Document Type

Dissertation

Degree

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor's Name

Stanislaw F. Wnuk

First Advisor's Committee Title

Committee chair

Second Advisor's Name

Kevin O'Shea

Second Advisor's Committee Title

Committee member

Third Advisor's Name

Joong Ho Moon

Third Advisor's Committee Title

Committee member

Fourth Advisor's Name

Anthony De Caprio

Fourth Advisor's Committee Title

Committee member

Fifth Advisor's Name

Deodutta Roy

Fifth Advisor's Committee Title

Committee member

Keywords

Novel nucleoside analogues, (β-halo)vinyl sulfone, β-keto sulfone

Date of Defense

6-28-2017

Abstract

The C-5 modified pyrimidine analogues are well-known anticancer and antiviral drugs which underscore further development of novel probes to study their physical, chemical, and biological properties. In my dissertation the syntheses and properties of (β-halo)vinyl sulfone and/or (β-keto)sulfone analogues of C-5 modified pyrimidine have been discussed. In the first part of the dissertion, the synthesis of 5-(β-halo)vinyl sulfones either by transition metal-catalyzed or iodine-mediated halosulfonylation reaction of 5-acetylene pyrimidine nucleosides have been explored. The novel (β-chloro/bromo/iodo)vinyl sulfones efficiently undergo addition-elimination reaction with different nucleophiles such as thiols, amines, amino acid, peptides to provide (β-substituted)vinyl sulfone analogues. The rate of these substitution reactions depends on the nature of halogen atom presents at the β-position and increases with the order of

I ≥ Br > Cl. (β-chloro/bromo/iodo)vinyl sulfones possess exclusively E stereochemistry while their β-substitued analogues possess either E (for β–thio analogues) or Z (for β–amino analogue) stereochemistry. It has been observed that the vinylic proton of (β-chloro) or (β-amino)sulfone analogue undergoes exchanges with deuterium in polar protic deutorated solvents. The antiproliferative activities of those analogues have been explored and was found that protected 5-(E)-(1-chloro-2-tosylvinyl)-2'-deoxyuridine inhibited the growth of L1210, CEM and HeLa cells in lower micromolar range.

In the second part of the dissertation the syntheses and reactivities of 5-(β-keto) sulfone of pyrimidine nucleosides were investigated. Thus, 5-(β-halovinyl)sulfone of uracil and cytosine nucleosides have been efficiently converted into corresponding 5-(β-keto) sulfone analogues by displacement of halogen with ammonia followed by acid-catalyzed hydrolysis of the resulting (β-amino)sulfone analogues. A number of electrophiles were trapped at the acidic α-carbon of the 5-(β-keto)sulfones by treatment with electrophiles such as methyl, benzyl, or allyl halide in the presence of base. The 5-(α-iodo-β-keto)sulfone analogues of uracil nucleosides have been tested as an alternative substrates to probe the incorporation of nucleophiles at α-carbon.

In the third part of the dissertation, the synthesis of 5'-phosphates of 5-(β-chloro) and 5-(β-keto) sulfones of 2'-deoxyuridine and their polymerase-catalyzed incorporation into DNA were evaluated. Thus, 5'-O-phosphorylated analogues have been efficiently incorporated into the DNA by human DNA repair polymerase (pol β) or bacterial polymerase (pol I).

Identifier

FIDC001985

Available for download on Tuesday, January 23, 2018

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