From: dyer@spdcc.com (Steve Dyer)
Newsgroups: sci.med
Subject: Re: DES structure? (and much, much more)
Keywords: estradiol, DES, diethylstilbestrol, clomiphene, tamoxifen
Date: 23 Jul 92 03:10:14 GMT
Article-I.D.: spdcc.1992Jul23.031014.6461
Distribution: usa
Organization: S.P. Dyer Computer Consulting, Cambridge MA

In article <14kmsdINNfgv@agate.berkeley.edu> shirriff@sprite.berkeley.edu (Ken Shirriff) writes:
>I noticed that DES is an estrogen, but its structure is totally different
>from other estrogens (in fact from all other steroids), because it doesn't
>have the four ring structure.  So what's going on here?  Does it get
>metabolized to a normal estrogen or does it work some other way?

Oh, I _hate_ ASCII graphics...

Remember that sex hormones (estrogens and androgens), glucocorticosteroids
(cortisone, cortisol) and mineralocorticosteroids (aldosterone), forms
of vitamin D, as well as their common precursor, cholesterol, are all
based on the canonical 4-ring steroid nucleus.  Rings A, B, C are adjacent
six-carbon rings, and ring D is a 5 carbon ring.  Each ring shares two
carbon atoms with its neighbor.


           / \ / \
          | C | D |
          |   |___|
     / \ / \ /
    | A | B |
    |   |   |
     \ / \ /


Estrogens are characterized primarily by having an AROMATIC ring A.
That is, it's a benzene ring, commonly drawn, as here, as alternating
single and double carbon-carbon bonds.  In fact, the benzene ring forms
a resonance structure where you can consider each C-C bond as equal
and spead out over the ring.

Estradiol is the primary estrogen produced by the ovaries.
Estrone is a common metabolite found in urine, and which
also has estrogenic activity.  Estrone is frequently found
with other active metabolites (estriol) in the urine of
PREgnant MARes, and these _conjugated estrogens_ are collected,
extracted and sold for use in estrogen replacement therapy,
as in PREMARin.  (Now you know where the brand name comes from--
not very sexy, I guess. :-))


Estradiol:                            Estrone:


                OH                           O
                |                            ||
           / \|/ \                      / \|/  \
          | C | D |                    | C |  D |
          |   |___|                    |   |____|
    // \ / \ /                   // \ / \ /
   | A || B |                   | A || B |
   |   ||   |                   |   ||   |
  / \\ / \ /                   / \\ / \ /
HO                           HO


Diethylstilbestrol is NOT a steroid, but it is fully active as
an estrogen, and is absorbed better.  It has the formula
HO-Phe-C(C2H5)=C(C2H5)-Phe-OH  Now, this doesn't tell you much.
Let's draw it in two dimensions using the same conventions as we
used above.  The phenyl groups are in the TRANS position around the
single carbon-carbon double bond relative to each other.  That means
that they're on opposite sides of the double bond (and so are the two
ethyl groups)


DES (Diethylstilbestrol):

                     OH
           /   / \\ /
          | C || D |
          | B || A |
    // \ / \\/ \ //
   | A || B |
   | D || C |
  / \\ /   /
HO

Notice the similarity between DES and estradiol.  Note too that the
molecule is symmetric.  The "B/C" rings don't really exist as
such, because they're not closed.  The ethyl groups form the sides
of these virtual B and C rings, although they're not fixed in space
the way the steroid ring is.  That is, they can flop around.  Note also
that this "suggestion" of the steroid nucleus, along with the
symmetric dual "A" rings is enough to fool the mammalian estrogen
receptor.

A number of other interesting and therapeutically useful drugs
have come from manipulation of this stilbestrol pseudo-steroid
nucleus.  Clomiphene (Clomid) is an antiestrogen, really a _partial
agonist_, which binds to the estrogen receptor, but doesn't cause the
full spectrum of estrogenic effects.  It is used as a fertility drug--
it increases the production of gonadotropins, thereby stimulating
ovulation.  It exists as a mixture of two isomers.

Clomiphene (Clomid):

cis- isomer (partial agonist)         trans- isomer (antagonist)
                              C2H5
                             /
                  O-CH2-CH2-N
            / \\ /           \                  / \\ 
       Cl  ||D  |             C2H5         Cl  || D |
       |   ||   |                          |   ||   |
 // \ / \\/ \ //                     // \ / \\/ \ //
| A || B |                          | A || B |
|   ||   |                          |   ||   |
 \\ /  // \                          \\ /  // \
      |   ||                              |   ||
      |   ||                              |   ||
       \\ /                                \\ /          C2H5
                                             |          /
                                             O-CH2-CH2-N
                                                        \
                                                         C2H5

Tamoxifen (Nolvadex):

only the trans- isomer is used

        /   / \\
       | C || D |
       |   ||   |
 // \ / \\/ \ //
| A || B |
|   ||   |
 \\ /  // \
      |   ||
      |   ||
       \\ /          CH3
         |          /
         O-CH2-CH2-N
                    \
                     CH3

A related drug, tamoxifen (Nolvadex), is also an antiestrogen/partial
agonist.  It is used in the treatment of certain forms of breast cancer
which are hormone-dependent.  Tamoxifen occupies the estrogen receptor
sites in estrogen-dependent breast cancer cells.  However, because
it does not function fully as a complete estrogen, the cells are
deprived of the estrogen they need to multiply.  Naturally, this
kind of therapy is only effective if the cancer cells are sensitive
to estrogen.  Not all cases of breast cancer are.  The A ring in
both clomiphene and tamoxifen is converted in the body to the 4-hydroxy
form (so it resembles the A ring in estradiol and DES.)  This is the
most active metabolite.

There has recently begun a study of the use of tamoxifen in post-
menopausal women who do NOT have breast cancer, to evaluate its
efficacy as a prophylactic against developing cancer of the breast.
(Essentially depriving microscopic cancer cells or pre-cancerous cells
from the positive stimulation of residual estrogen.) In addition, the
study will look at the drug's efficacy in preventing osteoporosis due
to estrogen deficiency.  Its partial agonist effect as an estrogen is
manifested by its calcium-sparing/bone-promoting actions in a manner
similar to estrogen, whereas it acts as an antagonist or "impeded
estrogen" when it comes to occupying estrogen receptors on breast
cancer cells which require the hormone to multiply.  This study is only
now being set up.  It's much too early to speculate what its effects
might be.

The drug is expensive, can cause menopause-like symptoms, but
seems fairly non-toxic (for an anti-cancer therapy), and the
hypothesis is that it may be sufficiently free from toxicity
to confer beneficial effects in prophylactic use.

Some of you might be asking what's the big difference between
clomiphene and tamoxifen--they are chemically similar, and seem to have
similar hormonal effects at estrogen receptors.  They also have similar
1/2 lives (about a week).  Yet one (clomiphene) has been in use for
almost 20 years as a fertility drug, whereas tamoxifen is the latest
breast cancer wonder drug--they were developed and are used for
entirely different purposes!  Go figure.  The cynic in me says that
tamoxifen is patented, whereas clomiphene is no longer patent
protected, so the investment in the testing of these drugs against
breast cancer was only cost-effective for the drug (tamoxifen) still
under patent.

-- 
Steve Dyer
dyer@ursa-major.spdcc.com aka {ima,harvard,rayssd,linus,m2c}!spdcc!dyer