• Tdp1
• topoisomerase
• indole

DNA topoisomerases are essential enzymes inducing DNA modification required during cellular processes such as replication, transcription, repair, etc... Human topoisomerases are classified in type I (Top1) and type II (Top2), depending on whether they cleave single-stranded or double-stranded DNA, respectively. All topoisomerases cleave the DNA phosphodiester backbone by nucleophilic attack from a catalytic tyrosine residue, which becomes linked to the phosphate end of the DNA break.
Top1 binds the ribonucleotidic chain, leading to the formation of Top1-DNA cleavage complexes (Top1cc). Various conditions can increase the frequency of these complexes, which are converted into DNA damage by cellular metabolism or preexisting DNA lesions.
Tyrosyl-DNA phosphodiesterase I (Tdp1) is a recently discovered enzyme that has been implicated 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.
For this reason, Tdp1 has been regarded 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.
On the basis of these considerations, a computational study was conducted by the research group of University of Naples in order to identify new lead compounds able to inhibit TdP. Attention was focused on indole-containing structures, as indole is considered a “privileged scaffold” for drug discovery. During my thesis project, two series of derivatives containing the indole nucleus were synthesized, featuring different substituents at various positions of the central scaffold, in order to perform a structure-activity relationship (SAR) investigation.