Molecular Design and Synthesis – Organic SynthesisResearch Topics

Synthesis of cyclic and acyclic oligopyrrolesThe 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 targetingOne 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 dendrimersDendrimers 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 polymersHyperbranched 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.

General remarksThese are the research topics of the group. It is possible to make a thesis in the framework of each of these topics.

PeptidomimeticsAlmost 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.

Drug design by NMR screeningA 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.

X

R2

R1

N NN

R4

O

OH

OAcH

OMe

MeO

MeO

OO

(-)-SteganacinX = OR of NRR'

Molecular Design and Synthesis – Organic SynthesisResearch Topics

Design and synthesis of peptidomimeticsPeptides 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.

Peptide-receptor complex

Desired biological effect

A B

C: Bioactive conformation

receptor

+

Destruction of the peptide

Undesired biologicaleffect

+ alternative receptor + peptidase

alternativereceptor- peptide complex

peptidase-peptidecomplex

Design of combinatorial libraries using parallel synthesis and microwave assisted synthesis methodsIn 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 microwave-enhanced solid-phase chemistry, opening the way for the generation of many biologically interesting structures. Different microwave-enhanced transition metal-catalyzed reactions are investigated.

Contact detailsWim.Dehaen@chem.kuleuven.beErik.VanderEycken@chem.kuleuven.beMario.Smet@chem.kuleuven.beWim.DeBorggraeve@chem.kuleuven.be

Websitewww.chem.kuleuven.be/research/organ/index.html

2-Aminoimidazoles, an interesting class of bioactive compoundsWe are focussing on the development of efficient synthetic approaches for the synthesis of polysubstituted 2-aminoimidazoles, 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 2-aminoimidazole moiety, they are rather difficult to synthesize via existing procedures.

N

NH2N

R NH

O

HNX

Br

N

HN O

SCl

H

N

N O

SCl

H

R1

N

N O

R3Cl

H

R1

R1B(OH)2 R3B(OH)2

Liebeskind-Sroglreaction

Chan-Lam coupling

N

HN O

Cl

R6

R3N

N O

ClCl

R6R6

CHO

NH2

-CN

O

Cl O

ClN

N O

R3Cl

R6MW

[Pd]

MW

N

N

N

O

R3Cl

R6

R

R

R3Cl

R6

N

N O

ClCl

R6

MeO

N

N O

R3Cl

R6

MeO

N

HN O

R3Cl

R6

HNR6

R

R

R3

O

Diels-Alder

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.

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

RO

ROS

S

OR

ORAr

Ar

Ar

Ar

pentacene helicene