The Half Decent Pharmaceutical Chemistry Blog

Tonight, we reaffirm our genuine hate for Mr. Watson by destroying DNA (or, at least, undermining it).

Hello and welcome to the show. Last Thursday was not only my 24th birthday, but people might have celebrated the anniversary of the discovery of the structure of DNA. Back in 1953, Adolf Watson and Crick came up with their hugely important finding and subsequently went for a pint of ale at the Eagle Pub in Cambridge. This will always remain a milestone in the history of science and mankind, despite the men who gave it to the World. In fact, (if you haven’t lived on the Moon during the last 4 months, you can skip this part) Herr Watson seems particularly keen of expressing narrow-minded, idiotic, racist, fascist views I’ve already commentated here.
On that occasion I realised nearly all of my readers agrees with Watson’s ideas: I respect everybody’s opinions and, therefore, always published whatever comment one wants to make (the only reason why comments are moderate is to prevent this blog to be full of spam). This, though, doesn’t mean at all that, to meet reader’s demands I am going to take everything I said and believe in back (as Watson apparently did). Thus, this will always remain an anti-Watson zone.

On S.N.S, I’ve already tried to make him losing his temper by giving an example of gay-lesbian-transgender piece of synthetic work, when describing testosterone. Today, despite my undeniable love for molecular biology, I celebrate Watson’s achievements by targeting DNA metabolism and showing how to effectively tackle biology using nothing but pure chemistry. So, tonight’s show is a little bit about anger: I suggest listening to Blur’s “Song 2” while performing these two, incredibly short syntheses.

Our target, ladies and gentlemen, is the biosynthesis of folic acid, a fundamental substance for the replication of DNA. In particular, a fruitful target to inhibit the biosynthesis of DNA (in mammals as well as bacteria) is tetrahydrofolic acid, a functional derivative of folic acid, which basically acts as a methylene donor.

In bacteria, tetrahydrofolic acid is synthesised from pteridine. The reaction requires two molecules of ATP, para-aminobenzoic acid and glutamate. In mammals, instead, you go straight from dihydrofolic to tetrahydrofolic acid.
Two enzymes play key roles here: first, dihydropteroate synthetase, which catalyses the formation of the covalent bond between phosphorylated pteridine and PABA, and dihydrofolate reductase, which yields the final product. While the former is found exclusively in bacteria, the latter represents a target for the design of both antibacterial and anticancer drugs.
And here is where chemistry come to play. Both Trimethoprim and Pyrimethamine are non-classic dihydrofolate inhibitors, in the sense that they retain only a small portion that mocks the structural motif of dihydrofolic acid, the substrate of the enzyme. This structure has proved to be just what it takes to efficiently interact with the active site of the reductase, actually preventing it from doing its job, through three hydrogen bonds: exactly those dihydrofolic acid forms.

Despite a similar structure and synthesis, Trimethoprim and Pyrimethamine are used in two, completely different contexts: while the former is an effective bactericidal (in association with sulfamethoxazole), the latter (as well as all the other non-classic inhibitors) is useful in the treatment of malaria.

Trimethoprim targets an enzyme present in both bacterium and mammalian host, but is quicker at acting on the former type, so, despite possible plasmid-related resistance strategies (reduce cell permeability, reductase overproduction, etc.), it is a reliable weapon against K. pneumoniae, Moraxella caterrhalis, P. pneumonia, Enterobacter, Serratia and Salmonella.
Its synthesis begins with ethoxypropanenitrile and trimethoxybenzaldehyde reacting in a condensation which occurs with some help from sodium ethanolate. Then, guanidine is added and, through a double nucleophilic attack, we directly obtain Trimethoprim.
Pyrimethamine is remarkably prone to react with the protozoal version of dihydrofolate reductase. As a result, it’s able to provide a good treatment against merozoites, with P. falciparum often mutating its enzyme to survive the exposure to this drug. Nevertheless, when in association with Chloroquine, it can serve as a highly effective prophylactic treatment and, in association with sulfadoxine, a cheap alternative to Chloroquine when this has become useless because of resistance.
This synthesis is rather short, too: all you need is ethyl propionate to react with phenylacetonitrile in a Claisen condensation. The carbonyl is subsequently methylated with diazomethane and strong nucleophile guanidine is added to complete the reaction and free methanol to yield the aromatic ring.
Live with that, Watson!