Targeting metabolic syndrome: Novel Benzopyrans and Quinolines as Peroxisome Proliferator-Activated Receptor agonists

For several decades, nature has provided a vast array of secondary metabolites with extensive therapeutic potential. The resulting immense interest has led to the pursuit of semi-synthetic and synthetic compounds modeled after natural products. Since its origin, our research group has dedicated efforts towards the isolation of bioactive secondary metabolites from plants within the Annonaceae family. Specifically, the benzopyran scaffold has attracted significant interest, as it was successfully isolated by our research group from the stem bark of Polyalthia cerasoides (Annonaceae), the first member of a new class of 2-prenylated benzopyrans, the natural polycerasoidol. Subsequently, polycerasoidol showed a dual full PPARα/γ agonist activity and anti-inflammatory effects, and emerged as a new hit compound with therapeutic potential to regulate lipid metabolism and glucose homeostasis. In a hit-to-lead strategy, the main objective of this thesis was set to develop new drugs based on the natural structure of polycerasoidol, potentially useful for the treatment of metabolic syndrome and associated cardiovascular comorbidities. To this end, the following specific objectives were proposed: 1. Synthesis and biological studies of a novel 2-prenylated benzopyran Synthesis of 2-(ethyl 4'-methylheptenoate)-6-(p-fluorobenzyloxy)-2-(methyl)-benzodihydropyran (BP-2) In vitro studies to determine the PPAR activity and the potential anti-inflammatory effects In vivo studies in a mice model of metabolic syndrome 2. Synthesis and biological studies of two series of novel 2- and 3-prenylated quinolines and tetrahydroquinolines Synthesis of two series of 2- and 3-prenylated quinolines and tetrahydroquinolines In vitro studies to determine the PPAR activity, the potential anti-inflammatory effects, and structure-activity relationships. In vivo studies in a mice model of metabolic syndrome In CHAPTER I of this Doctoral Thesis, the implications of PPAR receptors in targeting metabolic syndrome, highlighting the recent contributions of our group to the synthesis of biologically active benzopyrans, is briefly introduced. In CHAPTER II, the synthesis and evaluation of a novel benzopyran with PPAR activity are discussed. In the first section, the bibliographic background that led to the synthesis of 2-prenylated benzopyrans, including the methodology selected to develop BP-2, as well as the PPAR activity of benzopyrans is compiled. In the second section, the total synthesis of a novel 2-prenylated benzopyran is described, together with a description of the PPAR activity and molecular modeling studies carried out. In the third section, in vitro studies with BP-2 are presented, highlighting the potential anti-inflammatory effects of BP-2 by studying leukocyte-endothelium interactions. In the fourth section, in vivo studies performed using an ob/ob mouse model are described. The biochemical and anti-inflammatory effects were assessed. In CHAPTER III, the synthesis of novel quinolines and tetrahydroquinolines based on the benzopyran scaffold is described, and the PPAR activity of novel compounds is demonstrated. In the first section, the bibliographic background that led to the synthesis of quinolines and tetrahydroquinolines, including the methodology selected to develop our compounds, as well as the PPAR activity, is described. In the second section, the synthesis and biological studies of two series of 2-prenylated and 3-prenylated quinolines and tetrahydroquinolines are presented, including PPAR activity assessment and molecular modeling studies. Based on the generated data, a structure-PPAR activity relationship was established. In the third section, in vitro studies are described, including the activity of the compounds on a PPAR target gene and the evaluation of the potential anti-inflammatory effects of the lead candidates. Finally, in the fourth section, biochemical studies performed on an ob/ob mice model are described.