Porphyrin-based design of bioinspired multitarget quadruplex ligands

Article abstract of DOI:10.1002/cmdc.201300526

Secondary nucleic acid structures, such as DNA and RNA quadruplexes, are potential targets for cancer therapies. Ligands that interact with these targets could thus find application as anticancer agents. Synthetic G-quartets have recently found numerous applications, including use as bioinspired G-quadruplex ligands. Herein, the design, synthesis and preliminary biophysical evaluation of a new prototype multitarget G-quadruplex ligand, ^PNAPorphySQ, are reported, where peptidic nucleic acid guanine (^PNAG) was incorporated in the porphyrin-templated synthetic G-quartet (PorphySQ). Using fluorescence resonance energy transfer (FRET)-melting experiments, PorphySQ was shown to possess enhanced quadruplex-interacting properties thanks to the presence of four positively charged ^PNAG residues that improve its electrostatic interactions with the binding site of both DNA and RNA quadruplexes (i.e., their negatively charged and accessible G-quartets), thereby making ^PNAPorphySQ an interesting prototype of a multitarget ligand. Both the chemical stability and water solubility of ^PNAPorphySQ are improved over the non-PNA derivative (PorphySQ), which are desirable properties for drug development, and while improvements remain to be made, this ligand is a promising lead for the further development of multitarget G-quadruplex ligands.

Full text of DOI:10.1002/cmdc.201300526

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DOI: 10.1002/cmdc.201300526
Porphyrin-Based Design of Bioinspired Multitarget
Quadruplex Ligands
Aurꢀlien Laguerre, Nicolas Desbois, Loic Stefan, Philippe Richard, Claude P. Gros,* and
[a]
David Monchaud*
Secondary nucleic acid structures, such as DNA and RNA quad-
ruplexes, are potential targets for cancer therapies. Ligands
that interact with these targets could thus find application as
anticancer agents. Synthetic G-quartets have recently found
numerous applications, including use as bioinspired G-quadru-
plex ligands. Herein, the design, synthesis and preliminary bio-
physical evaluation of a new prototype multitarget G-quadru-
nature of their secondary structures. The therapeutic validity of
this approach is not firmly established yet, but it has been very
elegantly summarized by Stephen Neidle when he recently
stated that “a quadruplex-focused poly-targeting approach may
be especially useful for those genetically highly aberrant solid
cancers where multiple oncogene pathways may be disregulat-
[6]
ed”. Our recent reports on the use of synthetic G-quartets
PNA
[7]
plex ligand, PorphySQ, are reported, where peptidic nucleic
(SQ, also named TASQ) as bioinspired G-quadruplex ligands
PNA
[8–10]
acid guanine ( G) was incorporated in the porphyrin-templat-
have a particular resonance in this context:
our strategy ex-
ed synthetic G-quartet (PorphySQ). Using fluorescence reso-
nance energy transfer (FRET)-melting experiments, PorphySQ
ploits the nature-inspired self-association of G-quartets that is
responsible for the elevated G-quadruplex stability; thus, SQ
interact with quadruplexes lying atop their accessible G-quar-
tet, making them able to bind to virtually any quadruplex
structure since G-quartets are the major and ubiquitous struc-
tural component of quadruplexes. However, our first proto-
types of bioinspired ligands, namely DOTA-templated synthetic
G-quartet (DOTASQ), where DOTA is 1,4,7,10-tetraazacyclodo-
was shown to possess enhanced quadruplex-interacting prop-
PNA
erties thanks to the presence of four positively charged
G
residues that improve its electrostatic interactions with the
binding site of both DNA and RNA quadruplexes (i.e., their
negatively charged and accessible G-quartets), thereby making
PNA
PorphySQ an interesting prototype of a multitarget ligand.
PNA
[8]
Both the chemical stability and water solubility of PorphySQ
decane-N,N’,N’’,N’’’-tetraacetic acid, and porphyrin-templated
[9]
are improved over the non-PNA derivative (PorphySQ), which
are desirable properties for drug development, and while
improvements remain to be made, this ligand is a promising
lead for the further development of multitarget G-quadruplex
ligands.
synthetic G-quartet (PorphySQ) (Scheme 1), were rather per-
fectible: the former for its overall low quadruplex-affinity, the
latter for its quite limited water-solubility. A way to circumvent
both of these problems concomitantly was recently reported
in the DOTASQ series with the introduction of guanine resi-
dues with amine pendant arms (known as peptidic nucleic
PNA
acid guanine,
G) versus neutral guanines for the parent
PNA
Alternative secondary nucleic acid structures, notably DNA and
series. The resulting compound, named
DOTASQ
[
1]
[10]
RNA quadruplexes, are currently a major thrust of targeted
(Scheme 1), displayed improved water solubility, thanks to
the in situ protonation of its amine side chains, and quadru-
plex affinity, thanks to the strong interaction that takes place
between the wreath of positive charges around the SQ and
that of the phosphate negative charges around the native
G-quartet. Herein, we expand the family of bioinspired G-quad-
ruplex ligands, reporting the design, synthesis and preliminary
[
2]
cancer therapies. The recent and unambiguous demonstra-
[
3]
tions of the existence of G-quadruplex DNA in cells is giving
much impetus to the quest of valuable (i.e., efficient and selec-
[
4]
tive) G-quadruplex ligands. However, this enthusiasm is
somewhat offset by the discovery of more and more quadru-
plex-forming sequences in the human genome (belonging to
[
5]
PNA
the so-called “G4 genome”), making the structure-based ra-
tional design of ligands selective for a given subclass of quad-
biophysical evaluation of PorphySQ.
PNA
The design of both PorphySQ and PorphySQ relies on the
[
4]
ruplexes rather challenging. An alternative approach is to
design compounds that interact with quadruplexes whatever
the sequences they fold from, that is to say, whatever the
use of a porphyrin template to intramolecularly assemble the
SQ; the logic behind using a porphyrin platform was fourfold:
1) to promote the formation of a stable SQ through intramo-
lecular SQ/template p-stacking interactions (porphyrins are
[4,11]
known to be efficient quartet interacting compounds);
[
a] A. Laguerre, Dr. N. Desbois, L. Stefan, Dr. P. Richard, Prof. C. P. Gros,
2
) to uncover a novel way for porphyrins to interact with quad-
Dr. D. Monchaud
[12]
Institut de Chimie Molꢀculaire
Universitꢀ de Bourgogne (ICMUB)
CNRS UMR6302, Dijon (France)
E-mail: claude.gros@u-bourgogne.fr
david.monchaud@u-bourgogne.fr
ruplexes (they are indeed known to bind to quadruplexes
[13]
according numerous modes, including quartet
and loop
[14]
[15]
stacking, along with intercalation within or between quad-
[16]
ruplex units and also a more unusual disruptive mode in
[17]
which porphyrins unfold quadruplexes);
3) to exploit this
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cmdc.201300526.
quite unique SQ-mediated quadruplex interaction to make
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bromobutyronitrile (1 and 2) or 7-bromoheptanenitrile (3): the
reduction of the nitrile groups by using diisobutylaluminum
hydride (DIBAL-H) followed by an acidic treatment, provides
the corresponding aldehydes (95% yield) that are subsequent-
ly converted into tetrabromo-porphyrins via a quadruple Lewis
acid-catalyzed condensation on pyrrole, followed by an oxida-
tion using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)
(
16–19% yield). These compounds were subsequently convert-
ed into the corresponding tetraazido-porphyrins (1–3) via the
substitution of the bromines by either sodium azide (for 1 and
3
, 95–97% yield) or sodium 2-azidoethoxide (for 2, 67% yield).
Two of these three key intermediates (namely 1 and 2) provid-
ed crystals that were suitable for X-ray analysis (CCDC-977461
and 977462, respectively; Scheme 2 and the Supporting Infor-
mation), thereby unambiguously confirming their structures.
The reduction of the appended azido moieties of porphyrins
1
–3 was carried out with lithium aluminum hydride (LiAlH4),
and the corresponding tetraamino-porphyrin were not isolated
but directly engaged in hydroxybenzotriazole (HOBt)/1-ethyl-3-
(
3-dimethylaminopropyl)carbodiimide (EDCI)-promoted cou-
pling reactions with tert-butyloxycarbonyl (Boc)- protected
PNA
(
G)-OH, according to a previously reported methodology
[10]
(
Scheme 3). Unexpectedly, two of the three resulting por-
phyrins (4 and 5) were found chemically unstable (see the Sup-
porting Information). This instability was rather surprising, par-
[20]
ticularly in view of the literature precedents. However, these
inspiring examples differ from our systems in that the molecu-
lar links between the porphyrin and the guanine moieties are
more rigid than that of compounds 4 and 5. This may be im-
portant, notably in light of the known ability of polycationic
porphyrins to produce efficient photoinduced electron transfer
(
PET) reactions, including photocleavage (with DNA) and pho-
[21]
todamages (with nucleases, chiefly guanine). Indeed, given
that the molecular porphyrin/guanine links of 4 and 5 are
shorter (the former) and more flexible (the latter) than that of
6
, they might enable the guanines to come closer to the por-
phyrin ring, thereby promoting their own photodecomposi-
tion. The long and fully aliphatic (i.e., rigid) hexyl side chains of
PNA
Scheme 1. Chemical structures of DOTASQ, DOTASQ, PorphySQ and
[9]
compound 6 (and also of PorphySQ) thus prevent to some
extent this unwanted intramolecular photosensitization; as
PNA
PorphySQ, and schematic representation of the conformational plurality
of PorphySQ (in its open and closed conformation).
PNA
such, only compound 6 was engaged in the last step, that is
to say, an acidic treatment that removes the Boc protection,
PNA
porphyrins selective ligands (porphyrins, notably the emblem-
atic TMPyP4, are known to interact strongly with DNA whatev-
which leads to a final compound.
PorphySQ was thus ob-
tained in three steps from porphyrin 3 in a good chemical
yield (38% over three steps) and purity (Scheme 3 and the
Supporting Information).
[
18]
er its secondary structure); and 4) to lend further credence
to the use of structurally tuned porphyrins in the general con-
[
19]
PNA
PNA
text of anticancer strategies. The synthesis of PorphySQ is
Interestingly, PorphySQ differs from PorphySQ only by the
[9]
PNA
directly inspired by that of the parent molecule PorphySQ;
nature of its guanine residues ( G vs neutral purine), thereby
however, it turned out to be rather challenging (poor practical
convenience and reproducibility) so we decided to completely
reinvestigate the synthetic pathway (see the Supporting Infor-
mation), notably expanding the diversity of the porphyrinic
platform. The key intermediates of these syntheses are tetraazi-
do-porphyrins 1–3 (Scheme 2), differing by the length and
nature of the azido side chains (3-azidopropyl, 3-(2-azidoethox-
y)propyl and 6-azidohexyl for 1, 2 and 3, respectively). Their
synthesis was straightforward from commercially available 4-
enabling a direct visualization of the influence of the guanine
residues on the quadruplex-interacting properties. They were
assessed through fluorescence resonance energy transfer
[22]
(FRET)-melting experiments. This assay enables the evalua-
tion of the apparent quadruplex affinity of a candidate via the
temperature-induced modification of the FRET phenomenon
that takes place between two FRET partners—here, 6-fluores-
cein amidite (FAM or F) and carboxytetramethylrhodamine
(TAMRA or T)—present at both extremities of the studied oli-
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Scheme 2. Chemical synthesis of tetraazido-porphyrins 1–3.
PNA
Scheme 3. Chemical synthesis of PorphySQ.
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gonucleotides. The stabilizing property of a candidate
is expressed as an increase in melting temperature
(
DT ) imparted by the presence of the ligand.
1/2
Herein, four different doubly labelled oligonucleo-
tides were used, encompassing the three currently
studied relevant quadruplex families (two quadru-
plex-forming DNA sequences, found either at the te-
[
23]
lomeric level
or in promoter regions of onco-
[
24]
genes,
and one quadruplex-forming RNA se-
[
25]
quence) and a duplex-DNA used as control. The se-
quences were FAM-d[G (T AG ) ]-TAMRA (F21T), a 21-
3
2
3 3
nt sequence that mimics the human telomere, FAM-
d[CG CG CGCGAG AG ]-TAMRA (F-kit-T), a 21-nt se-
3
3
3
4
quence found in the promoter region of c-kit onco-
gene, FAM-r[G (U AG ) ]-TAMRA (F-TERRA-T), a 21-nt
3
2
3 3
RNA sequence that results from the transcription
of the telomeric DNA, and FAM-d[(TA) GC(TA) T (TA) -
2
2
6
2
GC(TA) ]-TAMRA (F-duplex-T), a 26-nt hairpin se-
2
quence. As depicted in Figure 1a, we firstly assessed
the difference of F21T stabilization of both PorphySQ
PNA
and
PorphySQ in the previously reported condi-
tions (i.e., in large excess of ligand as compared with
[
9]
DNA, 5.0 vs 0.2 mm, respectively). While only a fair
stabilization was observed with PorphySQ (DT1
=
/2
PNA
6.58C),
PorphySQ exhibits excellent quadruplex-
stabilizing properties (DT1/2 =23.68C), thereby firmly
supporting the validity of our approach. We thus de-
cided to further investigate its properties, notably via
its interaction with another quadruplex-DNA (F-kit-T),
a quadruplex-RNA (F-TERRA-T) and a duplex-DNA (F-
duplex-T) in classical conditions (i.e., at 1.0 mm dose).
PNA
As expected,
PorphySQ interacts almost equally
with quadruplexes whatever their nature (DT1/2 =7.1,
.4 and 5.58C for F21T, F-kit-T and F-TERRA-T, respec-
tively; Figure 1b) and is found enticingly to be quad-
Figure 1. a) FRET-melting curves: normalized FAM fluorescence (FFAM) plotted against
temperature for experiments carried out with F21T (ꢂ) at 0.2 mm, and PorphySQ (~) or
PorphySQ (*) at 5.0 mm, in cacodylate buffer (10 mm, pH 7.2) supplemented with
7
PNA
ruplex-over-duplex selective (it does not interact with
10 mm KCl and 90 mm LiCl. b) FRET-melting results of experiments carried out with la-
PNA
F-duplex-T). PorphySQ is thus a very interesting ex- belled oligonucleotides (0.2 mm): duplex-DNA (F-duplex-T), quadruplex-DNA (F21T and F-
PNA
PNA
Kit-T) or quadruplex-RNA (F-TERRA-T), and PorphySQ (&), PorphySQ (&) or DOTASQ
ample (fair affinity but high selectivity) of multitarget
quadruplex ligands. However, a rapid glimpse at the
(
&) at 1.0 mm dose, in cacodylate buffer (10 mm, pH 7.2) supplemented with 10 mm KCl
and 90 mm LiCl (F-duplex-T and F21T) or 1 mm KCl and 99 mm LiCl (F-kit-T and F-TERRA-
T). Not determined (n.d.), fivefold mathematical enhancement of the F21T stabilization
PNA
results obtained with DOTASQ in similar conditions
(
Figure 1b) clearly highlights the superiority of the (ꢂ5).
DOTA template over the porphyrin one (DT1/2 =12.5,
5.2 and 17.58C for F21T, F-kit-T and F-TERRA-T, respectively).
[10]
1
version of an SQ-based bioinspired quadruplex ligand recently
reported (PorphySQ). The structural modifications responsible
for the better performances of this new prototype is the re-
placement of the neutral purines of PorphySQ by the cationic
Additionally, both the water solubility and chemical stability of
PNA
PorphySQ, even if far better than that of PorphySQ, are still
not high enough to ensure not only further biophysical investi-
gations but also a decent bioavailability. This explains why we
have decided to focus all our ongoing efforts on the quest of
a template that would be even more efficient than the DOTA
ring.
PNA
G moieties, which results in an intramolecular SQ surround-
ed by positive charges (upon protonation of the pendant
amino side chain of this modified guanine). This wreath of pre-
cisely located cationic charges makes the SQ firmly interact
with the native G-quartets (i.e., the ligand binding site of the
quadruplex) thanks to the concomitant self-recognition of
G-quartets and strong electrostatic interactions (the native
G-quartets being surrounded by phosphate groups). SQ-based
G-quadruplex ligands can thus interact with virtually any quad-
ruplex, DNA and/or RNA, making them valuable multitarget
quadruplex ligands, and the preliminary results reported indi-
In conclusion, it is now agreed that synthetic G-quartets (SQ)
are valuable tools for the developments of many interesting
[
26]
applications, including the nature-inspired G-quadruplex rec-
ognition described herein. This capability originates in the
“
like-likes-like” self-assembly of two G-quartets, one synthetic
(
the ligand), the other native (the quadruplex target). The por-
PNA
phyrin derivative reported herein, PorphySQ, is an improved
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PNA
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Keywords: biomimetic ligands
quadruplexes · quadruplex ligands · synthetic G-quartets
·
guanine
·
porphyrins
·
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Received: December 13, 2013
Published online on && &&, 0000
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A. Laguerre, N. Desbois, L. Stefan,
P. Richard, C. P. Gros,* D. Monchaud*
&& – &&
Porphyrin-Based Design of Bioinspired
Multitarget Quadruplex Ligands
A template for targeting cancer: A
novel porphyrin-templated synthetic
G-quartet with peptidic nucleic acid
hanced DNA/RNA quadruplex-interact-
ing properties, both in terms of affinity
and selectivity, as compared with the
analogous non-PNA series.
PNA
side chains ( PorphySQ) displays en-
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These are not the final page numbers!