Exploring the Chemical Synthesis and Underlying the Pharmacological Application of Benzopyrone Derivatives as Anticancer Agents

Cancer is characterized by the uncontrolled growth of abnormal cells with malignant potential. As the second leading cause of death in most of the countries after cardiovascular diseases, cancer is a major public health problem in all populations, unrelated with wealth and social status. This disease is a financial and psychologic burden on both economy and families of patients. Failures in the treatment of metastatic disease and development of drug resistance are the main reasons for the high mortality rate. Hence, is of global interest to reduce this burden through early detection of cancer and appropriate treatment and care of patients. Tumor-associated carbonic anhydrase IX and XII have been consistently validated as markers of disease progression in many solid tumors. Their overexpression in cancer and contribution to tumor physiology shows their great potential as biomarkers and therapeutic targets, leading the research community to undoubtedly focus on these isoforms in the last two decades. The two main strategies to target the tumor associated CAs for cancer therapy include the development of monoclonal antibodies and the design and synthesis of small molecules that selectively inhibit CA IX and XII. Coumarins and chromones are two groups of naturally occurring heterocycle compounds widely distributed in nature. Their chemical and biological aspects have been studied in detail. Molecules containing the coumarin and chromone skeleton have a wide variety of biological activities. The potential of coumarin and chromone scaffolds together with the research results, regarding their pharmaceutical use and potential, are the background for the work of this thesis. In addition, the previous work of the group regarding coumarins and furocoumarins showed the potential of these scaffolds as selective inhibitors of the tumor associated CAs. Hence, the work herein present follows the study of coumarins and chromones as promising scaffolds for the development of CA IX and XII selective inhibitors. Accordingly, the first aim involved the development of possible potent, selective, and reversible CA IX and XII inhibitors by the synthesis of compounds based in the coumarin (furanocoumarins included) and chromone scaffolds. Coumarin and chromone based libraries were successfully synthesized and characterized. The predicted properties of the compounds were calculated, and the theoretical parameters were encouraging. Compounds EMAC10163b, EMAC10164d and EMAC10169m proved to be the most potent and isozyme selective compounds, within the EMAC10163, EMAC10164 and EMAC10169 series, respectively. The docking experiments that consider the IX isoform, highlighted that the rigidity of the EMAC10164 and EMAC10169 series helps to orientate the compounds in the binding pocket with the chromene portion toward the zinc. This lead also to a general better activity of these series. The influence of the substituents in the phenyl ring is not clear among the different series. In the hydrolyzed compounds (EMAC10163-open and EMAC10164-open) what seems important is the zinc chelation and the interactions between the newly formed carboxylate moiety in the catalytic site. The docking solutions, considering the XII isoform, are often characterized by the interaction with common residues such as Lys69, His117, Thr198 or Thr199. Also, the open compounds are stabilized by an array of hydrogen bonds involving the residues in the catalytic cavity. Overall, the coumarin and chromone scaffolds were validated as a suitable framework for the development of selective carbonic anhydrase IX and XII inhibitors. The investigation performed in the course of this project provided understanding of the bioactivity of the developed compounds and paved the way for further studies of this scaffolds and derivatives towards other targets associated with cancer.