Carbocyclic thymidine analogues for use as potential therapeutic agents

Article abstract of DOI:10.1080/15257770903091920

The discovery of azidothymidine's (AZT) activity against human immunodeficiency virus (HIV) provided strong rationale for the design of additional thymidine analogues. One drawback of many nucleoside analogues is the toxicity that often arises due to phos

Full text of DOI:10.1080/15257770903091920

Nucleosides, Nucleotides and Nucleic Acids, 28:633–641, 2009
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770903091920
CARBOCYCLIC THYMIDINE ANALOGUES FOR USE AS POTENTIAL
THERAPEUTIC AGENTS
Katherine L. Seley-Radtke and Naresh K. Sunkara
Department of Chemistry and Biochemistry, University of Maryland Baltimore County,
Baltimore, Maryland, USA
The discovery of azidothymidine’s (AZT) activity against human immunodeficiency virus
2
(HIV) provided strong rationale for the design of additional thymidine analogues. One drawback of
many nucleoside analogues is the toxicity that often arises due to phosphorylation by cellular kinases.
In order to overcome this problem, a number of truncated nucleosides lacking the 4 ꢁ-hydroxymethyl
group have been synthesized. In that regard, the synthesis and preliminary biological results for two
truncated carbocyclic thymidine analogues are presented herein.
Keywords Carbocyclic; nucleosides; pyrimidine; SAHase; neplanocin; aristeromycin
INTRODUCTION
Despite the significant biological activity exhibited by a variety of
novel unnatural nucleosides, the pursuit of new analogues continues in
an effort to decrease toxicity and improve efficacy in various biological
systems.[1] As a result, manipulation of the nucleoside scaffold both in
the heterocyclic base and the sugar moiety has resulted in a number of
potent antiviral and anticancer drugs.[1–4] In that regard, a number of
uridine and 5-substituted 2ꢁ-deoxyuridine nucleoside analogues (shown in
Figure 1) such as 5-(E)-(bromovinyl)-2ꢁ-deoxyuridine (BVDU,[5–7] A), 5-
trifluoromethyl-2ꢁ-deoxyuridine (F3TDR, B), 5-iodo-2ꢁ-deoxyuridine (IUDR,
C)[8] and 5-bromo-2ꢁ-deoxyuridine (D), and 5-fluoro-2ꢁ-deoxyuridine (E)
have exhibited antiviral and/or anticancer activity.[7,9–11]
Received 6 February 2009; accepted 28 May 2009.
This work was supported by the National Institutes of Health (RO1 CA97634, KSR). The authors
also want to thank Dr. Sunny Zhou of Northeastern University for performing the SAHase assays.
In honor of and in celebration of Morris J. Robins’ 70th birthday.
Address correspondence to Katherine L. Seley-Radtke, University of Maryland Baltimore County,
Baltimore, MD, 21250, USA. E-mail: kseley@umbc.edu
633

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K. L. Seley-Radtke and N. K. Sunkara
FIGURE 1 Biologically significant pyrimidine nucleosides.
One particular structural modification that has proven fruitful is found
in the carbocyclic nucleosides.[12–16] Carbocyclic nucleosides possess a
methylene group in place of the furanose oxygen in the sugar moiety
of the nucleoside. This structural change imparts significant stability to
the glycosidic bond, as well as increasing the overall lipophilicity of the
nucleoside.[17,18] A number of carbocyclic nucleosides have been synthe-
sized and many have been found to possess potent biological activity,
including the naturally occurring Neplanocin (NpcA) and Aristeromycin
[9,17,19–21]
(Ari).
To date most have been purine analogues, however due
to the significant biological activity found among 2ꢁ-deoxy and 5-substituted
2ꢁ-deoxy pyrimidines the synthesis of the analogous carbocyclic nucleosides
was also of interest and indeed, several have proven to be active.[9,10,18,22,23]
In that regard, the carbocyclic analogue of thymidine (F) (Figure 1)
exhibited activity against leukemia L1210 cell lines, as well as HSV-1 with
a MIC50 of 0.8 µg/mL.[9,22,23] Furthermore, carbocyclic analogues of 5-
substituted uridine (G-J) were found to be highly active in vitro against the
herpes simplex virus, both type 1 and 2.[9,17,20,22,23] The 5-iodo uridine
analogue (G) proved to be the most active against HSV-1 with a MIC50
in the range of 0.1–0.5 µg/mL.[9,22,23] Other examples of biologically

Carbocyclic Thymidine Analogues
635
FIGURE 2 Truncated purine carbocyclic nucleosides.
active carbocyclic pyrimidine analogues include cyclopentenyl cytosine
(CPE-C, K, Figure 1),[22,23] for which potent anti-West Nile activity was
observed.[24,25] Additionally, Chu et al. reported that L-fluorothymidine
(L, Figure 1) exhibited moderate activity against HIV.[24] The encouraging
activity exhibited by the pyrimidine nucleoside analogues and in particular,
thymidine analogues, provide an impetus to synthesize and explore the
therapeutic activities of these analogues.
Despite their potent activity, one of the drawbacks of some
carbocyclic nucleosides has been their susceptibility to phosphoryla-
tion by cellular kinases, resulting in significant cytotoxicity for the
triphosphate analogues.[26] In response to this, strategic removal of
the 4ꢁ-hydroxymethyl group of aristeromycin (Ari) and neplanocin
(NpcA) resulted in the development of new analogues (1ꢁR,2ꢁS,3ꢁR)-9-
(2ꢁ,3ꢁ-dihydroxycyclopentan-1ꢁ-yl)adenine (DHCaA) and (1ꢁR,2ꢁS,3ꢁR)-9-(2ꢁ,
3ꢁ-dihydroxycyclopent-4ꢁ-enyl)adenine (DHCeA) (Figure 1).[27] Interest-
ingly, both DHCaA and DHCeA retained potent antiviral activity but ex-
hibited reduced cytotoxicity since neither DHCaA nor DHCeA serve as
substrates for adenosine kinase or adenosine deaminase, both major causes
of cytotoxicity associated with Ari and NpcA.[28]
Related to this, we recently reported the synthesis of several carbocyclic
uridine and cytidine nucleoside analogues possessing the truncated scaffold
(Figure 2).[30] The cytidine analogue 2 exhibited interesting activity against
S-adenosylhomocysteine hydrolase (SAHase) and SAH nucleosidase. This
finding was interesting because 2 is a pyrimidine analogue and these are
adenosine-metabolizing enzymes.

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K. L. Seley-Radtke and N. K. Sunkara
FIGURE 3 Proposed truncated thymidine carbocyclic targets.
As a logical extension to our previous studies of truncated pyrimidine
nucleosides, synthesis of thymidine analogues 5 and 6 (Figure 3) was
considered and the results are reported herein.
RESULTS AND DISCUSSION
Traditional Mitsunobu coupling of the thymine ring to an appropriate
cyclopentyl intermediate was envisioned as a logical route to realize the
targets 5 and 6.[30–32] Synthesis began with the reduction of the known
protected carbocyclic ketone 7, a common building block in carbocyclic
nucleoside research that is obtained from commercially available D-ribose
in five steps.[33] Using literature methods,[34] the carbonyl group on in-
termediate 7 was stereospecifically reduced to the down alcohol 8 using
Luche[35] conditions with cerium (III) chloride heptahydrate as shown
in Scheme 1. Compound 8 was then coupled to N3-Bz-thymine 9 using
Mitsunobu conditions to afford 10 in 60% yield.[30–32]
Next, the benzoyl-protecting group on 10 was deblocked (Scheme 1)
by treatment with a 1% NaOH solution in MeOH to afford intermediate
11 in 75% yield.[30,32] The isopropylidene group of analogue 11 was then
removed using a mixture of TFA and H2O (2:1) in THF to result in the first
thymidine target 5.[30]
In order to obtain the saturated target 6, protected intermediate 11 was
reduced using 10% Pd/C and H2 at 25 psi to give 12 in 90% yield.[28,30] The
isopropylidene group of 12 was then deprotected under standard conditions
to quantitatively provide 6.[28,36]
Carbocyclic thymidine analogues 5 and 6 were then screened against the
National Cancer Institute’s 60 cell lines, as well as subjected to broad screen
testing against a number of viruses by Southern Research Institute. Unfortu-
nately neither 5 nor 6 showed any meaningful activity. In addition, because
of the unexpected inhibitory activity exhibited by our previous truncated
pyrimidine analogues against SAHase, 5 and 6 were also assayed against
this enzyme.[30] Not surprisingly however, since, as previously mentioned,
SAHase is almost exclusively an adenosine-metabolizing enzyme, neither of

Carbocyclic Thymidine Analogues
637
SCHEME 1 Synthesis of 5 and 6. Reagents and conditions: a, CeCl3 • 7H2O NaBH4, MeOH, 0◦C; b, i)
PPh3, DIAD, CH3CN, 0◦C to rt, 24 h; c, NaOH, MeOH, 12 h; d, TFA:H2O (2:1), 1 h, rt; e, 10% Pd/C,
H2, 25 psi, 25 min, rt.
these compounds proved to be an inhibitor. Current efforts are underway
to investigate additional modifications, and the results of those studies will
be reported as they become available.
EXPERIMENTAL
General Experimental Methods
All chemicals were obtained from commercial sources and used with-
out further purification unless otherwise noted. Anhydrous DMF, MeOH,
DMSO, and toluene were purchased from Fisher Scientific. Anhydrous
THF, acetone, CH2Cl2, CH3CN, and ether were obtained using a solvent
purification system (mBraun Labmaster 130). NMR solvents were purchased
from Cambridge Isotope Laboratories (Andover, MA, USA). All 1H and 13
C
NMR spectra were obtained on a JEOL ECX 400 MHz NMR, operated at
400 and 100 MHz respectively, and referenced to internal tetramethylsilane
(TMS) at 0.0 ppm. The spin multiplicities are indicated by the symbols s
(singlet), d (doublet), dd (doublet of doublets), t (triplet), q (quartet),
m (multiplet), and b (broad). Reactions were monitored by thin-layer
chromatography (TLC) using 0.25 mm Whatman Diamond silica gel 60-
F254 precoated plates. Column chromatography was performed using silica
gel (63–200 µm) from Dynamic Adsorbtions Inc. (Norcross, GA, USA), and

638
K. L. Seley-Radtke and N. K. Sunkara
eluted with the indicated solvent system. Yields refer to chromatographically
and spectroscopically (‘H and 13C NMR) homogeneous materials. Mass
spectra were recorded at the Johns Hopkins Mass Spectrometry Facility.
Elemental analyses were recorded at Atlantic Microlabs, Inc. (Norcross,
GA, USA). All chemicals were obtained from commercial sources and used
without further purification unless otherwise noted.
Preparation of 1-(2ꢁ-3ꢁ-O-Isopropylidenedioxycylopent-1-yl)-
thymine (11)
To 8[35] (0.75 g, 4.8 mmol), N 3-benzoylthymine (2.2 g, 9.61 mmol) and
PPh3 (3.14 g, 12 mmol) in anhydrous CH3CN (500 mL) at 0◦C was added
dropwise diisopropylazodicarboxylate (2.42 g, 12 mmol, 2.36 mL). After
stirring at room temperature for 15 hours, the mixture was concentrated
and purified by column chromatography eluting with EtOAc:hexane (3:1)
to afford 1.71 g of 10 as a white solid (66%). 1H NMR (400 MHz, DMSO-d6)
δ 1.32 (3 H, s); 1.38 (3 H, s); 1.84 (3 H, s); 4.68 (1 H, m); 5.31 (1 H, dd); 5.37
(1 H, dd); 5.79 (1 H, m); 6.21 (1 H, m); 7.22 (1 H, s); 7.51 (2 H, m); 7.72
(1 H, m); 7.92 (2 H, m). 13C NMR (75 MHz, DMSO-d6) δ 21.1, 22.4, 24.7,
26.4, 60.2, 68.8, 83.3, 84.7, 110.1, 111.7, 129.2, 129.4, 130.3, 131.6, 135.2,
138.7, 149.9, 163.5, 169.3, 171.5.
NaOH (10 mL, 1% in MeOH) was added to 10 (1.7 g, 4.7 mmol)
and the mixture allowed to stir at room temperature for 12 hours, then
neutralized with 1M HCl. The mixture was evaporated and the resulting
residue dissolved in EtOAc (50 mL), washed with H2O (25 mL), dried (an-
hydrous MgSO4), and the solvent evaporated under vacuum. The residue
was purified by column chromatography eluting with EtOAc:hexane (4:1)
to afford 0.95 g of 11 as a white solid (79%). 1H NMR (400 MHz, CD3OD)
δ 1.29 (3 H, s); 1.37 (3 H, s); 1.82 (3 H, s); 4.61 (1 H, d); 5.38 (1 H,
m); 5.41 (1 H, m); 5.79 (1 H, m); 6.21 (1 H, m); 7.11 (1 H, s). 13C NMR
(75 MHz, DMSO-d6) δ 24.6, 26.4, 60.23, 68.24, 83.47, 84.7, 110.1, 111.6,
129.4, 138.2, 151.4, 165.1, 171.5. HRMS: Calcd for C13H16N2O4 (M+H)+,
265.1111; Found, 265.1429.
Preparation of 1(2ꢁ,3ꢁ-Dihydroxycyclopent-2-enyl)-thymine (5)
To a mixture of trifluoroacetic acid and H2O (2:1, 50 mL) was added
11 (0.21 g, 0.75 mmol) and the mixture stirred for 2 hours. The solvent was
removed under vacuum and the residue purified by column chromatogra-
phy eluting with EtOAc:MeOH, (10:1) to afford 0.13 g of 5 as a white solid
(78%). 1H NMR (400 MHz, CD3OD) δ 1.85 (3H, s); 4.11(1H, m); 4.04 (1H,
t); 4.57(1H, m); 6.17 (1H, m); 7.19 (1H, m). 13C NMR (75 MHz, CD3OD)
10.9, 66.3, 72.9, 76.4, 110.4, 132.8, 136.3, 137.9, 151.9, 165.2. Anal. Calcd for

Carbocyclic Thymidine Analogues
639
C10H12N2O4 (0.10 H2O): C, 53.30, H, 5.40, N, 12.10. Found: C, 53.32, H,
5.50, N, 12.04.
Preparation of 1-(2ꢁ,3ꢁ-O-Isopropylidinedioxycylopent-l-yl- thimine
(12)
To a solution of 11 (0.500 g, 1.89 mmol) in MeOH (10 mL) Pd/C (10%,
0.040 g) was added and the mixture subjected to hydrogenation conditions
at a pressure of 0.17 MPa for 20 minutes. The mixture was filtered and the
filtrate concentrated under vacuum to afford 0.498 g of 12 as a white solid
1
(quantitative). H NMR (400 MHz, CD3OD) δ 1.26 (3 H, s); 1.37 (3 H, s);
1.81 (3 H, s); 1.88–1.98 (2 H, m); 4.63 (1 H, d); 5.35 (1 H, m); 5.41 (1 H, m);
5.79 (1 H, m); 6.21 (1 H, m); 7.11 (1 H, s). 13C NMR (75 MHz, DMSO-d6)
δ 24.6, 26.4, 60.3, 68.3, 83.5, 84.7, 110.1, 111.6, 129.1, 138.2, 151.3, 165.1,
171.5. HRMS: Calcd for C13H18N2O4 (M+H)+, 267.1267; Found, 267.1340.
Preparation of 1-(2ꢁ,3ꢁ-Dihydroxycyclopentyl-thimine (6)
Compound 12 (0.200 g, 0.75 mmol) was dissolved in a mixture of
trifluoroacetic acid and water (2:1, 50 mL) and stirred for 2 hours. The
solvent was removed under vacuum and the residue purified by column
chromatography eluting with EtOAc: MeOH (10:1) to afford 0.16 g of 6 as a
white solid (quantitative).1H NMR (400 MHz, DMSO) δ 1.42–1.52 (2 H, m);
1.72–1.78 (3 H, m); 1.89–1.97 (2 H, m); 3.81–3.87 (1 H, m); 3.96–4.18 (1 H,
m); 4.52–4.54 (1 H, d); 4.56–4.62 (1 H, m); 4.78–4.82 (1 H, d); 7.53–7.56 (1
H, d); 11.2 (1 H, s). 13C NMR (75 MHz, DMSO) 15.5, 19.9, 26.2, 59.8, 77.2,
85.9, 110.9, 137.5, 150.9, 163.8. Anal. Calcd. for C10H14N2O4 (0.10 H2O); C,
52.62, H, 6.22, N, 11.70. Found: C, 52.65, H, 6.34, N, 11.83.
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