#Retrotime - Cycloheximide

Cycloheximide 1 is a cheeky number that is worth a mention.  It is a tool compound with a proven track record of actually being useful, with its years of use in cellular biology.  Regarding retro, I have included a brief synthesis at the end, so no peeking as it will tarnish your retrosynthetic blank canvas.

Blockbuster - Atorvastatin

Most blogs appear to have a generic period of time, where the posts are as frequent as a British person winning Wimbledon.  To get the ball rolling (again) down the mountain of productivity, through the plain of peril to the crown of command, I am posting one of my first ideas for The Stirrer Bar.  I thought some aid memoires for drug molecules/tool compounds would be useful for translating molecular structures to biological functions etc. Queue wikipaste...

Beware non-benign alkyne

Alkynes will probably feature a lot in this blog due to their bioorthoganol nature – but beware, as a recent paper demonstrates, everything can change in the local environment of a protein.

The Peterson olefination

There are many different ways to synthesise alkenes in organic synthesis. The problem in many cases, especially those in macrocycles or non-cyclic systems is getting good E/Z selectivity. Several methods are possible however, one of the simplest is the peterson olefination. The reaction allows control of E/Z selectivity by the conditions used to remove the silane.  

Synthetic polymers self-assembling into catalytic structures

Modern organic chemists have access to a huge range of different chemical reactions and, these days, even the most complicated natural product could probably be synthesised if somebody wanted to. However, nature still does chemistry a hell of a lot better than even the best organic chemist; enzymes allow even the simplest organism to catalytically (and often asymmetrically) carry out organic reactions at room temperature in an aqueous environment. Being able an enzyme’s characteristics artificially would be, obviously, hugely advantageous. And there are a number of project on-going particularly using supramolecular chemistry, dendrimers or polymers. Another method, one of the first in a completely aqueous environment, has been described in a short communication in Angerwandte by the Palmans group. It utilises a simple polymer functionalised with L-proline allowing it to diastereoselectively catalyse an aldol reaction with cyclohexanone and p-nitrobenzaldehyde.

‘Arsenicals’

When I read the title of this paper – Arsenical-maleimide for the Generation of New Targeted Biochemical Reagents – I thought you’ve got to be kidding, but having perused the abstract, I realised that I had much to learn.

Quite interesting: Sodium bicarbonate

I suspect some people are reading that title thinking “really?” But the fact of the matter is that the synthesis of sodium bicarbonate was the first triumph of industrial chemistry and therefore the first entry of the private sector into the chemical arena, something that still sets chemistry apart from the other major academic sciences, biology and physics; this is one of the reasons that chemistry is so advanced today.

But why sodium bicarbonate, is it really that important? The obvious answer is yes, but for things that we all now take for granted; soap and white cotton shirts. If this still sounds weird the industrial synthesis of sodium bicaronbate was described in 1856 as “one of the great benefits, if not the greatest that modern science has bestowed on humanity” but why?

Reversible covalent inhibitors: the best of both worlds?

What’s not to love about covalent inhibitors? Well, unfortunately, quite a bit when you start thinking about it. Reversible inhibitors offer an extra layer of subtlety, they are tuneable, time-dependent and can modulate individual functions of proteins or biological systems by using several inhibitors in combination. That is as long as you can make them potent and selective enough; covalent inhibitors tend to solve the first problem in spades, once you make your covalent bond it’s staying there usually knocking out the enzyme target. Yet the greatest strength is the greatest weakness, unfortunately by improving the potency of your compounds the problems with selectivity are multiplied. If your covalent inhibitor goes to the wrong protein first well tough; this great if you’re a beta-lactam antibiotic trying to kill a bacterium, but killing things isn't what tool compounds are for. 

But what if you could make a reversible covalent inhibitor? Potentially you could gain the potency and, if well designed, the selectivity as well. Maybe this would still be difficult to incorporate into a drug, but as a basis for a sophisticated tool compound it could be extremely useful. Taunten et.al. have developed such a system that targets the amino acid cysteine. 

A non-functioning tool? - when’s the next paper?

This paper from Feringa’s Lab caught our eye.  The paper demonstrates the ability to incorporate azobenzene photoswitches onto sites of interest through a bio-orthogonal reaction.  The group synthesised two azobenzenes (Figure 1), one with a short PEG motif and one without, evaluated their physical properties when ligated to various targets.

Shaking Up Small Molecule Binding

I’ll be honest I thought I knew a fair bit about small molecules binding to proteins. If someone asked me what a phenyl ring in a molecule was doing I could talk earnestly about the entropic effect of displacing those water molecules, stacking interactions, Van der Waals forces, maybe even pi-charge interactions. I could have also talked about hydrogen-bonding and I would have certainly mentioned the hydrophobic effect (mind you that is more complicated than it looks sometimes) and how a molecule rotates (i.e. the less carbon chains and more rings the better).

One thing I certainly would not have mentioned was how individual bonds vibrate, but what do I know? 2 recent papers talking about deuterium effecting how compounds smell  and another using the IR spectra of nitrile groups to explain the observed binding affinity of a family of HIV drugs demonstrate how what I think I know and what I actually know are sometimes a disappointing distance apart.

George Orwell's rules on writing: applicable to science?

The 65^th anniversary of George Orwell’s 1984 this year and the BBC is putting on many programs discussing the work of the great author.  Orwell had some very strong views on how things should be written and wrote an essay on the subject about 6 rules that he thought should be at the centre of any piece of writing, so can they be applied successfully to science writing?

Bio-orthogonal profiling of protein methylation

Protein methylation is an important biological process e.g. histone lysine methylation is involved in both gene activation (on histone 3 and Lys 4, 36 and 79) and silencing (H3 Lys 9 or 27 and H4 Lys 20). But how can other protein methyltransferases (PMTs) be investigated? Genetic approaches are always useful, but can have limitations particularly if your protein isn’t very common, forms complexes with other proteins (which would be disrupted by its absence and cause phenotypic changes beyond protein methylation) or if your process results in a non-viable cell. Chemical approaches would be extremely useful and complimentary, but as always problems with selectivity have to be overcome; a particular problem with PMTs as SAM (S-Adenosyl methionine) is a particularly prolific enzyme co-factor.

What to do then? Islam et. al. have developed a rather elegant solution that could allow general examination of a variety of PMTs, by creating mutants of proteins that can accept a synthetic azido-SAM donor. The enzyme then tags its target as before but instead of a methyl an azide containing group is left behind, this can subsequently be reacted with tags (like biotin) which contain strained alkynes in a bio-orthogonal manner. 

Viva Survivor: Baldwin's rules

This is the first of the basic science posts we will be running about once a week; first up is Baldwin's rules (or guidelines as many prefer), for more detail look here. 

Baldwin’s rules are empirical observations of possible cyclisation reactions, classified according to the size of the ring being formed, the nature of the electrophilic portion of the molecule and whether the bonds are broken inside or outside of the ring.  Although the based on empirical observation they use stereochemical reasoning including orbital overlap and the preferred angle of attack of a nucleophile. Because they are essentially empirical they are not really rules in the Woodwood—Hoffman sense of the word, but should be thought of as guidelines; there are exceptions!

the stirrer bar

As you might be able to tell this is a new blog making it's way out into the big bad world wide web. Hopefully the title implies that this is going to be a science blog, and the fact that it's written by a couple of chemistry graduates probably gives you an idea of our area of interest. 

There are many chemistry blogs out there already and seeing as neither of us works on total synthesis (which is covered very well by other blogs here and here) or the pharmaceutical industry (covered excellently here) so we are going to try to write about our major area of interest namely chemistry at the interface of chemistry and biology. 

We are hoping that the blog can become a bit of a resource for people looking to learn a bit of new chemistry and so we are going to put up some named reaction posts and synthesis we like, but also posts on broader scientific areas we find interesting. Hopefully someone other than us two will find it interesting as well...