4a-l. This material is
available free of charge via the Internet at http://pubs.acs.org.
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