Halogenated Nucleobases And Flexible Nucleosides: Synthesis And Biological Investigation
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Date
2019-01-01
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Chemistry & Biochemistry
Program
Chemistry
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Access limited to the UMBC community. Item may possibly be obtained via Interlibrary Loan thorugh a local library, pending author/copyright holder's permission.
This item is likely protected under Title 17 of the U.S. Copyright Law. Unless on a Creative Commons license, for uses protected by Copyright Law, contact the copyright holder or the author.
Abstract
Nucleoside chemistry has provided a valuable framework for the development of medicinal compounds, as natural nucleosides, nucleotides, and nucleobases are essential to living organisms and play a major role in cellular development, signaling, and replication. Development of antiviral and antiproliferative compounds based on modified nucleos(t)ides and nucleobases has been extremely successful since the fields' inception in the 1960s and continues to be an expanding field of research. This work presents two projects based on nucleoside chemistry: modified pyrrolo[3,2-d]pyrimidine nucleobases as antiproliferative agents, and split-purine base fleximer nucleosides as antiviral agents. The pyrrolo[3,2-d]pyrimidine scaffold is a close mimic to the purine heterobases found extensively in nature. Halogenation at the C2 and C4 positions was previously found to impart antiproliferative activity against a wide variety of cancer cell lines, with EC50 values ranging from low micromolar to nanomolar levels. The continuation of the research is presented here and involves biological evaluation to determine the mechanism of action of these compounds and a structure-activity relationship study to probe the effect of substituents at the N5 position. It was found that these compounds exert their activity by alkylation of cellular DNA, and that activity can be enhanced by almost an order of magnitude through the addition of aromatic substituents at the N5 position. In addition, pharmacokinetic studies provided initial insight into the metabolic pathway and serum half-life of these compounds. A separate project saw the synthesis of fleximers with 2'-deoxyribose sugar moieties, which were tested against two viral lines to determine their potential as antiviral lead compounds. One of these compounds showed human cytomegalovirus inhibition at concentrations commensurate to the current standard of care, which offers a strong lead to the development of additional fleximer antiviral therapeutics. This represents the best activity against a DNA viral line to date for a fleximer compound, and is the first fleximer to show activity against the Herpesviridae viral family.