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Restriction of DNA conformation by spirocyclic annulation at C4': synthesis of the nucleoside building blocks

Kahane, Alexandra L.

Abstract Details

2004, Doctor of Philosophy, Ohio State University, Chemistry.
The development of novel oligonucleotide analogues displaying well defined and predictable association patterns with high complex stabilities are of considerable current interest as antisense therapeutics. We have designed a new class of conformationally restricted nucleoside analogues based on modification of the glycosyl moiety by spirocyclic annulation at C4’. This modification is hypothesized to impart resistance to cellular nucleases, provide enhanced duplex stability due to the resultant structural preorganization, and bestow increased lipophilicity relative to natural nucleosides. The sum of these adjustments should result, upon oligomerization, in the formation of ideal candidates for antisense therapies. In addition, these analogues may possess potent antiviral activities. A divergent strategy has been implemented to provide access to analogues based on each of the 2-deoxyribose, 2,3-dideoxyribose, 2,3-didehydro-2,3-dideoxyribose and ribose frameworks from a common lactone intermediate. This lactone is accessible in enantiopure form via an oxonium induced pinacolic ring expansion reaction, subsequent optical resolution through the use of R-(-)-mandelic acid, and simple functional group interconversion. Elaboration of the lactone to the 2-deoxyribose and ribose frameworks was achieved via a butenolide intermediate. Vorbruggen type glycosylation provided the spirocyclic 2’-deoxyribonucleoside analogues in good selectivities (88-100%) and moderate chemical yields (45-59%). However, application of this strategy to the spirocyclic ribonucleosides was not feasible. Introduction of an alpha-phenylthio substituent to the lactone allowed the stereoselective introduction of the nucleic bases. Oxidative elimination of the sulfide provided entry into the spirocyclic 2’,3’-dideoxy-, 2’,3’-didehydro-2’,3’-dideoxy-and ribonucleoside analogues. Access to spirocyclic 2’,3’-dideoxyribonucleoside analogues containing adenine was achieved by the application of sodium salt glycosylation methodology to the lactone intermediate. The array of conformationally restricted nucleosides produced includes representatives resembling each of the 2-deoxyribose, 2,3-dideoxyribose, 2,3-dideoxy-2,3-didehydroribose and ribose frameworks. Although a variety of glycosylation methods were needed, each analogue was isolated as a pure, beta diastereomer. With a viable synthetic route developed, these analogues were made available for antiviral evaluation and future incorporation into oligomers for assessment as antisense therapeutics. Indeed, uridine 4-10a has already been shown to be an inhibitor of human corona virus.
Leo Paquette (Advisor)
204 p.

Recommended Citations

Citations

  • Kahane, A. L. (2004). Restriction of DNA conformation by spirocyclic annulation at C4': synthesis of the nucleoside building blocks [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1072903762

    APA Style (7th edition)

  • Kahane, Alexandra. Restriction of DNA conformation by spirocyclic annulation at C4': synthesis of the nucleoside building blocks. 2004. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1072903762.

    MLA Style (8th edition)

  • Kahane, Alexandra. "Restriction of DNA conformation by spirocyclic annulation at C4': synthesis of the nucleoside building blocks." Doctoral dissertation, Ohio State University, 2004. http://rave.ohiolink.edu/etdc/view?acc_num=osu1072903762

    Chicago Manual of Style (17th edition)