Objetivo we intend to develop novel anti-HIV compounds based on structural principle of acyclic nucleotide analogues bearing phosphonate function. Our previous joint studies disclosed several classes of these compounds which exhibit powerful antiviral activity against retroviruses including HIV as well as against DNA viruses causing opportunistic AIDS related infections. Several compounds presently undergo clinical trials in various phases of progress. Synthetic alterations involved in this programme will concentrate mainly on three types of side-chain which were identified in the previous period and will focus on modifications of the heterocyclic bases. Particularly, they will concern systems with cumulated amino functions of various location at the base, diverse basicity and involvement in the heteroaromatic pi-system. We will study systems bearing aminoalkyl groups at the positions 2,6 and 8 of the purine, or C4 and C5 substituents in the pyrimidine ring, bases bear ing secondary and tertiary amino groups as well as quaternary bases, e.g. Nl-substituted pyridinium or nicotinamidinium rings, or derivatives of 2- amino/4-aminonicotinic acid with compensated charges. We also intend to investigate such structures which contain phosphonate-bearing chain linked to carbon instead to nitrogen atom (9-deazapurines, 1-deaapyrimidines).Another topics will concern additional minor modifications of the side chain in the HPMP series: it is intended to prepare adenine, guanine and 2,6-diaminopurine derivatives in which the hydroxyl group at the side chain is replaced by amino, alkylamino, dialkylamino, trialkylammonium function, or alkylthio, alkylsulfenyl and alkylsulfonyl group. Finally, we plan to study prodrugs of the established phosphonates (PMEA, pmpa) with the aim to increase their oral bioavailability and improve their pharmacological parameters. We will explore prodrugs which liberate the target drug by cascade mechanism triggered by specific enzymatic reaction and, also, to develop conjugates which simultaneously liberate another antiviral compound acting by mechanism different from the phosphonates. Particular attention will be paid to esters and amides derived from nitrogen sugars. All novel compounds will be subjected to detailed biological investigation encompassing broadspectrum antiviral and cytostatic evaluation as well as to various in vitro studies with selected enzymes (DNA pol, reverse transcriptase uridine phosphorylase, IMP dehydrogenase, etc.) Programa(s) IC-PECO/COPERNICUS - Scientific and technological cooperation between the European Community and European non-member countries, 1992- Tema(s) 0201 - CEEC participation in BIOMEDICAL AND HEALTH RESEARCH programme Convocatoria de propuestas Data not available Régimen de financiación CSC - Cost-sharing contracts Coordinador KATHOLIEKE UNIVERSITEIT LEUVEN Aportación de la UE Sin datos Dirección 10,Minderbroedersstraat 10 3000 LOUVAIN / LEUVEN Bélgica Ver en el mapa Coste total Sin datos Participantes (1) Ordenar alfabéticamente Ordenar por aportación de la UE Ampliar todo Contraer todo Institute of Organic Chemistry and Biochemistry - Academy of Sciences of the Czech Republic Chequia Aportación de la UE Sin datos Dirección 2,Flemingovo nam. 166 10 Praha 6 Ver en el mapa Coste total Sin datos
