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Analysis and Effect of Small-molecules Targeting Pre-microRNA Structures and Synthetic Efforts Toward a Novel Scaffold for RNA Targeting

出版	University of Rochester, 2019
URL	http://books.google.com.hk/books?id=PBdCzQEACAAJ&hl=&source=gbs_api

註釋"The growing understanding of functional non-coding RNA has seen a sharp rise in the importance of RNA both as a player in functional biology and for its role in the manifestation of many types of disease. This has stimulated the need for design and discovery of small molecules that can specifically interact with RNAs, for use as chemical probes and therapeutics. However, there is difficulty in the production of these molecules as the "rules" which govern the specific RNA interactions are not fully understood. This thesis discusses the application of a resin-bound dynamic combinatorial library (RBDCL) in the discovery of molecules which possess affinity and specificity toward unique RNA structures, as well as the modification and analysis of such molecules as RNA ligands in vitro and in celluo. Moreover, a novel RNA-focused small molecule library is proposed, centered about the use of a 2,5-diketopiperazine (DKP) chemical scaffold. Synthetic routes to this structure and their utility in exploring chemical diversity are discussed. Toward the utility of an RBDCL in evolving RNA binding molecules, an approach was carried out using the premature forms of microRNAs 21 and 96 as targets for small molecule interaction. In their mature states, both of these RNAs function as oncogenes in many forms of cancer. Derived molecules demonstrate ability to bind preferentially to a specific premature structure with strong affinities. Enzymatic studies performed in vitro elucidate the utility of the molecules binding modes in preventing the generation of the mature RNAs at low micromolar concentrations. In cancer cell cultures, treatment with these molecules corresponds to increases in apoptotic events, suggesting reinstated tumor suppressor function through microRNA inhibition. Apoptosis observed with treatment also displays an additive effect when treated with cell death related cytokines or chemotherapeutics. Heterocyclic substructures, particularly those with rod-like orienting ability, have displayed a high degree of utility in the generation of RNA-preferenced small molecules. The 2,5-diketopiperazaine is a synthetically simple heterocycle with a notable pedigree in biologically active molecules. Surprisingly, this molecular scaffold has as yet never been targeted to RNA structure interaction. Synthetic pathways to differentially substituted DKPs are explored both in solution and on solid-phase for application to a dynamic library. Analysis of the RNA interacting capability of the DKP scaffold was performed through the use of a previously known RNA-binding molecule. A mono-quinoline analogue containing a DKP structure was able to bind the HIV-1 frameshift stimulatory sequence of RNA with affinity comparable to the non-DKP molecules despite the loss of a quinoline heterocycle. This is the first instance demonstrating a 2,5-diketopiperazine containing molecule participating in RNA binding"--Pages viii-ix