Synthesis and antiproliferative activity of some 4′-C-hydroxymethyl α- and -β-D-arabino-pentofuranosyl pyrimidine nucleosides

Article abstract of DOI:10.1081/NCN-100002342

A suitably protected 4-C-hydroxymethyl-arabino-pentofuranose was prepared and condensed with the following nucleobases: uracil, 5-fluorouracil and thymine. The corresponding cytosine and 5-fluorocytosine derivatives have also been obtained respectively from the uracil and 5-fluorouracil nucleosides. Separation of the anomeric mixtures followed by deprotection afforded the target compounds that were found to be non-cytotoxic to CCRF-CEM leukemia cells.

Full text of DOI:10.1081/NCN-100002342

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SYNTHESIS AND ANTIPROLIFERATIVE ACTIVITY OF
SOME 4′-C-HYDROXYMETHYL-α- AND -β-D-ARABINO-
PENTOFURANOSYL PYRIMIDINE NUCLEOSIDES
Jean-François Griffon 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.
Version of record first published: 07 Feb 2007.
To cite this article: Jean-François Griffon , John A. Montgomery & John A. Secrist III (2001): SYNTHESIS AND
ANTIPROLIFERATIVE ACTIVITY OF SOME 4′-C-HYDROXYMETHYL-α- AND -β-D-ARABINO-PENTOFURANOSYL PYRIMIDINE
NUCLEOSIDES, Nucleosides, Nucleotides and Nucleic Acids, 20:4-7, 649-652
To link to this article: http://dx.doi.org/10.1081/NCN-100002342
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, 20(4–7), 649–652 (2001)
SYNTHESIS AND ANTIPROLIFERATIVE
ACTIVITY OF SOME 4ꢀ-C-HYDROXYMETHYL-
α- AND -β-D-ARABINO-PENTOFURANOSYL
PYRIMIDINE NUCLEOSIDES
Jean-Franc¸ois Griffon, John A. Montgomery,
and John A. Secrist III∗
Southern Research Institute, P.O. Box 55305,
Birmingham, Alabama 35255-5305
ABSTRACT
A suitably protected 4-C-hydroxymethyl-arabino-pentofuranose was prepared
and condensed with the following nucleobases: uracil, 5-fluorouracil and
thymine. The corresponding cytosine and 5-fluorocytosine derivatives have
also been obtained respectively from the uracil and 5-fluorouracil nucleosides.
Separation of the anomeric mixtures followed by deprotection afforded the
target compounds that were found to be non-cytotoxic to CCRF-CEM leukemia
cells.
In the search for new antineoplastic or antiviral agents, recent interest has been
focused on 4ꢀα-C-branched-chain sugar nucleosides: various 4ꢀα-C-branched-chain
2ꢀ-deoxynucleosides, such as 4ꢀα-C-methyl- (1–5), -fluoromethyl- (6), -cyano-
(1,7) -ethynyl- (1,3,8) and -ethenyl (1) -2ꢀ-deoxycytidine have been reported to have
potent antileukemic activity in vitro. Two 4ꢀα-C-branched arabino-pentofuranonu-
cleosides, 1-(4α-C-methyl- (4,5) and -fluoromethyl (1) -β-D-arabino-pentofura-
nosyl)cytosine have also exhibited a significant cytotoxic effect on leukemia cells.
Nevertheless, very few 4ꢀ-C-hydroxymethyl have been reported in the literature
and the authors have limited their work to the synthesis of β-D-xylo-, ribo- and
-2ꢀ-deoxyribo nucleosides (9,10). 4ꢀ-C-hydroxymethyl analogues of AZT, d4T, and
∗Corresponding author.
649
ꢁ
C
Copyright 2001 by Marcel Dekker, Inc.
www.dekker.com

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GRIFFON, MONTGOMERY, AND SECRIST
ddT have also been reported (7,12). Based on these considerations, a series of 4ꢀ-
C-hydroxymethyl-α- and -β-D-arabino-pentofuranosyl pyrimidine nucleosides has
been prepared and evaluated as potential anticancer agents.
CHEMISTRY
The suitably protected 4-C-hydroxymethyl-arabino-pentofuranose 8 was pre-
pared in 13 steps from L-xylose (Scheme 1). Selective benzoylation of the primary
hydroxyl group of the 1,2-O-isopropylidene intermediate 1, followed by silylation
of the 3-hydroxyl group, and debenzoylation gave 3. Oxidation of the 5 position of 3
under Pfitzner-Moffatt conditions afforded a 5-aldehydo pentofuranose intermedi-
ate which was subsequently subjected to an aldol condensation-crossed Cannizzaro
reaction sequence in the presence of formaldehyde in aqueous sodium hydroxyde
(10,12). The introduction of the C-4 linked hydroxymethyl in basic conditions also
resulted in the deprotection of the 3-O-t-butyldimethylsilyl group (1), but without
any epimerisation at the C-3 (13). The 3,5 and 6-hydroxyl groups of 4 were then
benzylated to afford 5. Cleavage of the 1,2-O-isopropylidene group followed by
methylation of the anomeric hydroxyl led to the methyl glycoside 6. The 2-hydroxyl
group of 6 was benzylated to give the tetrabenzylated derivative 7. Compound 8
was finally obtained after hydrolysis of the methyl glycoside 7 and acetylation of
the anomeric hydroxyl.
Condensation of 8 respectively with silylated uracil, thymine or 5-fluorouracil
afforded the fully corresponding benzylated nucleosides as α:β mixtures, separable
by silica gel chromatography. Conversion of 9α, β and 11α, β into the corres-
ponding cytosine and 5-fluorocytosine nucleosides 15α, β and 16α, β was carried
Scheme 1.

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4ꢀ-C-HYDROXYMETHYL PYRIMIDINE NUCLEOSIDES
651
Scheme 2.
out via a treatment with Lawesson’s reagent, which led to the 4-thioamide deriva-
tives, followed by a treatment with methanolic ammonia at 100◦C. Finally, benzyl
ether protective goups were cleaved by catalytic hydrogenation or treatment with a
boron trichloride solution to afford the target compounds 12–14α, 12β–14β and
17–18α, 17–18β (Scheme 2).
BIOLOGICAL EVALUATIONS
All the 4ꢀ-C-hydroxymethyl-arabino-pentofuranosyl pyrimidine nucleosides
12α, 13α, 14α, 17α, 18α and 12β, 13β, 14β, 17β, 18β were found to be non-
cytotoxic to CCRF-CEM leukemia cell at the highest level tested (40 µg/ml).
ACKNOWLEDGMENT
The investigation was supported by the National Cancer Institute, National
Institutes of Health (PO1-CA34200).

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GRIFFON, MONTGOMERY, AND SECRIST
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