Subject: Metal-containing drug summary

From: [email-masked]
Date: Tue, 10 May 1994 06:52:57 -0600 (CST)

Fellow Net-tenders,

	Below is a collection of responses to date on metal in drugs.  After
asking this question I had a few students go up and search J. Med. Chem., which
along with net answers and talking to the organo/medicinal folks here at
Memphis yielded the following (with apologies to Dave Letterman) 'Top 10' list. 
The review by Sadler (ref given below) is a veritable gold mine (no pun
intended) of 'inorganic drug' discoveries.
	Thanks for the many replies!

Tom Cundari

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1) Technetium for radioimaging.  We found a nice article in Coord. Chem. Rev.
by Clarke on Tc and its medical uses (1987, 78, 253). 

2) Fe-complexes.  As one  letters points out Ken Raymond and his group have
done excellent work here.   I'm embarassed I forgot this one since I was
sitting in the audience when he gave a seminar on this topic at the last ACS
meeting!  There is a good paper from his group (JACS 1993, 115, 6758)
describing work with Transferrin.

3) MRI contrast agents.  As one person pointed out, Gd(III) complexes are not
the only ones being studied.  I had seen Mn(II) work, but there is Fe(III) work
as well.

4) Metalloids including arsenic, antimony and boron.  The As complexes seem to
be historically significant for the treatment of syphilis and are still used for
some ailments. 

5) Gold.  In colloid form or as a complex, Auranofin (which seems to be a
carbohydrate complex of Au).  One of my students found a paper where Au was
tested as an anti-caner agent.

6) Pt anti-cancer drugs.  Well known application.

7) Bismuth.  I saw a poster on Bi complexes in San Diego and I believe the
application was anti-ulcer medicines.  Strangely enough, before seeing Doug's
e-mail about Pepto Bismol I ran across this one while checking out a bottle an
undergrad had (it's finals week here!).

8) Polyoxometallates have been investigated for anti-HIV potential.  Craig Hill
(Emory) has done the work I am familiar with.  There is a recent paper in J Med
Chem (1992, 35, 1216).

9) various chelates for treating heavy metal poison.  There is a mention of
EDTA for lead poisoning and I think Fe-chelation therapy also would come into
this area.

10)  Mercury, as used in things like Mercurichrome.  This is my personal
favorite since I can still recall my grandmother swabbing me down with this
stuff any time I got a cut!

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Thomas

Years ago a collegue and I tried to model Technetium compounds in an
effort to design better coordination compounds.  We were unsuccessful for
a number of reasons but I believe that this would be an excellent area in
which to work.

Technetium compounds are widely utilized in imaging and better agents
would fill the gaps that now exist.

Jerry L. Born
Professor of Pharmacy
The University of New Mexico
[email-masked]

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Tom -

I don't have a complete list for you of metal containing drugs, but I do
know that gold in a colloidal form is used to treat arthritis.

Bev

Beverly Bendiksen
Calgon Corporation
Pittsburgh, PA

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Dear Thomas,

I think EDTA had been used to flush lead from the body in cases
of lead-poisoning.
                                                             .
           HOOC                     COOH                     .
               \                   /                         .
                N---CH ---- CH ---N                          .
               /      2       2    \                         .
           HOOC                     COOH                     .
                                                             .
                       EDTA                                  .

And what about macrocyclic antibiotics, erythromycin etc?

Best,
Max

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       an area in which metal or metal ligands may be useful as (part of)
drugs is immunoconjugation of, say, radioisotopes with targetting agents
such as antibodies (see recent issues of the ACS journal Bioconjugate
Chemistry).  I do not know of anyone who has used CADD for this purpose, but
I guess in principle it could be done.

Best wishes,

Max

========================================
Max Vasquez, PhD
Protein Design Labs, Inc.
2375 Garcia Ave.
Mountain View CA 94043
Phone (415) 903 3744   FAX (415) 903 3730
e-Mail  wk01189 @ worldlink.com
========================================

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The most obvious case is ACE inhibitors...

Several refs on the subject:

Saunders, M.R. et al. JCAMD 1987, 1, 133-142.

Mayer, D. et al. JCAMD 1987, 1, 3-16.

Wyvratt, M.J. and Patchett, A.A. Med. Res. Rev. 1985, 5, 483-531.

DePriest, S.A. et al. JACS 1993, 115, 5372-5384.

Waller, C.L. and Marshall. G.R. J. Med. Chem. 1993, 36, 2390-2403.

and refs therein...

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*Research Chemist                                FAX   919-541-5394*
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*          Disclaimer: My opinions - not theirs...                 *
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Of course Lithium is a drug itself.

Bill Ross

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Tom,

I believe the current drug of choice for the treatment of iron overload
is a siderophore (small molecule iron binding agent) related to
a natural product called enterobactin.  Sorry, the name and structure
of the drug escapes me at the moment.  But, this class of compounds
has been studied extensively by Prof. Ken Raymond at UC, Berkeley.
Its mentioned in:  Raymond, K.N.; Muller, G.; Matsanke, B. F.
In Topics of Curr. Chem.; Boschke, F. L., Ed.; Springer-Verlag:
New York, 1984, pp 49-102 and in many of Raymond's more recent
publications.

Hope that helps!

Joe Urban

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Dear Dr. Cundari: With your message you touched a very sensitive topic because
so far there are no reliable general methods of modeling transition metal
systems. I am working now on this topic which requires quite a novel approach.
unfortunately, nothing comprehensive is published so far except an abstract 
and a poster to the 15 Austin Symposium on Molecular Structure (UT at Austin, 
March 1994).I would like to ask you to summarize all the replies to your 
question making them avalable to the interested persons.Regards, Isaac

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Isaac B. Bersuker                | E-mail:
Dept. of Chemistry               | [email-masked]
Univeristy of Texas at Austin    | Vox: (512) 471-4671
Austin, TX 78712                 | Fax: (512) 471-8696
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Hi, Dr. Cundari!

I am an M.D.-Ph.D. doing my Radiology Residency. My Ph.D. is in
Pharmacology and Biophysics with emphasis in computational chemistry.
I will attemp to shed some light on your question, and will get back to
you with a review article on the topic.

1) Chelating agents for the removal of toxic metals are already in
clinical use. For example, Penicillamine has a variety of uses in
Emergency Room medicine for toxic ingestion of metals. Which ones?
I don't remember at this time. Patients that receive multiple transfusions,
like those suffering from Sickle Cell anemia, receive chelating therapy
for Iron because of severe Iron overload. The review article should
have the name of the compound. Similarly, Wilson's Disease is a
devastating genetic disorder where Cu metabolism is impaired due
to the absence of a carrier protein Ceruloplasmin (pardon my spelling here).
I also believe they receive chelating therapy.

2) Other therapeutic agents in use today include gold salts for the
treatment of Rheumatoid arthritis. In the early days of "modern"
pharmacologic treatment many inorganic compounds were used for treatment.
Unfortunately, many were very toxic and felt out of favor quickly.
Silver nitrate is still used in some nurseries to treat/prevent ophthalmic
gonorrhea in the newborn, but most places use modern penicillin derivatives.
Obviously, many of the intravenous hyperalimentation formulae used
in hospitals today include metals as trace element supplements.

3) The most extensive clinical application of metals or organometallic
complexes has ocurred primarily in radiology. (At least to my knowledge!).
Early radiologists new that  the heavier metals were radiopaque to X-rays
and used multiple compounds to generate contrast in their images.
Today, almost all of these are no longer in use, and only the
iodinated organic compounds remain in use in radiography.
MRI has resurrected organometallics for radiologits. You are aware
of gadolinium complexes, but many other compounds are in preparation.
For example, Mn(II), and Fe(III) chelates for liver and tumor imaging.
Almost every week somebody describes a new compound in the
radiology literature (check out Magnetic Resonance Imaging,
Magnetic Resonance In Medicine, Journal of Investigative Radiology,
etc).

4) Porphyrin derivatives are used to identify tumors, particularly,
radiologically undetectable lung cancer. They are also used to
sensitize tumors prior to radiation therapy. Unfortunately, I don't
know if any of these are metalloporphyrins.

5) No, I don't know of any design effort using computational methods
that has been used or has been successful to design new drugs that
contain metals. Extensive applications exists in using computational
chemistry to understand metalloproteins. Who can forget the
heme group in MYOGLOBIN and HEMOGLOBIN! But, specific applications
in medicinal chemistry...

Regarding 5) I am involved in the rational design of new paramagnetic
metal chelates that can be used as intravenous MRI contrast agents.
Currently, my time is limited and I have only begun to do
density functional computations in some metaloporphyrins, but I have
accepted a fellowship in the NIH (Laboratory of Diagnostic Radiology
Research) where I hope to pursue this research full time. They are
interested in developing contrast media and have tested some variations
of FexOy particles embedded in Transferrin, an iron carrier molecule
in the body.

I have experience in the computational chemistry of mostly organic
compounds and I will complete my radiology residency in 1 more year
(hopefully be Board Certified in the same time! : - ) ). My experience
in Inorganic Chemistry is limited to a couple of Graduate chemistry
courses, so I am slowly learning the ropes to perform computations
with bioinorganic/organometallic compounds.
I have followed some of your work, particularly the computations
using Harold Basch and Morris Krauss effective core potentials, and
believe that you can make a significant contribution to medicinal
chemistry if you extend your computational expertise to the rational
design of contrast media.
Sorry for the bandwidth! I wish you well and will get back to you
with the reference!

good luck
gustavo mercier, jr
[email-masked] (notice the absence of the last "r" from my
                         last name!)
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There are not many drugs containing metals. The major problem is the
degradation
of the compound may result in free metal, which can be toxic. The Pt compounds
you mention are a particular case due to the particular problems arising in
canc
er
cancer, toxicity is only one of the issues. There are also some Au containing
aniinflammatory agents (non steroidal), see auranofin for instance. These
compounds are used as slow acting antiinflammatories. I berlieve that after
sometime in the market, some of them were removed, because of severe secondary
effects in some people. The uses are mainly in Rheumatism.
I do not think there are many more. For instance Fe containing things are for
the most part avoided, as they can become liver toxic, as many other dications.
I believe hat I would ake a serious look, if I were you to the area of bi
biosensors. I believe, some work has been done there theoretically.
 There are not many repored successes of drug design, and even fewer with
metal containg compounds. You may be aware of all the work on metalloenzymes.
Regards,
Hugo O. Villar,
Senior Scientist
Terrapin Technologies

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Hi!

Here is the reference I promised:

Inorganic Chemistry and Drug Design by Peter J. Sadler
In: Advances in Inorganic Chemistry, Vol. 36, pp: 1-48, 1991.

I believe the whole issue may have been dedicated to pharmaceuticals
and inorganic chemistry.

Finally, how could I forget?!

The most extensive  CURRENT MEDICAL application of organometallics are in
antineoplastics (as you already know), and Nuclear Medicine, a
cousin of Diagnostic Radiology. All (except for PET) radiopharmaceuticals
used today for imaging in Nuclear Medicine use heavy metals chelates. In fact,
the liver imaging agents developed for MRI where modeled after similar
agents in hepatobiliary imaging in Nuclear Medicine. They simply
exchanged the radioactive metal with the paramagnetic metal ion.

As far as I know, the most likely candidates to have applied some
rational drug design to metal containing pharmaceuticals are the
antineoplastic agents (I believe recently discussed in Chemical and
Engineering News), and the Nuclear Medicine people. The latter group
eagerly looks at the medicinal chemistry literature for compounds
that bind to receptors so they can tag them with their radioactive
metals. This practice is not always successful, as any chemist
familiar with principles of chemical reactivity may expect!

Good Luck,
gus mercier, jr.
[email-masked]

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Tom,

I am finishing up my thesis here at Duke. I am engaged in computational studies
on boronated nucleotides. I know that boron is technically a metalloid. If you
are interested (ie, fits what you are looking for, I can send some references
and a general overview). I look forward to your summary on the net!
-mark
           **********************************************
           *                                            *
           *   Mark A. Zottola                          *
           *   [email-masked]                      *
           *   Department of Chemistry                  *
           *   Duke University                          *
           *                                            *
           * 'The fault, dear Brutus, lies not with     *
           *  ourselves, rather within our CPU's...'    *
           *  (with due apologies to W.S.)              *

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Tom -

I don't have all the lit. here, but there are a number of others.
For example, there are the Gold anti-arthrritic (sp?) drugs,
and don't forget peptobismol -- which contains bismuth!(delicious).
Doug Dudis
Wright-Patterson AFB, OH

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Hi there

        There are several anti-arthritis drugs on the market which are
based on gold complexes.  Usually the structure consists of Au(II) linked
to a phosphine ligand and a sugar ligand (the trade name for one of these
drugs is auromycin).
        The scientific explanation for gold's anti-arthritis activity is
not well known, but it has been used for many, many years (some people
believe that the ancient Egyptians were the first to try it as a remedy!)
        I can give you some references if you are interested in this
topic.  I would also be interested in getting a summary of replies to
your initial query.

Thanks.

Byron DeLaBarre

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I would be most interested in the replies to your question. I am just
finishing a modelling project on Tc(V) complexes used for
radiopharmaceuticals. I don't know if any QSAR techniques have been
suddessfully applied to this class of compounds.

Susan C. Jackels
Department of Chemistry
Wake Forest University
Winston-Salem, NC  27109
Phone: (919)759-5514     FAX: (919)759-4656
Internet: [email-masked]

On sabbatical for 1993-1994 at:
Department of Medicinal Chemistry
308 Harvard Street S.E.
University of Minnesota
Minneapolis, MN 55455
Phone: (612)626-4429

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>Dear Dr. Cundari,
>We have had considerable success with density functional
>methods for transition metal complexes in Biology.
>See Noodleman, Case, Adv. Inorg. Chem.38,423-470,1992;
>Schmitt et al,JACS 114,6109-6119;also Ziegler, Chem. Rev.91,651-667, 1991;
>also Rosa and Baerends, Inorg.Chem.33,584-595,1994. Also, Density
>Functional Methods in Chemistry, Labanowski and Andzelm Eds. Springer-Verlag
>1991 for various transition metal complexes.
>Lou Noodleman
>Molecular Biology, MB1
>The Scripps Research Institute
>La Jolla, CA92037
>[email-masked]
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Thomas R. Cundari                         
Asst. Professor of Chemistry              
Computational Inorganic Chemistry Lab     
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