Les résistances aux traitements actuels contre le cancer incitent à trouver de nouvelles cibles thérapeutiques. Une de ces cibles, la hsp90 (heat shock protein 90), impliquée dans la maturation de protéines clientes oncogènes, se révèle très prometteuse car son inhibition induit la dégradation de ces protéines par la voie du protéasome.PU3 et PU24S sont des inhibiteurs de la hsp90 de type purine fonctionnalisés en position 8. Dans le but d’identifier des composés encore plus actifs et/ou de nouvelles familles d’inhibiteurs, nous avons développé de nouveaux procédés sélectifs métallo-catalysés permettant l’activation de liaisons C-H de divers hétérocycles, et en particulier des purines (adénines, xanthines). Ces nouvelles approches ont permis un accès direct et simple à de nombreuses purines fonctionnalisées en C-8 par des groupements aromatiques, hetéroaromatiques, éthyléniques et benzyliques. / Resistance to current treatments of cancer encourages finding new therapeutical targets. The heat shock protein 90 (hsp90) is a molecular chaperon which regulates the folding of many client proteins associated with all of the six hallmarks of cancer, and helps maintaining their proper conformation. Consequently, the hsp90 has become an exciting new target in cancer drug discovery since the inhibition of its ATPase activity leads to depletion of these client proteins via the proteasomal pathway. PU3 and PU24S are purine-based hsp90 inhibitors functionalized on C-8 position. In the aim to identify more active compounds and/or new subfamilies of inhibitors, we have developed new metal-catalyzed C-H activation processes of various heterocycles including purines and other azoles. These new and simple approaches have allowed the access to numerous C-8 functionalized purines bearing (het)aryl, alkenyl and benzyl moieties.

The generation of new chemical entities (NCEs) for use in chemical biology and drug discovery is of wide interest to both academia and the pharmaceutical industry. In order to generate NCEs, this project focused on development of new synthetic methodologies using transition-metal mediated [2+2+2] cyclotrimerisation of alkynes and unsaturated molecules to form bi- and tricyclic heterocyclic derivatives, some with structural resemblance to the quinocarcin family of natural products. Three different dialkynes (1,5-di(prop-2-yn-1-yl)pyrrolidin-2-one 2.117a, 1,6-di(prop-2-yn-1-yl)piperidin-2-one 2.118a and 4-benzyl-1,6-di(prop-2-yn-1-yl)piperazin-2-one 2.120a) were successfully synthesised. Several cyclotrimerisations were attempted, with the best yields being obtained when diethylacetylene dicarboxylate 2.113a was used as the monoalkyne and Cp*Ru(cod)Cl as the catalyst in refluxing toluene. New heterocyclic compounds with potential for diversification were synthesised using a diversity-oriented synthesis approach; specifically the build/couple/pair strategy for the synthesis of small molecules. Racemic nitrogen and oxygen building blocks were coupled with acrylonitrile, bromoacetonitrile and acyl chlorides. The pair step involved the intramolecular ring closure using transition-metal catalysed [2+2+2] cyclotrimerisations using microwave assisted radiation. The best catalyst for this approach was found to be CpCo(CO)2 at 150 ºC (300 W) in chlorobenzene. This provided a new methodology with potential for synthesising a diverse set of small molecules for biological testing. 20 compounds were subjected to chemosensitivity testing using the MTT assay. Several compounds were shown to possess activity in bladder (RT112) and breast (MCF-7) cancer cell lines. As these two cell lines are known to express extra-hepatic cytochromes P450 enzymes, it is possible that these are involved in generating cytotoxic metabolites that may damage DNA.

The generation of new chemical entities (NCEs) for use in chemical biology and drug discovery is of wide interest to both academia and the pharmaceutical industry. In order to generate NCEs, this project focused on development of new synthetic methodologies using transition-metal mediated [2+2+2] cyclotrimerisation of alkynes and unsaturated molecules to form bi- and tricyclic heterocyclic derivatives, some with structural resemblance to the quinocarcin family of natural products. Three different dialkynes (1,5-di(prop-2-yn-1-yl)pyrrolidin-2-one 2.117a, 1,6-di(prop-2-yn-1-yl)piperidin-2-one 2.118a and 4-benzyl-1,6-di(prop-2-yn-1-yl)piperazin-2-one 2.120a) were successfully synthesised. Several cyclotrimerisations were attempted, with the best yields being obtained when diethylacetylene dicarboxylate 2.113a was used as the monoalkyne and Cp*Ru(cod)Cl as the catalyst in refluxing toluene. New heterocyclic compounds with potential for diversification were synthesised using a diversity-oriented synthesis approach; specifically the build/couple/pair strategy for the synthesis of small molecules. Racemic nitrogen and oxygen building blocks were coupled with acrylonitrile, bromoacetonitrile and acyl chlorides. The pair step involved the intramolecular ring closure using transition-metal catalysed [2+2+2] cyclotrimerisations using microwave assisted radiation. The best catalyst for this approach was found to be CpCo(CO)2 at 150 ºC (300 W) in chlorobenzene. This provided a new methodology with potential for synthesising a diverse set of small molecules for biological testing. 20 compounds were subjected to chemosensitivity testing using the MTT assay. Several compounds were shown to possess activity in bladder (RT112) and breast (MCF-7) cancer cell lines. As these two cell lines are known to express extra-hepatic cytochromes P450 enzymes, it is possible that these are involved in generating cytotoxic metabolites that may damage DNA. / Fundação Para a Ciência e a Tecnologia (FCT)