Of Wine and Chemistry

I was away at a conference last week. One of those great small conferences where you can spend a lot of time interacting with people outside of the talks. It was great. I'm convinced the best science is discussed over beer and wine. I titled this blog post Wine and Chemistry because I like wine. It's not that I don't like beer. I do. I just can't drink very much of it before I feel bloated and uncomfortable. Thus I much prefer a nice red wine to drink while pondering the deeper aspects of asymmetric catalysis. I am not alone in this. Some friends of mine who were also at the conference are wine lovers and we had a nice little private wine tasting one evening. It was a wonderful experience as I got to taste a wine that was over 40 years old. The cork you see above is from that special bottle of Rioja. Although it was delicate and it broke when we pulled it from the bottle, it was in surprisingly good shape. The wine, on the other hand, was about 20 years past its prime. Not spoiled but it definitely was flat. It tasted like compost. That brings me to a little bit of chemistry. The wine was definitely oxidized but was not vinegar. It was stored well and the closure held up against the ravages of time. It was almost sherry like. Of course the one thing that distinguishes an oxidized wine like sherry is the presence of acetaldehyde. This had quite a bit of it. The tannins were completely gone. I wonder if there was any resveratrol left? Definitely not a wine I would pop and pour at a picnic but it was truly an experience to taste history.

Largazole and Histones

I have a certain affection for things that affect epigenetic regulation. Hence my interest in a class of enzymes called histone deacetylases (HDACs). These are zinc-dependent hydrolases that cleave the acetate group off of the lysine residues on the N-terminal tails of H3 histones. The bottom line is that deacetylation of these proteins that DNA wraps around turns off gene expression. In some cancers, tumor supressor genes are turned off and application of HDAC inhibitors turns them back on causing the cancer cell to die its normal death. That is a simplistic description. It is actually much more complicated than that. A simple animation of this is provided on the Methylgene web site.

In January, the Luesch group from Florida reported (J. Am. Chem. Soc., 130 (6), 1806 -1807, 2008. 10.1021/ja7110064) the isolation and characterization of an antiproliferative natural product called largazole. They subsequently synthesized it and discovered it was an inhibitor for HDACs (J. Am. Chem. Soc., 130 (26), 8455–8459, 2008. 10.1021/ja8013727). The synthesis is pretty efficient encompassing 8 steps with an overall yield of 19%. That's not too bad. Andy Phillips, in Colorado, has just published another 8 step synthesis and have confirmed the Leusch findings (Org. Lett., ASAP Article, 10.1021/ol8013478 ). In addition they have done some NMR conformational studies to show the solution structure of this interesting molecule.

What I find very interesting about this story is that the compound looks so very similar to cyclic peptide HDAC inhibitors developed in Japan (FK228, link to PDF). The sulfur gets buried into the active site pocket to bind the catalytic zinc while the cyclic structure binds to the surface of the enzyme. Both are necessary for the nanomolar level of inhibition of Class I HDACs that are observed for these compounds. Knowing the structure of FK228, I would have immediately made the connection between largazole's antiproliferative effects and HDAC inhibition. The original isolation paper does not speculate on that which makes me wonder if the Leusch group only made this connection later. I presume so.

The way this story has unfolded reminds me that I need to search more broadly when I am looking for HDAC inhibitor structures. Just searching on the keyword 'hdac inhibitor' is not enough and probably misses some compounds that people haven't yet connected to HDACs.

Atomic Noodles

Ok, I hear the voices from my last post and have decided to commit to trying to keep this blog going. My goal is to make sure I publish a post at least every week, if not more often. I've realized it doesn't have to be a chore and that I don't have to always have some latest greatest chemistry from the just uploaded ASAP's. I can do some fun stuff. I can even borrow from other stuff on the web. Why not? People do that all the time on their blogs.

Ok, then. How about a little bit of video? I know it's not directly chemistry, but it does fascinate me. From "The Ring of Truth: Atoms," here is Chef Kin Jin Mark pulling noodles.

To be or not to be

Oh, I know I've been ignoring this blog. I wondered if anyone even read it. It has dropped down on my list of priorities. But now I read over at Homebrew and Chemistry that my blog is being chopped from at least one person's reading list. I suppose I should have seen it coming. The question is, will this inspire me to reinvigorate Carbon Tet or should I let it die in quiet peace? Perhaps if people leave a comment or two it might help me make up my mind.

Drink your pharmaceuticals

An interesting report on the state of our drinking water appeared today on CNN. We've often heard of municipal drinking water being polluted with things like lead, MTBA, pesticides, etc. But this report talks about finding lots of different pharmaceuticals in our drinking water - everything from sex hormones to antibiotics to, yep, antidepressants. Actually in some places more than 50 different drugs were detected. While the amounts are very tiny (ppb or ppt) very little is known about the effects of even small amounts of drugs over a long period of time like decades. I think Dr. David Carpenter says it best:

"We know we are being exposed to other people's drugs through our drinking water, and that can't be good," says Dr. David Carpenter, who directs the Institute for Health and the Environment of the State University of New York at Albany.

Depressed?

Depression seems to be the illness of the 21st century and for more than 15 years Selective Serotonin Reuptake Inhibitors have been the pill of choice. Yes, the number of prescriptions of these antidepressants (effexor, prozac, seroxat, etc) has increased exponentially. So much so that these drugs being excreted by humans is negatively affecting wildlife. With all the billions of dollars being spent on these drugs has anyone ever asked the question, Do they help? Well, psychologists at the University of Hull have reviewed the results of about 50 clinical trials. Their conclusions? SSRI antidepressants do not really seem to provide a benefit to most people as compared to placebos. Sure, there's a little evidence that they help to some extent the most severely depressed, but the large majority of the millions of prescriptions really are doing nothing but causing gender confusion among the fish and frogs.

The Air Has Landed

The good, the bad and the ugly. Well, there's absolutely nothing ugly about the macbook air. It's absolutely gorgeous. Thin thin thin. It is much sturdier and lighter than I expected. It feels weightless. HUGE plusses for design and portability. The keyboard feels great. The screen looks fantastic. You can see some comparisons with my 15" macbook pro. It's definitely smaller by a long shot. I love the lighted keyboard. It seems to function even better than my MBP. 

As for performance, it's not the quickest horse out of the gate but it certainly wasn't as pokey as I expected based on the reviews out there. For most major tasks - keynote, pages, word, web browsing - it performs just fine. It even compared with my 2.0 GHz MBP in iphoto - granted with far fewer photos in the library. I don't need anything more intensive really, so this is good.

Did I mention it was thin? I can hardly tell it's in my bag when I carry it around. That's exactly what I need for traveling. For this reason it is fantastic for me.

One thing I noticed was that the charger works either way it is plugged in. I know some people have complained that the cord bends too much when plugged in if the plug is behind you. No worries. You can just attach the connector the other way around and no more 180 cord bending. The one negative thing that I would say is a real fault is the slow slow battery charging. I just noticed that it is only 35% charged after an hour plugged in when it was down to 15%. Apple, without a replaceable battery, you need to do better than this! Hopefully this can be resolved with a software update soon.

Overall I give this one Three Thumbs Up!

Something in the air

And it will be in my hands some time today! Just in time for me to take it on the plane tomorrow. Yes, the new Macbook Air is a perfect travel partner. I'll give you my review of it soon.

A new precatalyst for Heck Reactions

It's a beauty, isn't it? I mean, look at that monster! And it packs 4 palladium atoms per catalyst too. It just appeared in Organometallics (DOI: 10.1021/om7005613). They actually coupled together iodobenzene and styrene. The cool thing about this is that they could tune the reactivity of the catalyst by changing the metal complexed in the middle of the porphyrin. With M=MnCl it took almost 400 minutes for the reaction to complete, but with M=Mg it only took about 200 minutes. Ok, seriously. I don't mean to pick on Bart M. J. M. Suijkerbuijk, Sara D. Herreras Martínez, Gerard van Koten, and Robertus J. M. Klein Gebbink, but I really don't understand what the purpose of this research is. I guess you can get some understanding about the electronic nature of pincer ligands, but no one in their right mind would ever use something like this for a Heck reaction. It is pretty though. It even weighs 10 times more than your substrate. I guess that makes for easy weighing. Let's say you use 10 mol% of the catalyst. You can just use the same mass as iodobenzene and you're good to go.

Busy as a bee

That is me and why I have not posted lately. I still plan to. Don't give up on me. I'm still finding a few minutes here and there to read an article or two. If only the days were 72 hours long. *sigh*

Anyway, there's lots of buzz about Apple's new Macbook Air. Lots of negative comments going around on the mac forums. I don't understand this. Sure, this computer is not for everyone. Sure, this computer could not replace a primary computer. But let's be honest. This is a computer for travelers. This computer is ideal for me. I can't wait to get my hands on one. In the last five years I can't think of a single time I have used my optical drive while on a trip. Rarely have I ever had to use an ethernet cable while on the road and in the last two years I have never needed an ethernet cable. Who's going to travel with bulky firewire peripherals in their carry on bag? All these arguments against the macbook air are ludicrous. Obviously made by people who don't go on frequent short trips. So I ordered one as soon as they were announced.

 I know this is a chemistry blog. So let's talk about chemistry. This is the first laptop with a mercury free LCD display. And the glass contains no arsenic.