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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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September 24, 2006

Touch Me Not

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Posted by Derek

I see that Dylan found an old bottle of L-DOPA in his stockroom - I'd handle that one with gloves, but that's the medicinal chemist in me talking. He segues into a discussion of the MPTP story, which I talked about here a while back. Every med-chemist who's done work on central nervous system drugs knows the story, in my experience.

But that knowledge doesn't seem to be universal. I once, some years ago, had a lab associate from another group mention to me casually that he'd just made a batch of an intermediate, which when he drew it out on the hood sash, turned out to be the para-bromo analog of MPTP. I couldn't believe my eyes, and I stared at him in horror, wondering if this was some sort of joke. "You what?" It was then his turn to stare at me, wondering what was wrong. He had never heard of MPTP, of the irreversible Parkinson's syndrome that it causes, had no idea that there was a problem, and so on.

We established that he'd made a good-sized load of the stuff, but that he hadn't been handling it to any great degree (and had been wearing gloves when he worked up the reaction). I put the fear into him, warning him under no circumstances to touch the stuff or mess with any glassware involved, and contacted the toxic waste disposal folks. They charge quite a bit to haul things like that away, I think.

In the meantime, I read up on the structure-activity relationships that had been worked out for these compounds. A key paper by Mabic and Castagnoli in J. Med. Chem. (39, 3694) showed that the 4-bromo compound was, unfortunately, an "excellent substrate" for MAO-B, the enzyme that turns these structures into the neurotoxic species, so odds were excellent that the compound was trouble.

But not once it was taken away and destroyed, anyway. The person who made it developed no symptoms over the next couple of years that I was able to observe him, as far as I could see. (And I believe that you need a pretty good internal dose to get into trouble - light skin contact probably won't do it). Memos went out to everyone reminding them of these structures and why they shouldn't be messed with. But I still wonder how many people might stumble across these compounds and whip up a batch of something that shouldn't be made. That's another argument for electronic lab notebooks. You could set the things to start honking and flashing if you entered such a target structure into them, to alert the clueless. . .

Comments (23) + TrackBacks (0) | Category: The Central Nervous System | Toxicology


1. kiwi on September 24, 2006 9:24 PM writes...

the electronic notebooks thing is a good idea, we work a lot with small organophosphorus compounds, when i'm working on any new one i make sure i have a good read up on any known analogues, and their toxicity. but not everyone i know is this careful, which is a scary thought. and you can never find all the literature.

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2. secret milkshake on September 24, 2006 10:46 PM writes...

Careless organophosphate chemists get weeded out by natural selection. My former boss worked at a chemistry institute in Kiev in old bad Soviet times and they had a closed-off wing of the institute where "special projects" emploee worked on organophosphates. They got much higher salary than other chemists, never published anything and sometimes ambulance arrived and a some guy was carried out on a stretcher...

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3. kiwi on September 25, 2006 1:14 AM writes...

the problem is when careless organophosphorus chemists eliminate their more careful labmates...

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4. milkshake on September 25, 2006 2:32 AM writes...

Well you have to watch for the jerky-chicken dance of your labmates and have the atropine/pralidoxime combo ready.

I know what you mean, we had a guy in the lab (fortunately briefly) who would do things like washing benzyl bromide-containing flask in hot water in the sink or spill phenacetyl chloride all over the floor and then he would go and complain to the management when people around him did not like him...

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5. dan on September 25, 2006 2:49 AM writes...

1. for the uninformed, what is so lethal about organophosphates?

2. It seems surprising that the entire route involving p-bromo-MPTP would be scrapped midway through due to the toxicity of the intermediate. Don't we work with enough unpleasant things to know how to handle one more?

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6. kiwi on September 25, 2006 3:09 AM writes...

been on the recieving end of the old 'BnBr in the sink waiting for someone to hotwash their dishes' trick myself milkshake, so i feel your pain. and dan, try for starters. there is a fair bit of flexibility in the SAR for these things too.

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7. Phil-Z on September 25, 2006 8:16 AM writes...

I once turned around from the hood to see my "boss", a newly minted PhD, digging out a fist sized lump of DCC onto the bench balance in the middle of the lab! He'd read the notebook, but hadn't bothered to hit any of the refs, hadn't bothered to ask anyone, not even me when I was standing right there. I transferred to the mass spec lab shortly after this incident.

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8. Harry on September 25, 2006 9:07 AM writes...

I read a book about the "Frozen Junkie" incident a few years ago. I can't recall the name of it, but it followed the story through the implantation of embryonic Substantia Nigra cells into some of the victims. Some of them made significant improvement, but I later read that at least some of the recipients of the implants had severe problems with overproduction of domamine with spastic movements and a host of other problems.

That may be a bit of a cautionary tale about embryonic cell therapy. Possibly somene here who has followed this more closely than I can update the story.

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9. Derek Lowe on September 25, 2006 9:08 AM writes...

Dan, MPTP is in a different class than many other nasties. It's an insidious poison with no possible remedy - there are no markers of exposure until the irreversible symptoms start showing up. It'd be like scaling up a dimethylmercury process. (And in both cases, imagine the contortions you'd have to go through to prove that none of the stuff carried on to the final product).

There are usually so many different ways to skin cats that you can avoid nasty intermediates like these. In this case, the person really didn't have to make it; it just looked convenient. I can't imagine getting painted into such a corner that an MPTP-containing route was the only way out.

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10. milo on September 25, 2006 11:06 AM writes...

There are a lot of non-chemistry literate folks out there who are trying to make all sorts of things for various purposes. Is there a good, central repository (or book or review...) detailing the types of hazards discussed here? The hazards that some chemicals posses can be very real and very scary...

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11. LNT on September 25, 2006 2:05 PM writes...

I don't think most chemists are as aware of MPTP story as you seem to think that they should be. I made a series of compounds closely related to MPTP recently and had no idea of the danger I was in until you pointed it out. (imagine attaching a substituted thiophene in place of the phenyl ring) Thanks for pointing it out. But I presented these molecules to my project team, including several very experienced medicinal chemists, and nobody mentioned anything about a potential problem with these molecules. Maybe chemists that deal with CNS diseases are more aware of these things. We deal primarily with cancer and inflamation.

I'm not sure your electronic notebook idea really would work that well. Who would actually scan the notebooks for such "dangerous" compounds? An automated filter could be put in place, but what other kinds of structures would you look for?

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12. milkshake on September 25, 2006 3:58 PM writes...

You are not alone, we had one ambitious boss and at the meeting she proudly presented series of MPTP analogs with substituted indole in place of phenyl in MPTP. She looked at me as if I was making stuff up when I mentioned it.

Overproduction of dopamine from overgrown substantia nigra cell transplant - but this problem can be quickly fixed, selectively and irreversibly ;-)

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13. Jose on September 25, 2006 4:40 PM writes...

Does DCC have issues other than being an idiosyncratic sensitizer? That's fairly spooky, but certainly not irreversible Parkinon's....

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14. HOMO-LUMO on September 25, 2006 7:32 PM writes...

DCC (You Mean dichlorodicyanobenzoquinone?)?

Well, that reagent used for dehalogenation, mild acetal cleavage, etc? I have seen papers in which is postulated that it acts via (Generation in situ of CN-)nitrile hydrolysis.

MOreover 1,4-benzoquinones and specially catechols are well known to be wonderful compounds to get straight into DNA.

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15. Daniel Newby on September 25, 2006 7:49 PM writes...

Derek, I can't find it now that I want it, but I vaguely remember a report of a laboratory worker who developed Parkonsinism through minor contact with MPTP.

From the you-known-things-are-bad-when file: "Cigarette smoke and nicotine protect dopaminergic neurons against the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Parkinsonian toxin."

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16. kiwi on September 25, 2006 7:56 PM writes...

no, you are talking about DDQ (dichlorodicyanobenzoquinone). DCC is an esterifaction/ peptide coupling reagent, dicyclohexylcarbodiimide. is non-ideal in a number of ways, including being a potent allergen and sensitiser.

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17. Dr Snowboard on September 26, 2006 2:50 AM writes...

From memory, the toxicity is quite specific to N-Methyl? A long time ago (before the number of dopamine receptors spiralled out of control) I worked on 3-PPP as a lead and it involved going through the quat, reduction sequence but with N-propyl or higher. Technique must have been ok because still moving.
We did have a pot of MPTP which was used under conditions that Dustin Hoffman in Outbreak would have been proud of.

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18. Novice Chemist on September 26, 2006 8:10 AM writes...

Dr. Snowboard: Great movie! Do you remember the scene where the lab tech absentmindedly (while reading a comic book!) reaches into a spinning centrifuge full of Ebola virus?

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19. milkshake on September 26, 2006 1:45 PM writes...

I think N-methyl is quite required. It is the phenyl group that can be substituted, even replaced with a non-ary as long as the stuff is greasy - the 4-cyclohexyl version of MPTP works quite well in animals...

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20. Derek Lowe on September 26, 2006 2:42 PM writes...

My reading at the time was the methyl was by far the worst, but that ethyl was still something to worry about. NH is, as you'd expect, no problem, and N-benzyl is fine, too.

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21. Joe Jones on January 10, 2011 3:46 AM writes...

Just as a side note, the first url in your article goes to a page that requires a login. I'm sure most people already have it, but for those that don't, it's a bit of a dead end!

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22. joe Jones on January 10, 2011 3:48 AM writes...

Oh muppetry, I just realised this was from 2006. Ignore me. I jumped across from today's article and didn't check the date.

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23. Mattw on January 11, 2011 9:09 AM writes...

Oh but there was so much good behind that locked door!

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