• indole
• priviledge scaffold
• TDP

DNA topoisomerases exist in all living organism; they are essential enzymes inducing DNA modifications required during cellular processes such as replication, transcription, repair, etc… There are two mayor families of topoisomerases: type I (Top1) and type II (Top2). Top1 acts by cleaving a single strand of DNA, whereas Top2 cleaves both strands of DNA duplex. The DNA cleavage mechanism of all topoisomerases operates by the attack of catalytic tyrosine residues acting as nucleophiles, leading to the generation of topoisomerases cleavage complexes (Top1cc and Top2cc). The formation of these complexes, which can be increased by various factors, causes DNA damage for the work of the cellular metabolism or for pre-existing injury to DNA.
Topoisomerases inhibitors, binding at the enzyme-DNA interface, misaligns the DNA end, which precludes rebinding and results in the stabilization of Top1cc and Top2cc.
Camptothecin (CPT), a natural alkaloid isolated from Camptotheca acuminata, was the first small molecule identified as Top1 inhibitor, which showed a marked antitumor activity. Efforts to improve its toxicity profile and pharmacokinetics led to the development of two clinical water-soluble CPT derivatives, topotecan and irinotecan. However, CPTs are not ideal drugs as they display a number of limitations, including chemical instability, and potential induction of cellular resistance. To overcome the main drawbacks of CPTs, several chemical classes of non-CPT Top1 poisons were developed as promising antitumor drugs, including the phenanthridines and the indenoisoquinolines.
The main limitation of camptothecins, which is not been resolved yet, is the development of resistance. This is because there are alternative mechanisms for the repair of complex damages. Among these repair mechanisms, Tyrosyl-DNA phosphodiesterases (TdP) play a fundamental role. TDP1 and TDP2 are recently discovered DNA repair enzymes, involved in a variety of biological functions, in addition to the repair of trapped topoisomerase cleavage complexes. TDP1 and TDP2 were discovered and named based on the fact they process 3′- and 5′-DNA ends by excising irreversible protein tyrosyl-DNA complexes involving topoisomerases I and II, respectively. Specifically, TdP1 is involved in the repair of irreversible Top1-DNA covalent complexes, since it catalyzes the hydrolytic cleavage of the covalent bond between the Top1 catalytic tyrosine and the 3’-end of the DNA. Consequently, TdP1 has been considered as a potential co-target of Top1 for anticancer therapy, in that it seemingly counteracts the effects of Top1 inhibitors, such as camptothecin and its clinically used derivatives. Thus, Tdp1 inhibitors have the potential to augment the anticancer activity of Top1 inhibitors, by reducing the repair of Top1-DNA lesions. Based on these considerations, with the aim to identify new lead compounds able to inhibit TdP1, we focused our attention on compounds containing an indole nucleus, as indole is considered a ‘‘privileged scaffold’’ for drug discovery. So, during my thesis project, two series of indole derivatives, featuring different substituents at various positions of the central scaffold were synthesized, in order to perform a structure-activity relationship (SAR) investigation.