• topoisomerase 1
• non-CPT Top1 inhibitors
• antiproliferative effect

DNA topoisomerases (Top) are essential enzymes inducing DNA modification required during cellular processes such as replication, transcription, repair, etc. 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. Top1 relaxes supercoiled DNA by forming DNA single-strand breaks and relegates the broken strand to rapidly restore intact duplex DNA. At this stage, the enzyme is particularly vulnerable to a group of anticancer agents, the Top1 poisons, which reversibly trap the Top1-mediated cleavage complex, leading to irreversible DNA strand breaks, activation of apoptosis, and cell cycle arrest. Top1 inhibitors are a relatively new group of anticancer agents with a wide range of activity in hematological and solid tumors. Campthotecin was the first small molecule identified as Top1 inhibitor. Efforts to improve its toxicity profile and pharmacokinetics led to the development of two clinical water-soluble CPT derivatives, topotecan and irinotecan, as well as novel compounds currently under clinical evaluation. 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 not-CPT Top1 poisons were developed as promising antitumor drugs, including phenanthridines and indenoisoquinolines.
As part of the program in search for new antiproliferative agents, the aim of this thesis was to identify new polyheterocyclic system able to inhibit the action of Top1, having non-CPT structure. In the last decades, the research group, with whom I did my thesis work, studied several polyheterocyclic systems and recently directed its attention to a new class of non-CPT drugs characterized by a 2(3)-phenyl pyrazolo[1,5-a]quinazoline structure. In particular, it studied the influence on the Top1 inhibitory activity of a protonable chain linked at the 4- or 5-position of this scaffold by varying (i) length of chain, (ii) nature of linker between ring and chain, and (iii) nature of terminal basic site. For some of the synthesized pyrazoloquinazolinic compounds, biological results were very interesting and following these ones, a series of 6H-indazolo[2,3-a]quinazoline compounds bearing different combinations of alkyl substituents in 5- position of this new heterocyclic scaffold, able to inhibit the action of Top1, were synthesized.