Chemistry Reference
In-Depth Information
12.5.1 Anticancer and Anti-Inflammatory Activities
Cancer is a major public health burden worldwide. A large number of anticancer
agents including taxol, vinblastine, vincristine, camptothecin derivatives, opotecan
and irinotecan, and etoposide derived from epipodophyllotoxin are in clinical use
all over the world. While several promising agents such as flavopiridol, roscovitine,
combretastatin A-4, betulinic acid, and silvestrol are in clinical or preclinical develop-
ment. But increasing occurrence of cancer cases has triggered the search for efficient
anticancer agents for the prevention and cure of the disease.
Cell-surface of cancerous cells is abundant in oligosaccharide antigens, which
could act as markers for active or passive cancer. It has been observed that glycosyl
mimetics of glycosylated sugar residing over cancerous cells can serve as an effec-
tive antigen to evoke antitumor immune response in body, when conjugated with
some large biomolecules. Therefore, Danishefsky group synthesized the potent anti-
cancer vaccine in which antigenic oligosaccharides were linked to keyhole limpet
hemocyanin (KLH) polypeptide carriers by means of triazole moiety (
3
) (Fig. 12.3)
[38].
Carvalho et al. prepared a library of 1,4-disubstituted 1,2,3-triazole galactose
derivatives using Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition reaction.
The compounds demonstrated significant inhibition of
Trypanosoma cruzi trans
-
sialidase (TcTS) enzyme that plays a key role in recognition and invasion of host
cells and enables the parasite to escape from human immune response. In TcTS assay,
the compound (
4
) demonstrated maximum inhibition (37%), while other synthesized
sugar-triazoles displayed moderate to weak activity ranging between 0.5 mM and 1
mM. The
in vitro
assay against trypomastigotes of
T. cruzi
Y strain using benzimi-
dazole as a reference drug, the compound (
5
) demonstrated most powerful inhibition
with optimum activity in 100s of
m range [14].
-GalCer is the most potent agonistic antigen of the T cell receptor of nat-
ural killer T cells. Lee and coworkers have synthesized a series of 1,2,3-triazole-
containing
The
-GalCer analogs (
6
) by varying the length of lipid chain attached. It
has been observed that replacement of amide group with isosteric triazole enhances
theIL-4versusIFN-
bias of released cytokines. Also, the analogs carrying long-
chained triazoles exhibited stimulatory effect on cytokine production comparable to
-GalCer and showed a stronger Th2 cytokine response [39]. Likewise, Slamova
et al. have reported the synthesis
-2-acetamido-2-deoxygluco GlcNAc-triazole (
7
)
by click reaction under microwave condition, which was found to be hydrolyzed
by
Talaromyces flavus
CCF 2686
-
N
-acetylhexosaminidase and was furthermore
established to act as a strong ligand of rat and human natural killer cell activating
receptors (Fig. 12.4) [40].
In another effort, 1,2,3-triazole moiety was linked with biologically active 1,2,4-
oxadiazole heterocycles at one end and glucopyranosyl function at another end. Using
Cu(I)-catalyzed click reaction between 2,3,4,6-tetra-O-acetyl-
-D-glucopyranosyl
azide and propynyl 3-[3-aryl)-1,2,4-oxadiazol-5-yl] propionates, dos Anjos et al.
prepared a library of glycosyl-triazole linked 1,2,4-oxadiazole (
8
). The whole
library showed weak cytotoxic activity and demonstrated 22-25% cell-growth
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