Combinatorial synthesis of galactosyl-1,3,5-triazines as novel nucleoside analogues

Article abstract of DOI:10.1039/c1ob05733b

Herein we report a parallel solid-phase synthesis of 1,3,5-triazine based nucleoside analogues by a three-step substitution, starting from 2,4,6-trichloro-1,3,5-triazine. A library of 80 galactosyl-1,3,5-triazine compounds was prepared in high purity with

Full text of DOI:10.1039/c1ob05733b

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Organic &
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COMMUNICATION
Combinatorial synthesis of galactosyl-1,3,5-triazines as novel nucleoside
analogues†‡
Shenliang Wang,c Woo Sirl Lee,a Hyung-Ho Haa,d and Young-Tae Chang*a,b
Received 10th May 2011, Accepted 26th July 2011
DOI: 10.1039/c1ob05733b
Herein we report a parallel solid-phase synthesis of 1,3,5-
triazine based nucleoside analogues by a three-step substi-
tution, starting from 2,4,6-trichloro-1,3,5-triazine. A library
of 80 galactosyl-1,3,5-triazine compounds was prepared in
high purity without extensive reaction conditions or tedious
purification, suggesting the generality of this method.
commonly used as herbicides or pesticides.3 The introduction of
a carbohydrate moiety shows considerable promise in enhancing
the properties of the derivatives. Carbohydrates increase water
solubility and display a high density of functional groups for
recognition, thus improving targeting and minimising toxicity.4
To date, only a few examples of carbohydrate derivatized triazines
have been reported.5 In the monosaccharide family, galactose is
present in a number of natural and synthetic compound structures
and demonstrates unique biological properties.6 The upregulation
of galactosidase activity in breast and colon tumors suggests that
galactose might be a good choice for a selective ligand in drug
design.7 A combination of galactose and triazine moiety might
lead to nucleotide analogues with improved oral absorption and
tissue targeting. In this article, we report an efficient solid-phase
methodology for the preparation of 1,3,5-triazine galactose-based
nucleoside analogue compounds.
1,3,5-Triazine has proven to be a promising “druggable” scaffold in
a number of studies, and compounds bearing this scaffold exhibit
activities in diverse biological applications.1 The high biological
activity might be due to the structural similarity of the nitrogen and
carbon fused aromatic ring to natural components in organisms,
such as the bases in nucleosides and nucleotides (Fig. 1).
First the 1,3,5-triazine scaffold was linked onto
a
diisopropylidene-protected galactopyranose in solution phase
(Scheme 1). The reaction was carried out with an unusual
combination of base and solvent, namely NaOH in benzene,
affording a high yield of the mono-substituted triazine (95%).
Meanwhile, one dimension of diversity was introduced by
parallel loading eight amines (Table 1, entry A–H) onto aldehyde
functionalized PAL-polystyrene (PAL-PS) resin via reductive
Fig. 1 Structures of pyrimidine, the nucleoside pyrimidines and triazine.
During the last decade, our group and others have reported a
number of synthetic approaches for the rapid synthesis of 1,3,5-
triazine derivatives from cyanuric chloride.1a,b,2 It has been shown
that the three addressable positions, although they appear the
same in a three-fold rotational symmetry, have different reactivities
toward substitution, which could be controlled by sequential
elevation of the reaction temperatures. Thus these positions in
the triple branching scaffold could be leveraged to generate a
large structural diversity. The broad biological activity and ease of
synthesis make triazine an ideal combinatorial library scaffold.
However, on the other side of the high bioactivity of this
scaffold is its high cell toxicity. Some triazine compounds are
aDepartment of Chemistry & MedChem Program of Life Sciences Institute,
National University of Singapore, 117543 Singapore. E-mail: chmcyt@
nus.edu.sg; Fax: +65 6779 1691; Tel: +65 6516 6774
bLaboratory of Bioimaging Probe Development, Singapore Bioimaging
Consortium, Agency for Science, Technology and Research (A*STAR),
11Biopolis Way, #02-02 Helios Building, 138667 Singapore
cDepartment of Chemistry, Stanford University, California 94305, USA
dCollege of Pharmacy, Sunchon National University, Suncheon, Korea
† Electronic supplementary information (ESI) available: Experimental
details and LC-MS data of the products. See DOI: 10.1039/c1ob05733b
‡ This work was supported by A*STAR SSCC Grant (SSCC10/024).
Scheme 1 Solid-phase synthesis of a galactosyl-1,3,5-triazine library.
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Table 1 Properties of amine building blocks
Entry
A
Structure
M. W.
75.11
57.09
H-bond Donors
H-bond Acceptors
Rings
log P8
-1.12
0.07
2
1
1
0
0
1
B
C
99.17
1
2
0
1
1
1
1.49
D
115.17
-0.06
E
F
101.15
59.11
1
1
0
0
1
0
-4.15
0.09
G
H
129.24
137.18
1
1
0
0
0
1
2.90
0.84
1
125.17
1
1
1
-0.64
2
3
151.16
125.14
1
1
0
0
2
1
0.59
1.24
4
5
87.12
1
1
0
0
1
2
-0.86
133.19
1.57
6
7
207.23
165.28
1
1
2
0
2
3
1.01
2.19
8
9
85.15
1
1
0
1
1
1
0.84
0.08
122.17
10
111.18
1
0
2
1.19
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amination. The galactosyl triazine was attached onto the R1-amine
functionalized resin under mild heating. The other dimension
of diversity was introduced by parallel substitution of the third
chloride on the triazine scaffold. Each R1-amine-triazine resin was
divided into ten equal portions and reacted with ten amines (Table
1, entry 1–10) under elevated temperature. The final products
were cleaved from the solid support by mild acidic conditions.
In total, 80 compounds were prepared by this orthogonal solid-
phase synthesis.
This method is suitable for the rapid preparation of large
collections of 1,3,5-triazine-based nucleoside analogues without
extensive reaction conditions or steps or tedious purification, and
is not only limited to galactose. The current set of compound
will be tested in cell-based biological activity assays, as well as in
a Caco-2 cell-based transportation study.10 This method is being
applied to other carbohydrate building blocks and a larger 1,3,5-
triazine nucleoside library is in preparation.
The amine building blocks were carefully chosen from common
pharmacophore fragments based on Lipinski’s rule-of-five.9 Since
the molecular weight of galactosyl triazine is around 260 Da,
the combined molecular weight of the corresponding R1 and R2
amines was controlled around 240 Da. As there are already three
hydrogen bonding receptors on triazine scaffold, the number of
hydrogen bonding receptors on amine substituents was limited.
The number of additional hydrogen bonding donors in the
substituents was limited by the 2 donors already present on the
scaffold. The building blocks represent a broad range of structural
diversity, from acyclic to cyclic and polycyclic, and from aliphatic
to aromatic. Furthermore, it was ensured that the building blocks
had only one reactive amine group in each structure to confirm
the identity of the products.
The cleavage of final product from the resin was carried out
by 10% TFA in dichloromethane for only 5 min to ensure the
isopropylidene protecting groups were left intact. Removal of these
protecting groups will expose 4 free hydroxy groups, significantly
decrease the log P and might lower the cellular uptake. On the
other hand, the removal of acid-labile isopropylidene group might
be accomplished in the cytosol, especially in lysozome. Thus, we
decided to keep the current “prodrug-” like protected form.
While it is generally difficult to prepare nucleoside analogues
with high purity before purification, compounds prepared using
this method exhibited purities ranging from 75 to 99%, with
an average of 92%. Thus, they could be used in the biological
screenings directly without further purification. It is also worth
noting that the high purity of the final products justifies that the
triazinyl ether bond between galactose and triazine is stable under
harsh basic conditions.
Notes and references
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In conclusion, herein we report a methodology for the combina-
torial solid phase synthesis of 1,3,5-triazine nucleoside analogues.
6926 | Org. Biomol. Chem., 2011, 9, 6924–6926
This journal is
The Royal Society of Chemistry 2011
©