ABSTRACT
Important lessons useful to a medicinal chemist working in drug development are learned from the clinical failure of the anti-HIV drug, lodenosine (β-F-ddA), and its alleged toxicity. A hypothesis to explain the unexpected toxicity of lodenosine is based on the potent activity of seemingly negligible small amount of a contaminant (β-F-dA) that was present in the batches of lodenosine used in the clinical trials. β-F-dA is a strong hepatotoxic agent. The origin of the β-F-dA contamination in lodenosine was due to an incomplete deoxygenation step in the chemical synthesis. To overcome this problem, various approaches to produce lodenosine free from any traces of β-F-dA were developed; however, for economical reasons, they were not implemented. This chapter also describes the changes associated with swapping the ribose ring for a 4′-thioribose. The trends that led us to formulate a structure-activity relationship (SAR) for fluorinated nucleosides did not correlate well for the 4′-thioribose nucleosides, but some interesting chemistry and new chemical applications for the use of DAST in this family of nucleosides were discovered.
