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.

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.

What do flamingos, Cheetos and Quantum Chemistry have in common?

The vibrant colors of flamingos and Cheetos are both the result of related carotenoid dyes. Carotenoids (named for the vegetable in which they were first found!) are based on a linear conjugated diene skeleton, and provide nature with many colorful accents. Canthaxanthin, for example, is fed to captive flamingos to produce their characteristic pink color (a similar pigment found in brine shrimp does the same favor for wild flamingos). Astaxanthin is responsible for the characterstic color of lobsters. Canaries, whose signature color is a greenish yellow, can be turned red if they are fed paprika during their molt. The new feathers will grow in orange-red.

If you're tired of only changing the color of your hair, you can try for a pumpkin look for fall. The compound that gives this class of vegetable pigments its name - β-carotene - when consumed in large quantities by humans, will turn them orange. [Really, but don't try this at home! It was observed clinically in Britain during WW II when food shortages led some people to include large amounts of carrots in their diets.]

If you thought the bright color of Cheez-Whiz and Cheetos was artificial -- it's not. Bixin or annatto, a natural pigment used for centuries, is the source of that unforgettable orange. Researchers have recently elucidated the biochemical pathway for the synthesis of bixin and are pursuing genetic engineering approaches to its bulk synthesis in tomatoes [Florence Bouvier in Science, 300:2089-2091, June 27, 2003].

What does this all have to do with quantum chemistry? A very simple quantum mechanical model, the particle in a one-dimensional box, can be used to predict the color of conjugated dyes.