Synthesis of Carbovir and Abacavir from a Carbocyclic Precursor
Abacavir is a carbocyclic synthetic nucleoside analogue. Abacavir is converted by cellular enzymes to the active metabolite, carbovir triphosphate (CBV-TP), an analogue of deoxyguanosine-5′-triphosphate (dGTP). CBV-TP inhibits the activity of HIV-1 reverse transcriptase (RT) both by competing with the natural substrate dGTP and by its incorporation into viral DNA.
Synthesis and characterization of potent Abacavir impurities
Abacavir (ABC) is clinically associated with hypersensitivity reactions, risk for cardiovascular disease, etc. A possible way to minimize side effects is by modifying chemical structure. Three esters of ABC containing amino acid (glycine) and dipeptide esters (glycyl-glycine) were synthesized and their activity on HIV-1 III B replication in MT-4 cells was evaluated. One of the newly synthesized esters—Gly-ABC—demonstrates low-cytotoxicity and high-anti-HIV-1 activity in MT-4 cells, as well as low-mitochondrial toxicity and high-genetic barrier to resistance.
Ail efficient synthesis of the highly potent anti-HIV carbocyclic nucleosides (-)-carbovir and (-)-abacavir has been accomplished from D-(-)-ribose using a rhodium(I)-catalysed tandem hydrosilylation-intramolecular aldol strategy to access it key intermediate.