DESIGN, SYNTHESIS, PHARMACOLOGICAL AND MOLECULAR MODELING EVALUATION OF NOVEL PYRAZOLO PYRIMIDINE DERIVATIVES AS HUMAN A3 ADENOSINE RECEPTOR ANTAGONISTS

Ph.DDOCTOR OF PHILOSOPH

Structural, physical and biological studies of gold (lll) bis(pyrrolide-imine) Schiff base macrocyclic and pseudomacrocyclic complexes : targeted chemotherapeutic agents.

Thesis (Ph.D.)-University of KwaZulu-Natal, Pietermaritzburg, 2013.Abstract available in the print copy

Coumarin and Its Derivatives

Coumarins are widely distributed in nature and can be found in a large number of naturally occurring and synthetic bioactive molecules. The unique and versatile oxygen-containing heterocyclic structure makes them a privileged scaffold in Medicinal Chemistry. Many coumarin derivatives have been extracted from natural sources, designed, synthetized, and evaluated on different pharmacological targets. In addition, coumarin-based ion receptors, fluorescent probes, and biological stains are growing quickly and have extensive applications to monitor timely enzyme activity, complex biological events, as well as accurate pharmacological and pharmacokinetic properties in living cells. The extraction, synthesis, and biological evaluation of coumarins have become extremely attractive and rapidly developing topics. A large number of research and review papers have compiled information on this important family of compounds in 2020. Research articles, reviews, communications, and concept papers focused on the multidisciplinary profile of coumarins, highlighting natural sources, most recent synthetic pathways, along with the main biological applications and theoretical studies, were the main focus of this book. The huge and growing range of applications of coumarins described in this book is a demonstration of the potential of this family of compounds in Organic Chemistry, Medicinal Chemistry, and different sciences related to the study of natural products. This book includes 23 articles: 17 original papers and six review papers

Syntheses and applications of small molecule inhibitors of miRNAs miR-21 and miR-122

MicroRNAs (miRNAs) are regulatory RNA molecules of 22 nucleotides that (in part) control up to 60% of all genes in humans. They act by binding to the 3' untranslated regions of target messenger RNAs, leading either to translational repression or mRNA degradation. In addition to being involved in the regulation of several fundamental cellular processes, the misregulation of miRNAs has been linked to a wide range of diseases including cancer. Particularly, miR-21 is significantly upregulated in nearly all types of human cancers, and its overexpression is often associated with poor prognosis. The downregulation of miR-122 is found in more than 70% of hepatocellular carcinoma cases and miR-122 is a required factor for the replication of the HCV virus. The modulation of miRNA function is commonly achieved using oligonucleotide agents. However, compared to oligonucleotides, small molecules have several advantages, such as fast activity, systemic delivery, and excellent cell permeability. Taking advantage of luciferase-based reporters, two separate high-throughput screens of >300,000 compounds each, were conducted to discover new small molecule inhibitors of miR-21 or miR-122. Several hit compounds were re-synthesized, their ability to inhibit miR-21 was validated, and the most promising compounds were investigated by SAR studies, which revealed two additional, structurally diverse classes of miR-21 inhibitors. Similarly, extensive SAR studies of previously discovered miR-122 inhibitors were performed in order to better understand the molecular requirements for the miR-122 inhibitory activity. The hit compounds identified in the HTS were analyzed through secondary assays that led to the identification of two new promising miR-122 inhibitors. Furthermore, the knowledge gained during the SAR studies was further used to synthesize several small molecule miR-21/miR-122 inhibitors as probes to explore their mechanisms of action. MicroRNAs represent promising, novel drug targets, and small molecule miRNA inhibitors provide tools to study the molecular mechanisms of miRNA biogenesis and have the potential to be new therapeutic agents for the treatment of cancers and viral infections

Exploring protein flexibility during docking to investigate ligand-target recognition

Ligand-protein binding models have experienced an evolution during time: from the lock-key model to induced-fit and conformational selection, the role of protein flexibility has become more and more relevant. Understanding binding mechanism is of great importance in drug-discovery, because it could help to rationalize the activity of known binders and to optimize them. The application of computational techniques to drug-discovery has been reported since the 1980s, with the advent computer-aided drug design. During the years several techniques have been developed to address the protein flexibility issue. The present work proposes a strategy to consider protein structure variability in molecular docking, through a ligand-based/structure-based integrated approach and through the development of a fully automatic cross-docking benchmark pipeline. Moreover, a full exploration of protein flexibility during the binding process is proposed through the Supervised Molecular Dynamics. The application of a tabu-like algorithm to classical molecular dynamics accelerates the binding process from the micro-millisecond to the nanosecond timescales. In the present work, an implementation of this algorithm has been performed to study peptide-protein recognition processes