The Half Decent Pharmaceutical Chemistry Blog

Following last week’s massive news, this is the right time to turn into reality an idea that came to me almost a year ago. You see, this blog has been tremendously fun to write and  I genuinely believe it has perfectly represented me as an undergraduate who studies pharmaceutical chemistry. However, those days are about to end, as my entrance in the eerie world of graduate studies will take place in October and, moreover, pharmaceutical science isn’t going to play the part in my life it used to. Therefore, a blog which clearly points at pharmacy as its main theme will suddenly get meaningless.

So, I have decided to close this blog in July, a couple of days after graduation. But this doesn’t mean at all I will leave the scientific Blogosphere.

One of the most important things I have realised in these two years is that I really like to have a place where I can literally throw my thoughts in and, amazingly, people can come and leave their opinions, safe in the knowledge I will never censor them (unless they are rotten spammers).
What’s more, I love what We are doing with our blogs (and by “We” I mean only scientific bloggers: I hate people who set up blogs just to talk about their useless and miserable lives). We can really make science entertaining and enjoyable. We are already making the difference, changing the way science is discussed. We have ideas! We are the Future! We CAN!
Ehm, well, elections are about to come here in Italy (and somewhere else): I might have been influenced and exaggerated a bit…

Still, I do believe scientific blogs are great opportunities and I want to remain part of this community for many years. I just feel I need something different, something in which I can find myself fully represented for the years to come: that’s why this blog will be closed and I will move one, to a new project (and, hopefully, a higher quality level).

To sum up, I will keep writing here, as there are good things left to be written. Then, once no longer a pharmaceutical chemist, I’ll close it.
Meanwhile, I will work at my new blog, which will formally open in September (can’t provide a date at the moment) but be (pompously) unveiled next week.

Thank you for reading this blog: I hope (and actually believe) you will like what I’ve planned for the future.

The REAL reason why I have dramatically reduced the number of posts has little to do with the fact that I’m working at my graduation thesis project. Actually, it has been a consequence of my quest for an interesting available project for the next year: before choosing whether to submit any application, you need to read as much as possible about not only the area of research involved but also on the group’s itself, and if invited for an interview, you need to prepare yourself properly. Let’s say the last months have been all but relaxing and stress-free.
Call it superstition but I decided to never mention my application forms for a PhD studentship. Even my family and friends had no idea what was really going on. Until now, when I’ve been formally offered one at Imperial College, London, that I have obviously accepted.

So, from October 2008 I’ll live in one the biggest, most chaotic, coolest and most exciting cities on the planet. To be honest, I have almost exclusively considered England for my PhD as I wanted to live in place where I could fully interact with the locals even outside the lab (where your English is generally sufficient to interact with colleagues and boss). No enquiry was sent to lovely places such as France, Germany (although I considered Switzerland), Sweden, etc., and, because I somehow wanted to remain in Europe (at least for the PhD), England looked the ideal solution.
Generally speaking, though, I have always wanted to become a PhD and to work at a project abroad, even before I realised what my main interests were, and always been attracted by the dear old Blighty (I guess many of you don’t know what this means, do you?).

I was interviewed by both Oxford (department of biochemistry) and Cambridge (the famous MRC Laboratory of Molecular Biology), but we were both looking for something else. Anyway, I am going to dedicate a post to this as I’ve had radically different impressions about them: all I want to say, at the moment, is that I may still consider Cambridge for a PostDoc, whereas I sincerely doubt I’ll have anything to do with Oxford University in the future (although they still have to tell me whether I got the job or not).

By the way, I’ve managed to get what was at the very first place in my wish-list (by a large margin, indeed): a position at the Gene Regulation and Chromatin Group of the MRC Clinical Sciences Centre at Hammersmith hospital, which is part of the faculty of medicine of Imperial College.

The studentship is a 4-year Gordon Piller Studentship kindly provided by Leukaemia Research and offers a £16,228 annual stipend plus fees, with an allowance of £11,564 towards research costs. However, I hope you to believe money is the least of the reasons I find this project so appealing. I will certainly provide more details later on, but, to sum up, I just would like you to want it encompasses all my major interests in molecular biology.

Stay tuned: massive news to come soon…

Now that the major attraction of this blog, Saturday Night Synthesis, is over, I face the issue of coming up with something to make this blog worth-reading. A friend of mine has recently come up with a pretty intriguing idea: gossip.
Plainly, he believes I should as most of newspapers these days which, for example, show much more interest in Sarkozy’s love affairs rather than in his opinions on, say, illegal immigration. In fact, focusing my catchy introductions on popular topics would attract readers, so that I could eventually trap them in a labyrinth of scientific facts.

Well, let’s give it a try, by looking at one of favourite countries: France. Now, you all know Monsieur Sarko (who, if you are American, is the French president), 53, divorced from his second wife Cecilia, 50, and almost instantly turned to and got married with Italian, former super-model, Carla Bruni, 40. Can you find in your heart the force to blame him?

This switch might have inspired a French group when focusing their attention on a less glamorous switch not between models but heterochromatin proteins HP1β and HP1γ (doi:10.1038/embor.2008.1).
Despite not being as sexy as Carla Bruni, these histone modifiers are equally very interesting, as their role is far from being understood.
For many years, due to their HMTase activity (which stands for histone methyl transferase) and their huge presence at pericentromeric heterochromatin domains, they have been considered to act as pure silencers of gene expression. Recently, however, many findings has started undermining the basis of this assumption. HP1γ, for instance, has been frequently spotted at active euchromatic genes and a transcription-dependent recruitment has been proposed.

What the article mainly focuses on is the way these proteins act on HIV-1 5’ long terminal repeat, a well-known promoter of retroviruses. Interestingly, both NF-kB and protein kinase signal-transduction pathways stimulate this promoter and both phosphorylate epigenetic-regulation hot spot serine 10 on histone H3.
Obviously, I can’t (and don’t want to) tell you how these French reach their conclusions because that would mean breaking copyright rules. However, going back at the beginning story of Sarko’s love affairs, they postulate a switch between mainly transcription repressing HP1β/transcription stimulating HP1γ due to the aforementioned H3S10 phosphorylation, which they describe using the appealing expression Phospho-Switch. What this names underlines, though, is that not only is the phosphorylation the key aspect of this mechanism, but that it comprehensively overcomes the already existing tri-methylation of lysine 9 on histone H3 (to which HP1β binds), possibly altering HP1β binding site on histone 3 so much that it’s displaced and, after a brief moment while ChIP experiment shows nothing on the 5’-LTR, HP1γ is quickly recruited. Which is basically like displacing an old wife and quickly getting a younger, hotter new one, isn’t it?

In case psi*psi were reading this, happy birthday and, to already answer your question, no: there are no gels in this molecular biology affair.

Tonight is the night...

Hello and welcome to the last episode of Saturday Night Synthesis of this series. Simply looking at tonight’s protagonist you might wonder what makes this antiviral drug so special to be in our grand finale. Well, quite a lot to be honest as this synthesis is basically the only reason why, last year, I thought of  describing a synthesis of a drug on any given Saturday night, despite the fact that I hate this sort of weekly, compulsory posting, that forces you to write something on a certain day, turning a great hobby in a work-like duty.

There is no particular reason, I’ll admit, to like this synthesis so much. But, you know, love is always irrational and illogic. The moment I started to study the chemistry of Vidarabine it was love at first sight. Actually, I doubt love is right expression: it’s more a sort of Sturm und Drang, an explosion inside of me, an erupting ensemble of primeval, hidden passions that all comes out at the same time, a cathartic burst of feelings.

All of sudden I feel like I’m in a Caspar David Friedrich painting and my ears are filled with Felix Mendelssohn’s “Fingal’s Cave”.
So, I don’t care too much how drug works (as many other antiviral drugs it’s a fake nucleotide which, after a cycle of phosphorylations, targets the viral DNA polymerase both inhibiting it or yielding an incorrect DNA strand because Vidarabine is basically an adenine bound to D-Arabinose instead of D-Ribose)  or what its clinical applications are (herpes simplex and varicella Zoster). I just want to see this wonderful, touching, enantioselective synthesis, hoping you’ll like it.

The concerto opens with pentose carbohydrate D-Xylofuranose, whose hydroxyls are not only all protected with benzoyl groups, but also with a spatial orientation which is exactly the opposite of that of D-Arabinose. However, changing the orientations of those substituents is easier than what it may seem. First, bromide is added, in acetic acid, and this yields a mono-brominated intermediate, which reacts with chloro-mercuric adenine in what is, by a large margin, my favourite name reaction: the enantioselective Koenigs-Knorr reaction.
Apparently, the reaction begins carbonyl from the protecting benzoyl group in 2’ promoting the formation of a five-term cyclic ketal through the displacement of bromide from the 1’-position. This is also helped by the HgX-group, which tends to evolve into a stable bi-halogenated derivative compound, leaving a negative charge on the purine, therefore, quickly binding to the sugar.  However, all this amazing orchestration gave us a useless intermediate where the sugar is bound to the wrong part of the purine.
Luckily, the benzoyl group breaks the bond with the nitrogenous base twice, so, we end up, once again, with an alpha-oriented ketal, with a delocalised positive charge. The purine undergoes a rearrangement and, now with the negative charge where it ought to be, stereoselectively (with a beta-oriented linkage) binds to the sugar.
At this stage, the structure has reached a decently nucleotide-like shape. So, it’s time to turn Xylose into Arabinose, by epimerising both 2’ and 3’ hydroxyls. First, the protecting group are removed with gaseous ammonia and methanol.
An alpha-oriented cyclic ketal encompassing the 5’ and 3’ position is yielded by adding acetone and, with this protection in place, methanesulfonyl chloride is added, giving a lovely leaving group to the 2’-OH.
Acetic acid and 100°C will do the job of opening the ketal and sodium methoxide yields a beta-oriented epoxide between 2’ and 3’.
This last structure is finally opened, featuring correctly-oriented products, with sodium benzoate in a mixture of DMF and water, so that, at last, Vidarabine is yielded.

Spring has finally arrived! Therefore, I enjoyed my duty of correcting exams in the sun. Not a long job, to tell you the truth, but rather gratifying and useful given my interest in eventually becoming a lecturer, one day.

Now, I’ve decided to draw some absolutely meaningless graphs to analyze the trend of the results. First, the fundamental question of which gender did the best job: ladies (always to go first) or gentlemen?

The former seem to have done slightly better.
Then, because the exams was taken not only by my colleagues, but also by some weird people who study an incredibly pointless thing, which should give them the opportunity find a job as pharmaceutical promoters among pharmacists: what a life! So, here things change a little bit, showing a difference between male pharma chemists and these wannabe, pharmaceutical traveling salesmen.
Last but not least, how the whole test went. Not very well, as the third graph shows (considering 12.5 means no mistakes).
See you soon, with more relevant data from my thesis project (hopefully).