The Half Decent Pharmaceutical Chemistry Blog

Tonight, you are invited to a masquerade ball.

Good evening and welcome to a secret episode of Saturday Night Synthesis. Totally inspired by my recent watching of Kubrick’s last film, Eyes Wide Shut, tonight we talk of a drug whose action could be briefly explained with its characteristic of being masqueraded as a thymidine and then perform its synthesis, all dressed up like it was still carnival and Jocelyn Pook’s “Masked Ball” casts an spell of mystery, decadence and sin upon the scene. It is thanks to this mask, in fact, that Brivudine (aka BVDU) exerts an effect against viruses such as varicella zoster and, above all, herpes simplex 1. Both major targets, thus, belong to the Herpesviridae family: therefore, they present a double-stranded, linear DNA, a broad host spectrum and a relatively quick replication cycle.

While polymerases are replicating the viral DNA, nucleoside analogues tend to be incorporated into the growing strand with predictable dramatic consequences. Virus-encoded thymidine kinase selectively activates the drug phosphorylating it to its 5 '-diphosphate derivative.
After this step, cellular enzymes continue phosphorylating the molecule, until it becomes a 5'-triphosphate, which is finally capable of acting as an alternative substrate against the viral DNA polymerase. This, in turn, leads to a block of this incredibly active enzyme, on which both HSV-1 and VZV rely massively for their replication cycle.
To sum up, this drug is recognized as a normal thymidine by the enzymes which phosphorylate it, despite having a bigger substituent instead of a methyl. This, though, is the sole difference between the two and this striking similarity makes Brivudine so effective.

To achieve this impressive level of effectiveness, you don’t need to go through a particularly complicated pathway, though. The synthesis starts from a Uracil with a vinyl group in 5, brominated in DMF. Both carbonyls are subsequently protected with sylil chloride in HMDS.
Now, everything is in place for the main event: a rather protected 1-chloro-deoxyribose reacts with the Uracil derivative in, sadly, a non-stereoselective reaction (see below), yielding in turn both enantioforms.
Before the therapeutically useful product could be isolated (namely, the 2R), all the protection are removed by adding sodium methylate.
Important news: this edition of Saturday Night Synthesis will finish next Saturday (8th). Stay tuned: we are preparing our grand finale!