Investigating the antitumoral activity and mechanism of action of a xanthone derivative

Chapter I refers to the introduction, and has the role of providing an initial overview of the issues addressed directly or indirectly in the rest of the study. Initially, an overview of the cell cycle, its regulation and control is given. In the sequence, a greater emphasis is given to mitosis, which is described in detail from its cascade of events to the molecular machinery of the mitotic spindle. Still at this stage, the dynamics that occur between kinetochore-microtubules, correlated errors and their due corrections are described. Next, we provide an overview of the Spindle Assembly Checkpoint (SAC), dissecting the functions triggered by this mechanism, as well as the proteins involved in this important cellular control mechanism. Following, an introduction was given about drugs that use the targeting of mitosis for cancer therapy, namely through microtubules, providing an overview of current approaches, their limitations and future directions. Finally, a correlation was made between xanthones and cancer, demonstrating how this class of compounds (as well as their derivatives) is already used as a starting point in the development of new anticancer drugs. Chapter II concerns what motivated the project, as well as its specific objectives. Chapter III refers to the materials and methods used throughout the study, so that it was possible to dissect the mechanism of action of the compound. Chapter IV will demonstrate the results about the compound's mechanism of action, through: in vitro characterization of the compound's antimitotic activity, identification of the underlying mechanism of action and evaluation of the combined treatment of PX2 with paclitaxel in promoting cell death of tumoral cells. Chapter V provides a discussion, correlating previous studies and the present study. Chapter VI provides general conclusions about the mechanism of action of PX2 and the prospects for future research. Chapter VII contains a list of all references cited in the course of the thesis.This work was supported by CESPU - Cooperativa de Ensino Superior Politécnico e Universitário Crl [grant number ComeTarget_CESPU_2017 and ComeTax-PFT-IINFACTS-2019]. This research was partially supported by FCT/MCTES - Foundation for Science and Technology from the Minister of Science, Technology and Higher Education and European Regional Development Fund (ERDF) under the projects, co-financed by COMPETE 2020, Portugal 2020, PTDC/SAU-PUB/28736/2017 (POCI-01-0145-FEDER-028736) and within the scope of UIDB/04423/2020, UID/QUI/5000612019, and UIDP/04423/2020 (Group of Natural Products and Medicinal Chemistry). ACH thanks FCT for her PhD grant (SFRH/BD/140844/2018). DRPL thanks FCT for her PhD grant (SFRH/BD/140844/2018). JXS thanks for the FCT PhD Programmes, specifically by the BiotechHealth Programme (PD/00016/2012), and for the grants (SFRH/BD/98105/2013 and SFRH/BD/116167/2016). To Departamento de Química da Universidade de Aveiro (Portuguese NMR network) for the NMR analysis