The Half Decent Pharmaceutical Chemistry Blog

Tonight, it’s time to show off your red ribbons.

Good evening and welcome to a, predictably, World AIDS Day’s based episode of Saturday Night Synthesis. Judging by the incredible number of red ribbons that have popped up all over the place (TV programmes, websites, newspapers, etc.), it’s almost impossible not to notice that, as every year, today we should all stop and spend a little bit of our time thinking about this terrible disease called AIDS. Honestly, I’ve never particularly liked this sort of one-day-only events, because they sound like: “Ok, let’s talk about it for a couple of hours, saying banal things and, perhaps, inviting someone suffering from it to a TV show (to explain AIDS isn’t transmitted like influenza or leprosy). Then we’ll all walk home feeling good because we nodded our head in approval for a long time and won’t think about it for the next 365 days.” That’s incredibly selfish, pointless and stupid, especially when it comes to AIDS because, unlike, say, malaria, it’s not just about charity to certain countries. AIDS is a constant threat everywhere: from the poorest African countries to the richest and most exclusive boulevards in L.A., from the roughest streets of Eastern Europe to the (apparently) happiest and most trouble-free families in Northern Europe.
So, frankly, a single day isn’t enough, but it’s nevertheless important to have such events to remember that, although science is making slow but constant progresses in the treatment of this disease, it’s ultimately up to us to avoid it, taking few, simple precautions. In the rich, Western World, people still die from AIDS and 2 millions are estimated to be living with HIV/AIDS this year. So, please, don’t come up with old the-Church-is-responsible-because-don’t-allow-catholics-to-use-condoms refrain, which would sound appropriate if talking about other nations: many people (especially straight ones) aren’t aware of how dangerous AIDS still is and tend to underestimate the risk, after the 1990s shock.
The key message, to highlight endlessly, is that our habits remain the most effective anti-retroviral medication to date for what is a constant threat.
Given the theme of the day, here we are to present the synthesis of the very first inhibitor of HIV reverse transcriptase to be clinically employed in the treatment of HIV infections: AZT. Being the first member of a now quite large family of drugs, we know a lot about its role even as a single antiretroviral agent, although nowadays a standard regimen features more than one nucleoside inhibitor (plus non-nucleoside and protease inhibitors, given the high rate of resistance).
AZT stands for azidothymidine and the name, together with a brief glance at its structure, explains how this drug and its congeners work: HIV reverse transcriptase is a key enzyme  for any retro-virus, such as lentiviruses HIV-1 and –2. This family, in fact, encompasses viruses with a single-stranded, diploid (two identical copies are in the virion), RNA genome, which has to be transcribed into DNA by the said enzyme. So, reverse transcriptase is fundamental for the replication of the viral genome, because the following, key event of the infection is the integration of the newly (retro)transcribed viral DNA into the host’s DNA: if this doesn’t occur, the virion won’t be replicated. Otherwise, when the host duplicates its genome, the viral one gets duplicate as well. When the host’s RNA polymerase transcribes, you’ll yield viral proteins too. Actually, the translation of the pro-virus (viral RNA turned into a little longer, correspondent DNA) results in a so-called (immature) poly-protein, which undergoes maturation through the action of a viral protease.

AZT (also known as Zidovudine) can impair the activity of reverse transcriptase through two mechanisms, once phosphorylated by a kinase: it can, in fact, either physically block the access of normal nucleotides to the active site of RT or be incorporated in the growing strand blocking the process because of the lack of a 3’ OH.
Things aren’t all that good once you turn at the adverse effect. Predictably, as any other pioneering drug, AZT easily causes a myriad of nasty complications to patients whose immune system is already dramatically compromised. Most common toxicity is myelosuppresion, which in turn leads to anaemia and neutropenia. That’s one of the reasons many people firmly believe these drugs to be even worse than HIV infection itself. Although I disagree, I can see their point: the use of these drugs implicates a series of severe adverse effects which would be incredibly hard to cope with for a perfectly healthy person. Their impact on individuals with a progressive inability to respond even to the mildest of the diseases can be intolerable. In a nutshell, the cure is worse than the illness.

The synthesis of Zidovudine is a pretty quick one: unsurprisingly, you start from deoxythymidine, with a protected 5’, primary, hydroxyl; the remaining, unprotected, secondary, 3’-OH reacts with methanesulfonyl chloride, to yield an excellent leaving group. Potassium phthalimide removes a proton from the amine, which in turn leads to an oxygen binding to the 3’, beta position of the sugar. This intermediate is then opened by adding sodium azide, which binds the 3’ position, obviously attacking the structure in alpha.
The synthesis is over once acetic acid has removed the protecting group from the 5’-OH, yielding a beautifully faked nucleotide: azidothymidine.
To be continued…