Project Archive

The project aims to design new pharmacologically active molecules, develop new innovative methods of synthesis of different heterocyclic systems with a perspective to find new selective medicinal preparations for the treatment of oncological, cardiovascular and CNS diseases. The synthesis of lipophilic compounds and studies of their properties will be a contribution to one of the important scientific challenges of elaboration of effective self-assembling cationic amphiphilic compounds for drug and gene delivery. Total cost of the project – LVL 1,405,600. The research will be accomplished by November 30, 2012.

Team leader Dr.chem. Aiva Plotniece (aiva@osi.lv)
Deputy team leader Dr.chem. Arkadijs Sobolevs (arkady@osi.lv)

During the last year our research team under umbrella of this project have continued to model, synthesise and study self-assembling amphiphilic cationic compounds as transport molecules and heterocyclic compounds as pharmacologically active substances. New series of original enantiopure self assembling compounds were synthesised using biotechnological approach. The control by hydrolytic enzymes of remote stereocentres on a model of 1,4-dihydropyridine-3,5-dicarboxylates was also studied during this period. Diastereoselective amidation of 2-aminoethoxymethyl containing 1,4-dihydropyridine derivatives was discovered during the last year. The elaborated method is a promising tool for the synthesis on original rows of aminoacid containing 1,4-dihydropyridine derivatives. New catalytic methodologies for the synthesis of dihydropyridine derivatives and other heterocyclic systems have been developed. Potentially biologically active selenium and tellurium derivatives have been synthesised according to ‘green chemistry’ protocol. Formation of nanoaggregates and encapsulation of magnetic nanoparticles into vesicules formed by self-assembling cationic compounds has been investigated. Studies of nanoaggregates using molecular modelling methods have been performed.

The new multidisciplinary team has been established for the development of new patent-free anti-cancer agents based on innovative approach to use as pharmacological target zinc containing enzymes (ZCE) – carbonic anhydrases (CA), histone deacetylases (HDAC), tumor necrosis factor-a converting enzyme (TACE / ADAM-17) and matrix metalloproteinases (MMP).  The aim of the project is to develop inhibitors of ZCE. This approach is widely recognised during last decade as a promising approach for the development of new anti-cancer agents for the treatment of tumours. In order to decrease the cost of development of new drugs as well as save natural resources the project also involves development of green chemistry and development of alternative methods for biological screening. For the efficient implementation of the project the team unites scientists from several scientific fields – mathematics and computer science, physics, chemistry, biology and pharmacology. Total cost of the project – LVL 1,392,159. The research project will be completed by November 30, 2012.

Team leader Prof. Edvards Liepiņš
Deputy team leader Dr. chem. Raivis Žalubovskis (e-mail: raivis@osi.lv)

The project team is divided on four subunits – computational chemistry and Nuclear Magnetic resonance (NMR) studies, synthesis of ZCE inhibitors, development of green chemistry for drug chemistry, and biological screening. During the first half of the project the computational work based on publicly available X-ray structures of ZCE (CA, HDAC) has been performed and new structures of ZCE has been generated. Also NMR studies on ZCE are in progress in order to deepen understanding of the geometry of ZCE in solution. The synthesis of designed ZCE inhibitors partly has been performed in field of sulfamides, sulfonamides as well as bioisosteres of coumarin and hydroxamic acids. In green chemistry Cu and Fe catalysed reactions as well as organocatalysis are under investigation and have resulted with three international publications. Biological screening systems for ZCE have been developed and optimized and determination of inhibitory activities for ZCE inhibitors synthesised on CA I, CA II, CA IX, HDACs and MMPs are under investigation.

DeZnIT (Design of zinc metalloenzyme targeted drugs using an Integrated Technology approach) is a collaborative project between partners in Finland, Italy, The Netherlands, Latvia, Denmark and UK• DeZnIT will develop integrated technology for design of zinc metalloenzyme inhibitors, relevant to major diseases such as cancer, inflammation and obesity

Under the EU Sixth Framework Programme (FP6) for Research and Development 3.2 million Euros have been awarded to the DeZnIT research project. The main objectives of the DeZnIT program are to develop new drug design technology specifically focused on the family of zinc metalloenzymes and to use this technology to identify new candidate drugs. DeZnIT is a highly integrated, pan-European, research project conducted by a consortium of seven partners involving leading experts in computer-aided design, synthetic and medicinal chemistry, structural biology and the molecular biology of these enzymes. The project is coordinated by InhibOx, a biotechnology company based in Oxford, UK.

Zinc is a biologically ubiquitous element and is known to be indispensable for growth and development. It is present, and essential, in at least one enzyme of each of the six classes established by the International Union of Biochemistry. DeZnIT will focus on therapeutically important zinc-containing enzymes such as carbonic anhydrases, histone deacetylases and ADAM/MMP.

Drug design against zinc enzymes is challenging because of specific problems associated with interacting with the metal atom. By combining new theoretical and computational approaches to drug design with world-leading expertise in the biology of these enzymes and the synthesis of inhibitors, DeZnIT aims to make a major contribution to our understanding of these enzymes and enhance our ability to design potential candidate drugs.

The DeZnIT consortium
Four research groups and three SME companies join forces in the DeZnIT consortium. Each group contributes specific expertise that is required for this project.

1. InhibOx Ltd, Dr. Paul W. Finn (Co-ordinator), UK
2. TopoTarget A/S, Dr. James Ritchie, Denmark
3. Key Drug Prototyping, Dr. Flip Hoedemaeker, The Netherlands
4. Latvian Institute of Organic Synthesis, Dr. Peteris Trapencieris, Latvia
5. University of Tampere, Professor Seppo Parkkila, Finland
6. University of Florence, Professor Andrea Scozzafava, Italy
7. University of Oxford, Professor W. Graham Richards, UK

Further information
For more information please contact Dr. Paul Finn, InhibOx Ltd. phone: +44 1865 811185, e-mail: paul.finn@inhibox.com