Chemistry Reference
In-Depth Information
Gangliotriaosylceramide (Gg3; expressed on mouse lung ECs, see Table 10.3 for
structure) is a strong ligand of GM3, and Gg3 trisaccharide- carrying polystyrene
adsorbs onto a GM3 monolayer strongly and specifi cally with an apparent affi nity
constant of
K
a
= 2.5
1 0
6
M
− 1
[13] . The GM3 - Gg3 heterotypic interaction may
account for B16 metastasis to lung, and liposomes containing Gg3 or GM3 inhibit
this metastasis [9, 10]. Furthermore, adhesion of melanoma cells through GM3-
Gg3 interaction enhanced tyrosine phosphorylation by c-Src (cellular Src from the
Src family of tyrosine kinases) and focal adhesion kinase (FAK), and enhanced
GTP binding to RhoA and Ras (GTPase proteins). Increased motility of melanoma
cells mediated by GM3-dependent adhesion to ECs has been regarded as the initial
step in melanoma cell metastasis, where up-regulation of c-Src, RhoA, Ras and
FAK may provide a pathophysiological foundation for this initial step in the meta-
static process.
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21.3
Carbohydrates as DNA - Binding Motifs
A very important aspect of carbohydrate recognition, although much less studied
than the examples described above, is the interaction between carbohydrates and
DNA. DNA-binding drugs that contain carbohydrates have been known for over
50 years, but the role of the carbohydrate portion of these drugs has been unclear
for a long time. The fi rst studies on the importance of the carbohydrate moiety
for the biological activity of DNA binders were carried out with the family of
anthracycline antibiotics [14, 15]. The number and the substitution pattern of
carbohydrate chains have a profound effect on biological activity, and removal
of the sugar side-chain results in inactivation of the antibiotic. Structural studies
by X-ray crystallography and nuclear magnetic resonance have revealed that
the carbohydrate makes van der Waals contacts with the minor groove of the
DNA.
There is enough evidence to support the importance of the saccharide moiety
of anthracyclines for their interaction with DNA, but this is not as clear for other
DNA-binding drugs that contain carbohydrates. However, the discovery of the
enediyne antitumor antibiotic calicheamicin opened a new view on the carbohy-
drates as DNA binders [16]. Calicheamicin binds to DNA in a sequence- selective
manner and causes site-specifi c double-stranded cleavage. The major DNA contact
surface of the antibiotic is an aryltetrasaccharide moiety that interacts with the
minor groove of the DNA duplex. Derivatives lacking two or more carbohydrate
units exhibit less effi cient and nonselective cleavage, indicating that the oligosac-
charide portion of calicheamicin is the principal DNA-binding element and is
largely responsible for the oligopyrimidine selectivity. The preferred target
sequences are TCCT, TCTC and TTTT, and the carbohydrate tail of the antibiotic
is oriented toward the 3
-end of the tetranucleotide surface [17]. The aryltetrasac-
charide segment binds to the DNA minor groove in an induced- fi t mechanism,
′
