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.

2 Comments

  1. The analogues not being rigid may actually be advantageous. Since there isn’t 100% overlap in the structure, being able to rotate may supply that extra wiggle room needed for biological acivity.

  2. True, but a simple rotation won’t do in this case. Something like a parallel shift is necessary, which would involve serious bending of the acetylene.

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