Chemical synthesis of fluorinated carbocyclic nucleoside analogues

Benckendorff, Cæcilie Maianna Margrethe

Abstract

Since the discovery of their pharmaceutical potential, nucleoside analogues have become one of the most important classes of chemotherapeutic agents in the treatment of many cancers and viral infections. In many chronic illnesses, such as HBV or HIV infections, nucleoside analogues have become the go-to option in first line treatment regimens. Although nucleoside analogues have a long and rich history in the space of medicine, they are not without their limitations, and often they suffer from poor cellular uptake, metabolic stability and a growing resistance profile. As such, the development of new generations of nucleoside analogue remains of considerable interest.
In the interest of furthering a hereto under-explored pharmacophore space, the work described within this thesis will centre around the synthesis of 6’-fluorinated carbocyclic nucleoside analogues, wherein the ethereal oxygen has been replaced by a CHF or CF2 moiety.
A novel methodology to the insertion of a CF2 fragment, inspired by the work of Dilman and co-workers, was investigated. In this investigation, two different sources of a CF2 carbene were trialled. Although some CF2 insertion was observed, it was decided that these methods were unsuitable.
A synthesis was instead developed, delivering 6’-mono and gem-difluorinated carbauridine analogues on gram-scale. With a reliable access to these analogues, diversification of the pseudo-sugar ring was explored, affording a small library of 16 nucleoside analogues, of which 10 were novel. Of these 16 nucleosides, 10 were evaluated against two cancer cell lines, PANC-1 and U87-MG. One analogue showed moderate but promising activity against U87- MG cells, cementing the pharmaceutical potential of the replacement of the furanosyl oxygen with fluorinated carbon.

Citation

Benckendorff, C. M. M. (2023). Chemical synthesis of fluorinated carbocyclic nucleoside analogues. (Thesis). Keele University. Retrieved from https://keele-repository.worktribe.com/output/529473

• Thesis Type: Thesis
• Deposit Date: Sep 27, 2023
• Publicly Available Date: Jun 6, 2024
• Public URL: https://keele-repository.worktribe.com/output/529473
• Additional Information: Embargo on access until 5 June 2024 - The thesis is due for publication, or the author is actively seeking to publish this material.
• Award Date: 2023-06