Further Adventures of a Chemist in Biology

Sincere apologies for not writing regularly on the blog. My chemical career trajectory has recently taken an unplanned turn and has required me to learn an other new skill set to succeed. I am now the CTO for my PI's biotechnology company, which sounds cool to say, but isn't as much fun as discussing science. My duties have now switched to making sales pitches, finding investors, writing SBIR grants, and making sure projects are progressing, I still found a little time to sneak in some science experiments last week. So lets get down to pretty pictures.

I xenografted some mice in the lab a few weeks ago for a collaborative project that didn't go anywhere. Last week, the tumors grew past the point of no return, and at UCLA once they hit 1.5 cm we are mandated to euthanize the mice. Last week I also found myself with a little extra time and with the help of a fellow chemist we made some fluorescent molecules that "potentially" have interesting tumor targeting properties. As I had mice with tumors too big, and molecules that target tumor cells, I pretty much said what the hell and injected this molecule into the mice (Yes, I had ARC approval). A picture of the results is below with the control mouse on the left, injected mouse on the right. Areas colored red have the highest intensity, areas colored dark blue have the lowest intensity.

It is a result like this that makes me happy for working at the crossroads of Chemistry and Biology. I love being able to make a chemical at the bench and walking downstairs to tail-inject my mice and see the results immediately. The molecule obviously has strong uptake into tumors. The question everyone naturally will ask next is, "how does this happen? What is the uptake mechanism?" Those are questions I'm not sure how to answer, if anyone has suggestions let me know.

Mitch
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Nexium's Dirty Little Secret

This is Prilosec OTC (omeprazole, also marketed as losec, antra, gastroloc, and a number of other names in other countries):

This is Nexium (esomeprazole, also marketed as sompraz, zoleri, lucen, etc):

Did you note the difference?  I'll give you a second to look again.

Omeprazole was brought to market by (what is now) AstraZenica in 1989.  It is used in treatment of gastroesophageal reflux desease (GERD, commonly known as acid reflux).  It is a proton pump inhibitor which works by blocking the production of gastric acid by parietal cells.  It was a blockbuster drug.  In the year 2000 alone, omeprazole made $6.26 billion.  But in 2001, omeprazole's patent was set to expire.  AstraZenica needed something to fill their pipeline, so they looked at their data for omeprazole.

Omeprazole is an example of a little-known class of chiral molecules where the stereogenic atom is not carbon.  We  typically think of stereocenters with carbon as the central atom.  But this is an example of a stereogenic sulfur atom (in case you're wondering where the fourth 'thing' bonded to sulfur is, it is a pair of electrons.  See the explanation of chiral sulfoxides for more information.  Ellman's chiral auxiliary is a good example of chiral sulfoxides in use).  Omeprazole is a racemic mixture: an equal mixture of (R) and (S) enantiomers.

In looking at their data on omeprazole, they noticed that the (S) enantiomer was more potent than the (R) enantiomer (according to this website, 4 times more potent).  So in 2001, AstraZenica prepared and won FDA approval for enantiomerically pure (S) omeprazole, which they called... esomeprazole.  Very creative.

So in 2001 when omeprazole lost patent protection, esomeprazole came to market.  In theory, you should be able to take a smaller dose of esomeprazole to achieve the same efficacy of omeprazole.  Indeed, the top suggested dose of omeprazole is 80 mg, and the top suggested dose of esomeprazole is 40 mg.  The only difference between the two drugs is the optical purity.  Omeprazole is a racemic mixture, and esomeprazole is optically pure (S) enantiomer.

So while I'm no health care professional (and my opinions should not be taken as such), it seems to me that if you're taking prescription esomeprazole, you should ask your doctor if a higher dose of omeprazole (which would be cheaper if you get the generic version) would work just as well.

What's also interesting to me (which I did not know until I was reading up for this post), is that omeprazole and esomeprazole are technically prodrugs: the ingested compound is not actually the active molecule.  Under acidic conditions (like in gastric acid), omeprazole is converted to a tetracyclic cation which is then covalently bound to ATPase:

Note that the tetracycle is achiral - it has no stereocenters, sulfur or otherwise.  So whether you take the chiral esomeprazole or the racemic omeprazole, both are converted to the same achiral tetracycle.  Again something to note if you're taking the optically pure version of the drug.

Also, another interesting piece of trivia:  omeprazole competitively inhibits the CYP2C19 and CYP2C9 enzymes.  Other drugs - like warfarin and diazepam (valium) depend on these enzymes for metabolism.  As a result of the competitive inhibition, these drugs cannot fully metabolize.  The effective concentrations of these drugs is increased.  People taking warfarin or diazepam should be warned if they are planning on taking omeprazole.

So now you know: omeprazole and esomeprazole are effectively the same drug.  I'm not sure why one would take prescription esomeprazole when omeprazole is available (over the counter in most places).  I understand omeprazole sometimes has more side effects than esomeprazole in some patients, so if that's the case, so I get taking the drug which minimizes side effects.  Make sure you also read this interesting article written in 2002 about the history of omeprazole.

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Cytotoxic Gold Nanoparticles

Vincent Rotello

Sarit Agasti and Chae Kyu Kim

In a new AOP from Nature Chemistry, Vincent Rotello's group report a new way of killing cells. There system uses gold nanoparticles (AuNPs) as the core, and attached to the core is a diaminohexane group. The diaminohexane fragment is sheathed from the cell by cucurbit[7]uril (CB[7]).

Once the AuNPs enter the cell they can be triggered to expose its cytotoxic diaminohexane appendages by introducing 1-adamantylamine (ADA); ADA outcompetes the diaminohexane for CB[7].

The paper shows some very nice chemistry and it does a nice job selling the point that their gold nanoparticles are toxic to cells. However, I am worried when they say they are "exploring this strategy in vivo..." as the current generation of their system seems indiscriminate. But, I always enjoy being proven wrong.

Link to paper: Recognition-mediated activation of therapeutic gold nanoparticles inside living cells
Other recent papers by Vincent Rotello

Mitch
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Why is High Fructose Corn Syrup so bad for you?

Is high fructose good for you or bad for you?

How many of you said bad?  Leads to obesity, right?  Gotta stay away from HFCS, right? That's what 'everyone' says, right?

Consider: The sugar we call 'table sugar' is sucrose: a disaccharide: a molecule of glucose and a molecule of fructose (two monosaccharides) covalently bonded to each other.  Sucrose is broken into fructose and glucose by enzymes within living organisms (like humans).  Humans don't use sucrose for energy, first we break it into glucose and fructose and metabolize the monosaccharides for energy.  So we ingest sucrose, digest it to glucose and fructose, then use the monosaccharides for energy.

One molecule of sucrose becomes 1 molecule of glucose and 1 molecule of fructose.  That means that sucrose is digested to a 50/50 mixture of fructose and glucose.

Consider: High fructose corn syrup is a straight mixture of unbonded glucose and fructose.  There are two common types of HFCS: HFCS 55 and HFCS 42.  HFCS 55 is ~55% fructose and ~42% glucose.  HFCS 42 is ~42% fructose and ~53% glucose.

So what's the difference?

Sucrose becomes a 50/50 mixture of fructose and glucose.  HFCS 55 is a 55/42 mixture of fructose and glucose.  Chemically, there's no difference between fructose from sucrose and fructose from HFCS.  Our bodies can't tell the difference between fructose from sucrose or fructose from HFCS.  We've been fretting so much about a 5% difference between the fructose content in the two sweeteners.

If our body can't tell the difference, and the percent content of fructose is essentially the same, why is HFCS so much worse for us than 'natural,' or 'organic' sugar?

It's not.

HFCS is no worse for us, and causes no more obesity than table sugar.  Once ingested, table sugar and HFCS are metabolized by our bodies in exactly the same way.

So what's the problem?  Well, the problem is sugars (both sucrose and HFCS) are in EVERYTHING.  Too much sugar (again, either from sucrose or from HFCS) IS bad for us, and will lead to higher caloric intake, and eventually weight gain.  So the problem is too much sugar - not too much HFCS, and the solution is to eat less sugars overall - not to ban HFCS from everything.

But that's not what 'everyone' is saying.  And the court of public opinion can be quite harsh.  So harsh, in fact, that the HFCS manufacturers are attempting to rebrand.  No longer will we find HFCS on the ingredient list.  Now, we will see 'Corn Sugar.'  This means the same thing.  It's the same 55/43 mixture of fructose to glucose, but they're rebranding to move away from the negative associations.

What do you think?  Good idea or bad idea?  Should we just ban HFCS/Corn Sugar?  Should we regulate the amount of sweetener that's allowed to be in a Suggested Serving Size?  Do you agree with the decision by the HFCS manufacturers?