Synthesis and anti-HIV-1 activity of 4-substituted-7-(2′-deoxy- 2′-fluoro-4′-azido-β-d-ribofuranosyl)pyrrolo[2,3-d]pyrimidine analogues

Article abstract of DOI:10.1016/j.bmcl.2011.09.040

Three novel 4-subsituted-7-(2′-deoxy-2′-fluoro-4′-azido- β-d-ribofuranosyl)pyrrolo[2,3-d]pyrimidine analogues were designed, synthesized, and tested for their anti-HIV-1 activity. Initial biological studies indicated that among these pyrrolo[2,3-d]pyrimid

Full text of DOI:10.1016/j.bmcl.2011.09.040

Bioorganic & Medicinal Chemistry Letters 21 (2011) 6770–6772
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Bioorganic & Medicinal Chemistry Letters
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Synthesis and anti-HIV-1 activity of 4-substituted-7-(20-deoxy-20-fluoro-40-azido-
b-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine analogues
Xiaohe Guo a, Yujiang Li a, Le Tao a, Qiang Wang a, Shuyang Wang b, Weidong Hu b, Zhenliang Pan c,
Qinghua Yang b, Yanmei Cui b, Zhaopeng Ge b, Lihong Dong a, Xuejun Yu a, Haoyun An a, Chuanjun Song b,
Junbiao Chang a,b,
⇑
a The Fine Chemical Key Lab. of Henan Province, Henan Academy of Sciences, Zhengzhou 450002, PR China
b Department of Chemistry, Zhengzhou University, Zhengzhou, Henan Province 450001, PR China
c School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan Province 450001, PR China
a r t i c l e i n f o
a b s t r a c t
Three novel 4-subsituted-7-(20-deoxy-20-fluoro-40-azido-b-
D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine
Article history:
Received 5 July 2011
Revised 10 September 2011
Accepted 13 September 2011
Available online 16 September 2011
analogues were designed, synthesized, and tested for their anti-HIV-1 activity. Initial biological studies
indicated that among these pyrrolo[2,3-d]pyrimidine ribonucleoside analogues, 4-amino-7-(20-deoxy-
20-fluoro-40-azido-b-
activity (EC50 = 0.5 0.3
o[2,3-d] pyrimidine
o[2,3-d] pyrimidine 11 showed moderate activity (EC50 = 13 8 and 5.4 0.3
cytotoxicity of these compounds has also been assessed. No significant cytotoxicities were found for
any of these compounds with concentrations up to 25 M.
D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine 10 exhibited the most potent anti-HIV-1
l
M), while 4-hydroxy-7-(20-deoxy-20-fluoro-40-azido-b-
D
-ribofuranosyl)pyrrol-
-ribofuranosyl)pyrrol-
9
and 4-amino-5-fluoro-7-(20-deoxy-20-fluoro-40-azido-b-
D
Key words:
l
M, respectively). The
Pyrrolo[2,3-d]pyrimidine
Ribonucleoside
Anti-HIV-1 activity
Synthesis
l
Ó 2011 Elsevier Ltd. All rights reserved.
Since 7-deazapurines are ideal shape mimics of the parent pur-
ines, the corresponding ribonucleosides can replace naturally
occurring RNA-constituents as substrates or inhibitors. Thus, it can
be expected that further modifications on the pyrrolo[2,3-d]pyrim-
idine moiety may generate new pharmacologically active
compounds against human immunodeficiency virus.1–3 On the
other hand, several purine nucleosides containing the 20-deoxy-
delight, when alkene 4a was subjected to a premixed solution of
iodine chloride and sodium azide in THF, the desired product 5a
was isolated in 89% yield. Subsequent protection of the 30-hydroxy
group and displacement of the iodide with m-chlorobenzoyloxy
group provided 7a. Treatment of 7a with sodium methoxide re-
sulted in the formation of 8 in 60% isolated yield, demethylation1
of which then gave the 4-hydroxy pyrrolo[2,3-d]pyrimidine deriv-
ative 912 in good yield. On the other hand, treatment of 7a with sat-
urated mathanolic ammonia at 70 °C would give 4-amino
pyrrolo[2,3-d]pyrimidine derivative 1013 in moderate yield. Start-
ing with 1b14 and following the same sequence as described for
the synthesis of 10, 4-amino-5-fluoropyrrolo[2,3-d]pyrimidine
derivative 1115 could also be synthesized. It needed to be indicated
that, during the deprotection of 1b, apart from the desired product
2b, substantial amount of the corresponding 4-methoxy derivative
resulting from displacement of the chloride by methanol was also
formed, which explained the relatively lower yield of the step
compared to the synthesis of 2a.
20-fluoro-b-
potential antiviral and anti-leukemic agents.4–6 Specially, a 7-dea-
zapurine analogue, 2,4-diamino-7-(20-deoxy-20-fluoro-b-
-arabino-
D-arabinofuranosyl moiety have been synthesized as
D
furanosyl)pyrrolo[2,3-d] pyrimidine, has been reported to exhibit
good in vitro anti-HBV activity.7
As a continuous research program of our laboratory searching
for antiviral agents,8 we now report the design and synthesis of no-
vel
4-subsituted-7-(20-deoxy-20-fluoro-40-azido-b-
D-ribofurano-
syl)pyrrolo[2,3-d]pyrimidine analogues 9, 10, and 11 (Scheme 1),
which can specifically inhibit HIV-1 replication.
As shown in Scheme 1, treatment of the known nucleoside ana-
logue 1a9 with saturated methanolic ammonia gave 2a in 88% iso-
lated yield. Selective substitution of the primary hydroxy group
with iodide,10 followed by treatment with DBU furnished alkene
4a in 37% yield over the two steps. Next, the key reaction, addition
of iodine azide to the double bond of 4a was attempted.11 To our
The anti-HIV-1 activity of compounds 9, 10 and 11 were evalu-
ated by MTT method16 and the results were listed in Table 1. All
three compounds tested could inhibit HIV-1 (wild type) replica-
tion. However, none was as effective as AZT. Among them, com-
pound 10 exhibited the most potent anti-HIV-1 activity
(EC50 = 0.5 0.3
moderate activity (EC50 = 13 8 and 5.4 0.3
The cytotoxicity of these compounds had also been assessed. No
l
M), while compounds 9 and 11 only showed
lM, respectively).
⇑
Corresponding author.
E-mail address: Changjunbiao@zzu.edu.cn (J. Chang).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.09.040

X. Guo et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6770–6772
6771
Scheme 1. Reagents and conditions: (i) NH3.CH3OH, 0 °C to rt, 88% for 2a, 46% for 2b; (ii) I2/PPh3/imidazole, THF, rt, 59% for 3a, 87% for 3b; (iii) DBU, THF, 60 °C, 62% for 4a,
45% for 4b; (iv) ICl, NaN3, THF, rt, 4 h, 89% for 5a, 72% for 5b; (v) BzCl, Et3N, DMAP, CH2Cl2, 0 °C, 5 min, 83% for 6a, 81% for 6b; (vi) m-CPBA, m-CBA, K2HPO4, n-Bu4NHSO4,
CH2Cl2/H2O, rt, 36 h, 64% for 7a, 13% for 7b; (vii) CH3ONa/CH3OH, rt, 5 h, 60%; (viii) Me3SiCl, NaI, CH3CN, rt, 5 h, 60%; (ix) NH3.CH3OH, 70 °C, 24 h, 33%; (x) NH3.CH3OH, rt, 24 h,
40%.
Table 1
Acknowledgment
Anti-HIV-1 activity and cellular toxicity of compounds 9, 10 and 11.
a
b
Compounds
EC50
(
l
M)
CC50
(
lM)
We are grateful to the National Natural Science Foundation of
China (Outstanding Young Scholarship to J. Chang, #30825043)
and the Outstanding Scholar Foundation of Henan Province
(#094100510019) for financial support.
9
13
0.5 0.3
5.4 0.3
8
P25
P25
P25
P25
10
11
AZT
0.084 0.0026
a
References and notes
EC50
CC50
(
l
M) is the concentration that inhibits HIV-1 (wild type) by 50%.
M) is the concentration of the compound at which 50% of the cells were
b
(
l
destroyed.
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significant cytotoxicities were found for any of these compounds
with concentrations up to 25 M.
In summary, three novel 4-subsituted-7-(20-deoxy-20-fluoro-40-
azido-b- -ribofuranosyl)pyrrolo[2,3-d]pyrimidine analogues were
designed, synthesized and their anti-HIV-1 activity evaluated in vi-
tro. Initial biological studies indicated that compound 10 showed
promising activity against HIV-1 replication. Further investigations
of the biological activities of 10 are currently underway.
l
D
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CD3OD) 159.1, 152.6, 151.4, 124.6, 104.5, 101.4, 97.8 (JFC = 9.0 Hz), 96.3
(JFC = 193.5 Hz), 82.5 (JFC = 17.3 Hz), 76.1 (JFC = 23.8 Hz) and 63.7; m/z (ESI)
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J = 9.6, 5.7 Hz, H-10) 6.68 (1H, d, J = 3.6 Hz, H-5), 5.30 (1H, dt, J = 54, 5.7 Hz, H-
20), 4.74 (1H, dd, J = 20.7, 5.7 Hz, H-30) and 3.89 (2H, s, H-50); 13C NMR (75 MHz,
D2O) 161.4, 149.9, 144.7, 124.3, 109.8, 103.9, 97.9 (JFC = 8.9 Hz), 96.2
(JFC = 193.9 Hz), 82.7 (JFC = 17.2 Hz), 76.0 (JFC = 23.7 Hz) and 63.7; m/z (ESI)
333 (M++Na, 100%) and 311 (15) [found: M++Na, 333.0738. C11H11FN6NaO4
requires 333.0724].
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3.87 (2H, s, H-50); 13C NMR (75 MHz, CD3OD) 157.6, 154.0, 147.7, 145.4
(JFC = 244.8 Hz), 106.9 (JFC = 28.0 Hz), 97.8 (JFC = 9.2 Hz), 96.2 (JFC = 193.6 Hz),
82.0 (JFC = 17.3 Hz), 75.9 (JFC = 23.7 Hz) and 63.6; m/z (ESI) 328 (M++H, 100%)
[found: M++H, 328.0973. C11H12F2N7O3 requires 328.0970].
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