Si-Directed Nitrenium Ion Cyclization: Development & Application. Novel Inhibitors of Ebola-Cell Entry
Yermolina, Maria V.
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Part I: Synthetic organic chemistry is continually used for the synthesis of the desired biologically active target molecules that can be potentially used as suitable therapeutic agents. As an applied science, it aims at the discovery and development of novel compounds through the chemical aspects of identification, thorough synthetic alteration of new chemical moieties, and further development of their bio- and structure-activity relationship. In accordance with it, an application of organic synthesis towards the study of novel inhibitors of filovirus cell-entry is discussed in Chapter I. The Ebola and Marburg viruses comprise the family of Filoviridae viruses and both cause a severe hemorrhagic fever with unmatched mortality rate up to 90%. Although there has been considerable progress towards the production of viable vaccines for the prophylaxis of Ebola, the concurrent development of chemotherapeutic agents, capable of immediate pharmacological intervention, is also of great importance. On account of understanding of the mechanism of virus action, general review on morphology, activity, and virus pathogenesis is introduced in Chapters 1.1-1.4. Several existing small-molecules, that have been found to act as filoviral inhibitors, are presented in Chapter 1.5. Chapter 2 details the synthesis of a novel library of molecules, and the optimization and analysis of their antiviral activity using an HIV-based pseudotyped virus, Human 293T or HeLa cells, together with luciferase assay. Part II: Nitrenium ions (R2N+) contain positively charged nitrogen atoms. Their definition, formation, and reactivity are discussed in Chapters 4.1 & 4.2. Previously, our group developed and employed a mild procedure for the synthesis of 5- and 6-membered hydroxylactams via the cyclization of an alkenyl-O-alkyl hydroxamates with phenyliodine(III) bis(trifluoroactetate) (PIFA) that is briefly reviewed in Chapter 4.4. Nonetheless, further Chapter 5.1 details a novel method for the synthesis of 4 to 8-membered α-vinyl and α-(2-silylvinyl) lactams involving the iodine(III) reagent via exo-trig oxidative cyclization of unsaturated O-alkyl hydroxamates, which encompass an allylsilane moiety. Preliminary, a brief discussion on peculiarity and reactions of allylsilanes with numerous heteroatom electrophiles are covered in Chapter 4.5. Finally, the application of our new method as a pivotal transformation in the endeavor of the total asymmetric synthesis of a novel dehydropumiliotoxin alkaloid 235C is discussed in Chapter 7.
Subjectsilicon mediated cyclization
silicon directed cylization of nitrenium ion
alfa-vinyllactam Ebola virus
inhibitors of filovirus-cell entry