Transcript Document

Molecular Design and Synthesis – Organic Synthesis
Research Topics
General remarks
These are the research topics of the group. It is possible to
make a thesis in the framework of each of these topics.
Synthesis of cyclic and acyclic oligopyrroles
The synthesis and properties of cyclic (porphyrins, corroles, ...)
and acyclic oligopyrroles (dipyrromethanes, dipyrromethenes,
...) are investigated. Dendrimer porphyrin derivatives are
prepared, for instance by nucleophilic aromatic substitution
reactions of Suzuki reactions. The applications of these systems
as sensors for anions and neutral molecules are studied.
Drug targeting
One of the main problems in the treatment of malignant cancers
is that the drugs used also attack healthy cells. Some of the very
specific physiological properties of cancer cells are being
exploited in order to make the treatment more selective.
Because the cell metabolism is derailed in these cells, certain
surface receptors are overexpressed. As a consequence, the
cancer medication can be rendered more effective by linking it to
the corresponding ligands for these receptors. Upon binding to
the receptor the drug-ligand conjugate is internalised in sick
cells.
This ‘Trojan Horse’ strategy is currently applied in our lab to the
bioreductive drug Tirapazamine.
This principle is illustrated in the following images where a
fluorescent probe is labeled with a vitamin. The unlabeled probe
is hardly taken up by the cancer cells while the labeled system
within one minute is visible inside the cell. This also shows that
this approach can be applied to visualisation of the sick cells.
Synthesis of dendrimers
Dendrimers and dendrons are prepared using a convergent
approach. The dendrons are prepared from heterocyclic
monomers (triazines, pyrimidines, triazoles, carbazoles, ...). The
properties of these dendrimers are studied in collaboration with
other groups.
Synthesis of hyperbranched polymers
Hyperbranched polymers are prepared in a single step in most
cases starting from an AB2 monomer. The synthesis is
straightforward and important parameters are the polydispersity
and the degree of branching. We are particularly interested in
hyperbranched polymers with a degree of branching of 100%.
These can be prepared by the condensation of isatin monomers.
We are currently developing new hyperbranched polymers as
solid supports for solid phase chemistry.
Drug design by NMR screening
A more rational approach towards drug design (in contrast with
the combinatorial library approach) is based on NMR
screening. Using a state of the art NMR spectrometer, a set of
small molecules is tested for weak binding to an enzyme or a
receptor. After this first round of screening, NMR study is used
to detect which compounds bind in each others proximity.
Peptidomimetics
Almost half of the drugs on the market act on GPCRs, which
remain the most attractive target class for pharmaceutical and
many biotech companies; especially peptide GPCRs are
deemed promising drug targets. GPCRs are also promising
targets for the development of new biodegradable, safe, specific
and non-toxic insecticides. Lindane for instance, is an
insecticide that is currently widely used (e.g. in shampoo’s for
lice). Lindane acts through a GABA-A receptor. The problem
with Lindane is that insects have become resistant and that it is
very toxic. The latter can be explained by the fact that the
neurotransmitter GABA has an identical structure in all animals.
However, if we could develop selective insecticides starting from
GPCRs with insect-specific ligands, we would not face toxicity
problems.
In this project we propose to apply a microwave-assisted
combinatorial approach via so called “privileged templates” to
address this problem. We will investigate biaryl-containing
medium-sized ring compounds on their potential as “privileged
structures” for the development of non toxic specific insecticides
starting from newly isolated GPCRs with insect-specific ligands.
Microwave-assisted transition metal-catalyzed reactions as
Stille-, Suzuki- and Heck-reaction as well as Ring Closing
Metathesis (RCM) and Cu(I)-catalyzed Click Chemistry will be
investigated for these purposes.
In a second approach the GPCR-ligand oligopeptide sequence,
which is still showing activity, will be translated into a
conformationally restricted cyclic peptidomimetic.
O
O
OAc
H
R1
X
R4
O
MeO
H
MeO
O
R2
N N
OMe
(-)-Steganacin
X = OR of NRR'
N
Molecular Design and Synthesis – Organic Synthesis
Research Topics
Design of combinatorial libraries using parallel synthesis and
microwave assisted synthesis methods
In the search for new drugs, huge amounts of compounds have
to be screened in order to find one useful lead. Chemical
diversity is one of the keywords in successfull drug design. In
order to achieve this chemicall diversity parallel synthesis is
used.
Using parallel synthesis equipment, the same type of reaction is
repeated with a diverse set of starting materials.
The solid-phase synthesis along with the high-throughput
screening has emerged as a powerful tool for the discovery of
novel drug candidates. The synthesis of combinatorial libraries
based on so-called "priviledged structures" is of particular
interest due to the ability to provide high-affinity ligands for more
than one type of receptors, depending on their substitution
pattern.
The 2(1H)-pyrazinone scaffold can allow the easy introduction of
a wide range of pharmacologically active groups with the ability
to address the diverse set of biological targets. Besides their
broad physiological activities, 2(1H)-pyrazinones can be used as
important building blocks in the synthesis of various heterocyclic
compounds. Diels-Alder reactions of 2(1H)-pyrazinones with
ethylene afford bicyclic products which provide access to various
scaffolds of pharmaceutical interest such as bridged analogues
of piperazine drugs or β-turn mimics. In this project we study the
transfer of some of these reaction pathways to the microwaveenhanced solid-phase chemistry, opening the way for the
generation of many biologically interesting structures. Different
microwave-enhanced transition metal-catalyzed reactions are
investigated.
R
NH2
6
R6
Cl
CHO
N
C
N
Cl
R6
N
O
Cl
N
R3
MW
R6
H
N
O
Cl
N
R3
[Pd]
O
Cl
-
MW
O
N
Cl
O
R
MeO
R6
MeO
Cl
R6
N
O
R6
N
O
R6
H
N
R6
O
N
R
N
R3
H
N
O
O
Diels-Alder
Cl
Cl
N
Cl
N
R3
Cl
N
R3
Cl
N
R3
R6
2-Aminoimidazoles, an interesting class of bioactive compounds
We are focussing on the development of efficient synthetic
approaches for the synthesis of polysubstituted 2aminoimidazoles, the central structural elements of many
marine sponge alkaloids. Many of them exhibit a wide range of
biological activities. The alkaloids, isolated from the marine
sponge Agelas sp., such as keramadine, are found to be the
antagonists on serotonergic receptors of the rabbit aorta. A
bright yellow sponge, Leucetta cf. chagosensis, collected from
the Egyptian Red Sea, contained imidazole alkaloidal
compounds that are active against the AIDS OI pathogen
Cryptococcus neoformans and that show inhibitory effects of
inducible nitric oxide synthase (iNOS).
As most of these alkaloids contain an N-1 substituted 2aminoimidazole moiety, they are rather difficult to synthesize via
existing procedures.
H2N
R
N
N
H
H
O
R1B(OH)2
Cl
N
S
Chan-Lam
coupling
H
Cl
O
R3B(OH)2
N
S
Liebeskind-Srogl
reaction
H
Cl
A
O
N
R3
Polycyclic molecules , such as pentacenes and helicenes are
synthesized in view of using them as materials with respectively
novel semiconducting and NLO-properties.
S
S
B
+
R1
N
Heterocyclic molecules are designed and synthesized as novel
antiviral, antiParkinson- and antiAlzheimer-drugs. The study of
the biological properties in relation to the chemical structure is
carried out in collaboration with external partners, such as the
Rega institute.
Ar
X
C: Bioactive conformation
receptor
+ alternative
receptor
alternative
receptorpeptide
complex
Ar
HN
Design and synthesis of peptidomimetics
Peptides are involved in a large number of biological processes.
However they show severe limitations in terms of metabolic stability
and druggability. The general idea is to replace peptides with
peptidomimetics which show the same biolocigal activity but don’t
suffer from the same shortcomings as peptides. Different
approaches are followed in this research.
The conformation of the peptides can be stabilised by introducing
secondary structure mimics. For this purpose we developed a
number of new beta turn mimicking systems which can be built into
a peptide sequence. These compounds were built into kinins and
into the bioactive loop of the Bowman Birk Protease inhibitor.
Alternatively, the functional groups important in binding to the target
receptor have to be identified and transferred to scaffolds which
can present them in the correct spatial conformation to undergo
optimal binding.
R
R1
N
Br
N
R3
R
H
N
O
+ peptidase
peptidase
-peptide
complex
Peptide-receptor complex
Undesired
biological
effect
Destruction of the peptide
Desired biological effect
Contact details
[email protected]
[email protected]
[email protected]
[email protected]
OR
RO
OR
Ar
Ar
RO
S
S
pentacene
helicene
Website
www.chem.kuleuven.be/research/organ/index.html