• TDP
• benzothiopyrano
• topoisomerases

DNA topoisomerases (Top) are established molecular targets of anticancer drugs. There are two major families of Top: Type I (Top1) and Type II (Top2) depending on whether they cleave only one or two DNA strands. A common feature of topoisomerases is their catalytic mechanism, which, in all cases, consists in a nucleophilic attack of a DNA phosphodiester bond by a catalytic tyrosyl residue from the topoisomerase. The resulting covalent attachment of the tyrosine to the DNA phosphate is either at the 3′-end of the broken DNA, in the case of Top1 enzymes (Top1 and Top1mt), or at the 5′-end of the broken DNA for Top2 ones. As result, a covalent complex was generated between the protein and DNA via a phosphotyrosyl bond (Top1cc and Top2cc).
Under normal circumstances, the rate of religation is much faster than the rate of cleavage, which allows the Top1-DNA cleavage complexes to be a transitory intermediate event of the Top1 catalytic cycle. However, a variety of conditions have been shown to increase the frequency of Top1-DNA cleavage complexes by reducing or inhibiting the rate of the religation reaction. For example, Top1 inhibitors, such as camptothecin (CPT) and its clinically used derivatives, as well as several non-CPT Top1 inhibitors, including the indenoisoquinolines and the indolocarbazoles, selectively and reversibly bind to the Top1-DNA interface and slow the rate of Top1-mediated DNA religation.
Tyrosyl-DNA phosphodiesterases (TDP1 and TDP2) were recently 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.
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. Thus, Tdp1 inhibitors have the potential to augment the anticancer activity of Top1 inhibitors, by reducing the repair of Top1-DNA lesions.
During my thesis project, a series of derivatives featuring the benzothiopyranoindole nucleus and hydroxylic groups at different position of the central scaffold were synthesized, in order to perform a structure-activity relationship (SAR) investigation and to obtain compounds with high TDP1 inhibitory activity.