Articles by: Phil

Estrogen analogues

The authors of this paper (Chem. Eur. J. 2008, early view) have synthesized a series of new estrogen analogues where the B and C ring of estrone (1) and 17β-estradiol (2) are replaced with a simple alkyne spacer. The steric bulk of the omitted rings is replaced by suitable substitution of the two remaining “A” and “D” rings (phenols 3 and 4).

Estrogen structures

An overlay of the 3D structures of estrone (1, yellow) and 3 (white, R = 2-Cl, R’ = Me) shows a considerable offset between the corresponding carbonyl groups (O – O distance of 1.67 Å). I also wonder about the rotational flexibility of the linker – the “text-book”-property of steroids is their rigidity, but the new analogues can rotate about the triple bond.

Estrogen overlay with analogue

The biological properties of these new compounds have not yet been measured. I wonder if they will be comparable to estrogens. If this radical structural simplification still yields bioactive compounds, this will be a remarkable achievement. On the other hand, flexibility always has an entropic cost when the molecules bind to their target, so I don’t expect the activities to be too high. Also, the new class of compounds is probably less selective than the original estrogens. But this is all speculation as long as the biology hasn’t been done.

By March 28, 2008 2 comments synthetic chemistry

Strained Acetylenes for Click-Chemistry

This ACIE article caught my attention. Here, a “click-chemistry” based approach is used for in vivo labeling of glycoproteins. The strained acetylene 1 is linked to biotin to give 2. Cells that have been cultured in a way as to introduce N-azidoacetylsialic acid into glycoproteins were exposed to acetylene 2, then stained with avidin-FTIC (this is a fluorescein-labeled protein with a very high affinity for biotin). As a result, the glycoproteins at the cell surface fluoresce.

strained-acetylenes.gif

What happens chemically is a [3+2]-cycloaddition of the azido-substituted sialic acid (Sia) to the acetylene to give 3. The special thing here is the absence of copper(I), which would be cytotoxic and is normally required as a cycloaddition catalyst. Instead, the addition runs without any metals because of the strain of the eight-membered ring.

This also reminds me of Sharpless’ work for the fragment-screening of HIV-1 protease inhibitors (e.g. this ACIE article). He also used the [3+2]-cycloaddition with inhibitor fragments containing azido and acetylene groups. The fragments would effectively add in situ, i.e. inside the binding site, to form strong inhibitors. Here, the enzyme itself acts as a catalyst or template by arranging the most suitable fragments in a favourable orientation.

By February 22, 2008 7 comments science news

Blessings and curses

Hello!

My name is Phil. I’m doing my Ph.D. at ETH Zürich (that’s right, in Switzerland), where I’m working in the field of Medicinal Chemistry. This is my first post, hooray!

One of my group jobs is to take care of the LC-MS system we bought last year. You know, that magic box where the people from CSI can put some saliva sample in, and ten seconds later the display tells them exactly which drug the person was abusing at his/her time of death. Unfortunately it’s not all that easy in reality. For synthetic chemistry, it is both a blessing and a curse. As long as it works, it is extremely useful, especially for complex reaction mixtures like the ones in cross-coupling reactions and such. However, it requires a lot of maintenance because something seems to go wrong several times a week. In a way that’s not so surprising because more than 50 people use the machine, and I imagine not all of them think much about what kind of substances they inject.

Still, it sometimes annoys me when the technical difficulties are completely left away in TV series. You never see one of the CSI people cursing at a clogged HPLC column. But I guess that’s why I know I’m a Chemist.

By February 12, 2008 1 comment Uncategorized