Chemistry Reference
In-Depth Information
Figure 7.5
Chemical formulae of G-quadruplex ligands that inhibit cell proliferation in a way
independent of telomerase elongation
for appreciation of
in vitro
telomerase inhibition, TRAP (telomeric repeat amplifi -
cation protocol) has been revaluated. The results indicate that the inhibitory effect
of many G-quadruplex binders on telomerase elongation has been overestimated
because these molecules were shown to be good inhibitors of the PCR step used
for the amplifi cation protocol.
84
Moreover, some of these G-quadruplex binders
(telomestatin, RHPS4, BRACO 19) (Figure 7.5) have been shown to inhibit cell
proliferation in a way independent of telomerase elongation.
85 - 90
It has been sug-
gested that they stabilize the multiple G-quadruplex structures that can be formed
transiently along telomeric DNA,
91,92
thus altering the recognition of the telomeric
sequences by proteins from the shelterin (TRF2 and POT1)
85 - 89
or that they can
inhibit telomere replication.
93
The resulting increase in genomic instability has been
found to depend on the type of cancerous cells.
33,90
This selective toxicity for cancer
cells can be explained by the fact that telomeres from normal and cancer cells
exhibit differences in structure, stability and accessibility.
94
There is therefore a growing interest in considering G-quadruplexes as poten-
tial targets for new antitumour drugs.
64,65,91 - 93,95,96
The past few years have seen con-
siderable development in design and synthesis of novel and effi cient G - quadruplex
binders.
97
At present, the most effi cient one is telomestatin.
85 - 88,98 - 100
In general, an
effective G-quadruplex binder is planar and, in most of cases, positively charged.
On the basis of the very few structural data of G-quadruplex binders available
nowadays, it has been proposed that the interaction occurs via
- stacking and elec-
trostatic interactions.
101 - 106
Design of new binders that are easily synthesized is still
a challenge.
A promising recent approach relies on the use of metallo-organic complexes,
based on the assumption that the central metal could be positioned over the cation
channel of the quadruplex, thereby optimizing the stacking interactions with the
π
