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Tesi Federica Porta

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Tesi Federica Porta Department of Pharmaceutical Sciences PhD Course in Pharmaceutical Sciences -XXIX Cycle- Design, synthesis and biological evaluation of novel antiproliferative compounds as potential anticancer agents Tutor: Prof. Alessandro Pedretti Coordinator: Prof. Marco De Amici Federica Porta R10459 Academic year 2015/2016 It is not the most intellectual or the strongest species that survives, but the species that survives is the one that is able to adapt to or adjust best to the changing environment in which it finds itself. Attributed to Charles Darwin Abstract Selectivity for cancer cells is one of the most important characteristics of anticancer agents. The transition from cytotoxic chemotherapy to molecularly targeted cancer drug discovery and development resulted in an increasing number of successful therapies that impacted the lives of a large number of cancer patients. The extreme toxicity and the development of resistance have made it essential to keep searching for new potential targeted anticancer agents, endowed with higher efficacy and minor toxicity. In order to achieve this goal, I followed different approaches: - starting from antiproliferative compounds, I sought their molecular target; - developing STAT3 inhibitors, I obtained dual-target compounds with enhanced cytotoxicity; - employing computationally driven drug design, I investigated new chemical scaffolds, able to disrupt STAT3 dimerization and characterized by suitable drug-like properties. 1,2,5-Oxadiazoles have received considerable attention in recent years from Prof. Barlocco’s research group because of the interesting results as potential antitumor agents. Among all, MD77 displayed a very interesting antiproliferative profile. Therefore, I focused my research efforts in the identification of its molecular target employing a combined synthetic-computational approach. I synthetized a wide pool of MD77 derivatives which were evaluated for their antiproliferative activity by the MTT-assay on human colon cancer cells by Dr. N. Ferri (University of Padua, Italy) and underwent a structure-activity relationship analysis using Activity Miner module of Cresset Forge, in collaboration with Prof. S. Guccione’s research group (University of Catania, Italy). The obtained disparity matrix will be used as query in search of a potential target. Platinum based anticancer drugs are still among the most effective drugs used for the treatment of solid cancers. Their strong side effects and the increasing resistance are limitations to their use. Even if DNA was established to be the primary target of platinum drugs, an extensive investigation into their biochemistry highlighted the evidence that also non-DNA targets, such as STAT3, are involved in determining cytotoxic effects. The second part of my PhD project, carried out in collaboration with Dr. I. Rimoldi’s research group (University of Milan) and Dr. N. Ferri (University of Padua), aimed at the identification of Pt(II) complexes endowed with antiproliferative activity due to a dual mechanism of action: interference with DNA replication and inhibition of STAT3 signaling pathway. Among the synthesized derivatives, Pt-15b and Pt-16a were selected for in vivo studies thanks to the collaboration with Prof. C. Marzano and Prof. V. Gandin (University of Padua), showing that the chemotherapy with these compounds reduced the tumor mass similarly to cisplatin and, despite the higher dose, they seemed to be better tolerated than the reference compound. A dual targeting approach was also pursed, in collaboration with Prof. A. Sparatore’s research group, by investigating a new series of sulfurated compounds as STAT3 and NF-kB inhibitors. Dithiolethiones (DTTs) and methanethiosulfonates (MTTSs) were synthetized in light of their recently reported chemopreventive and anticancer activities. Fragment-based drug design (FBDD) has emerged as promising methodology to generate lead molecules against therapeutic targets in the past decade. Compared with high-throughput screening hits, the advantage is that the identified small molecules are expected to be efficiently optimized into a drug candidate which maintains low molecular weight and possesses both binding affinity and favorable pharmacokinetic profile. The aim of this branch of my PhD project was the identification of new chemical scaffolds able to disrupt STAT3 protein-protein interactions and characterized by an increased activity and appropriate drug-like properties, employing a FBDD approach. The computational protocol was firstly validated and then applied on a larger base set of fragments leading to nine drug candidates. The synthesized compounds and the commercial ones were evaluation by an in vitro binding assay to determine their affinity for the target. This project was partially supported by PRIN Research Project, grant no. 20105YY2H_007. TABLE OF CONTENTS I Chapter 1: Introduction .......................................................................................................................... 1 1.1 Cancer ................................................................................................................................................. 2 1.1.1 Chemotherapy and targeted therapy .................................................................................... 3 1.2 STAT3 ................................................................................................................................................... 5 1.2.1 STAT3 signaling pathway ....................................................................................................... 6 1.2.2 STAT3 inhibitors ..................................................................................................................... 7 1.3 Platinum based anticancer drugs ........................................................................................................ 8 1.3.1 How platinum-based chemotherapeutics work .................................................................... 8 1.3.2 Structure-activity relationships ........................................................................................... 10 1.3.3 Platinum compounds and STAT3 ......................................................................................... 11 1.4 Topoisomerases ................................................................................................................................ 12 1.4.1 DNA Topoisomerases inhibitors .......................................................................................... 13 1.5 Hit finding .......................................................................................................................................... 15 1.5.1 Scaffold hopping .................................................................................................................. 15 1.5.2 Fragment-based drug design ............................................................................................... 15 Chapter 2: MD77 derivatives ................................................................................................................ 17 2.1 Research project ............................................................................................................................... 18 2.2 Synthetic chemistry ........................................................................................................................... 20 2.3 Results and discussion....................................................................................................................... 25 2.3.1 Antiproliferative activity ...................................................................................................... 26 2.3.2 AlphaScreen-based assay .................................................................................................... 28 2.3.3 Cresset Forge ....................................................................................................................... 28 2.3.3.1 Computational methodologies ...................................................................................... 31 2.3.4 Crystallographic studies ....................................................................................................... 32 2.4 Conclusions ....................................................................................................................................... 33 Chapter 3: Platinum (II) Complexes ....................................................................................................... 35 3.1 Research project ............................................................................................................................... 36 3.1.1 3-aminomethyl-1,2,5-oxadiazole derivatives as ligands in Pt(II) complexes ....................... 36 3.1.2 3-hydroxylaminomethyl-1,2,5-oxadiazole derivatives as ligands in Pt(II) complexes ......... 36 3.2 Synthetic chemistry ........................................................................................................................... 38 3.3 Results and discussion....................................................................................................................... 40 3.3.1 3-aminomethyl-4-methyl-1,2,5-oxadiazoles ....................................................................... 40 3.3.1.1 Analysis of the coordination environment of Pt(II) core ............................................... 41 3.3.1.2 Aqueous stability and lipophilicity ................................................................................
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