Synthesis and biological activity of 4′-thio-L-xylofuranosyl nucleosides

Article abstract of DOI:10.1081/NCN-100002420

A series of 4′-thio-L-xylofuranosyl nucleosides were prepared and evaluated as potential anticancer and antiviral agents. The details of a convenient and high-yielding synthesis of the carbohydrate precursor 1-O-acetyl-2,3,5-tri-O-benzyl-4- thio-L-xylofuranose (6) are presented. Proof of structure and configuration at all chiral centers of the nucleosides was obtained by proton and carbon NMR. All target compounds were evaluated in a series of human cancer cell lines in culture and as antiviral agents.

Full text of DOI:10.1081/NCN-100002420

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SYNTHESIS AND BIOLOGICAL ACTIVITY OF 4′-THIO-L-
XYLOFURANOSYL NUCLEOSIDES
Kamal N. Tiwari a , Lea Messini a , John A. Montgomery a & John A. Secrist III b
a Southern Research Institute , P.O. Box 55305, Birmingham, Alabama, 35255-5305,
U.S.A.
b Southern Research Institute , P.O. Box 55305, Birmingham, Alabama, 35255-5305,
U.S.A.
Published online: 07 Feb 2007.
To cite this article: Kamal N. Tiwari , Lea Messini , John A. Montgomery & John A. Secrist III (2001) SYNTHESIS AND
BIOLOGICAL ACTIVITY OF 4′-THIO-L-XYLOFURANOSYL NUCLEOSIDES, Nucleosides, Nucleotides and Nucleic Acids, 20:4-7,
743-746, DOI: 10.1081/NCN-100002420
To link to this article: http://dx.doi.org/10.1081/NCN-100002420
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, 20(4–7), 743–746 (2001)
SYNTHESIS AND BIOLOGICAL ACTIVITY
OF 4ꢀ-THIO-L-XYLOFURANOSYL
NUCLEOSIDES
Kamal N. Tiwari, Lea Messini, John A. Montgomery,
and John A. Secrist III∗
Southern Research Institute, P.O. Box 55305,
Birmingham, Alabama 35255-5305
ABSTRACT
A series of 4ꢀ-thio-L-xylofuranosyl nucleosides were prepared and evaluated
as potential anticancer and antiviral agents. The details of a convenient and
high-yielding synthesis of the carbohydrate precursor 1-O-acetyl-2,3,5-tri-O-
benzyl-4- thio-L-xylofuranose (6) are presented. Proof of structure and configu-
ration at all chiral centers of the nucleosides was obtained by proton and carbon
NMR. All target compounds were evaluated in a series of human cancer cell
lines in culture and as antiviral agents.
As a part of research in our laboratories to develop novel anticancer and anti-
viral agents we have been pursuing the synthesis of 4ꢀ-thionucleosides for the past
several years (1–8). Based upon the significant activity in animals from certain ara-
bino and 2ꢀ-deoxy thionucleosides (1,7,8), we have prepared a series of new purine
and pyrimidine 4ꢀ-thio-L-xylonucleosides. All the sugar intermediates and the cor-
responding nucleosides have been characterized and the anomeric configuration
was determined by PMR.
Our goal in this L-xylofuranose series, as with other 4ꢀ-thionucleoside analogs,
was to prepare a series of compounds that included natural and modified purines
and pyrimidines, chosen on the basis of biological evaluations within the series and
biological information from our laboratories and others suggesting compounds with
∗Corresponding author.
743
ꢁ
C
Copyright 2001 by Marcel Dekker, Inc.
www.dekker.com

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TIWARI ET AL.
Scheme.
desirable properties. We have developed a five step sequence to the key interme-
diate 6. Conversion of D-arabinose to methyl 2,3,5-tri-O-benzyl-D-arabinofura-
noside (3) was accomplished in two steps by the usual method. Conversion to
dibenzyl dithioacetal 4 employingbenzylmercaptanandstannicchlorideproceeded
in 63% yield after chromatographic purification. Cyclization at C-4 involving a
single inversion, thus converting the D-arabino to the L-xylo configuration, was

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4ꢀ-THIO-L-XYLOFURANOSYL NUCLEOSIDES
745
accomplished employing triphenylphosphine, iodine, and imidazole in 72% yield.
The final step, replacement of the benzylthio group at C-1 by an acetoxy group,
involved treatment of 5 with mercuric acetate in acetic acid at room temperature.
The overall yield of 6 from 1, including four column purifications, was 32%, and
afforded a ca. 1:1 mixture of α,β anomers.
A series of purine nucleoside analogs was prepared through the coupling of 6
and 2,6-dichloropurine. A Lewis acid catalyzed reaction utilizing stannic chloride
(6) in acetonitrile was found to be an efficient method to achieve this coupling, and
30 and 25% yields of α and β anomers of 7 were obtained after chromatographic
purification/separation. After treatment with ethanolic ammonia to produce the re-
spective blocked 2-chloroadenine nucleosides 8α and 8β, removal of the O-benzyl
groups was accomplished with boron trichloride in dichloromethane at −50◦C to
yield the final nucleoside targets 9α (55%) and 9β (45%). Treatment of 7α and 7β
with sodium azide in 95% aqueous ethanol at reflux produced the corresponding
2,6-diazido intermediates 10α and 10β, which were subjected to reduction with
stannous chloride in dichloromethane to afford the blocked diaminopurine nucleo-
sides 11α (80%) and 11β (82%). Deblocking of 11α and 11β with boron trichloride
in dichloromethane produced the target diamino nucleoside 12α (71%) and 12β
(75%). The conversion of 12β to the corresponding guanine nucleoside 13 (45%)
was accomplished by treatment with adenosine deaminase under standard condi-
tions. Though the deamination was slow, it went to completion at room temperature
in 72 hours. Cytosine, Thymine and Uracil were coupled (8) with thiosugar 5 to
afford 14α (31%), 14β (30%), 16αβ (60%) and 18αβ (70%) respectively which
were deblocked by boron trichloride to give the desired nucleosides 15α (70%),
15β (70%), 17αβ (65%) and 19αβ (65%) respectively.
In order to provide confirmatory evidence that the carbohydrate configuration
and the anomeric configurations of our target compounds had been properly as-
signed, the NMR spectra of several compounds were examined by NOE difference
spectroscopy.
BIOLOGICAL DATA
All the compounds were screened for cell culture cytotoxicity against several
different human cancer cell lines and a variety of viruses HBV, RSV (Respiratory
Syncytial), influenza, influenza A/PR/8, HHV8, and CMV for antiviral activity.
None of the compounds have significant cytotoxicity and activity against any of the
viruses tested except for compounds 12α, 15α, and 15β, which showed very good
activity against CMV.
ACKNOWLEDGMENT
This investigation was supported by NIH Grant No. CA34200.

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REFERENCES
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2. Tiwari, K.N.; Montgomery, J.A.; Secrist, J.A., III. Nucleosides Nucleotides, 1993, 12,
841–846.
3. Secrist, J.A., III; Riggs, R.M.; Tiwari, K.N.; Montgomery, J.A. J. Med. Chem., 1992,
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4. Tiwari, K.N.; Secrist, J.A., III; Montgomery, J.A. Nucleosides Nucleotides, 1994, 13,
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5. Secrist, J.A., III; Parker, W.B.; Tiwari, K.N.; Messini, L.; Shaddix, S.C.; Rose, L.M.;
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Montgomery, J.A.; Secrist, J.A. III. Nucleosides, Nucleotides & Nucleic Acids, In Press
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