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Temozolomide Is Explosive

Here’s some surprising information to learn about a drug that’s been around for decades. Temozolomide (TMZ) is a chemotherapy agent, used in several intractable conditions such as glioblastoma. It’s pretty vicious stuff – the mechanism is through alkylation of guanine residues in DNA, a brute-force approach with numerous side effects – but it does extend life in its target indications, up to a point.

Chemically, it’s an odd beast, and it’s probably the only imidotetrazinone that anyone ever sees. Its nearest drug relative is dacarbazine (used in melanoma chemotherapy) and in vivo TMZ is broken down into a very similar structure, which is the active form. It serves as a good prodrug for that one, though, and its good penetration through the blood-brain barrier before that happens accounts for its use in CNS oncology. The species that attacks the DNA, though, is a simple (and very reactive) one: methyldiazonium, from the methyl group coming off that ring nitrogen. You could say that TMZ is a prodrug for a prodrug for methyldiazonium, which is never going to be a drug that can just be administered by itself.

That’s led to TMZ being proposed recently as a chemical reagent, since a stable solid precursor to such a reactive species is always worth looking into. It has its disadvantages – temozolimide is genotoxic and teratogenic, so it has to be handled carefully, but honestly, anything that generates a small diazonium compound so readily is going to be similarly hazardous. But the paper linked suggested that it would be a stable, weighable reagent for this purpose (although I note that they also described it as “non-toxic”, which I would probably take issue with).

But it appears that there’s an even more direct hazard, according to this new paper in Organic Process Research and Development. The literature says that TMZ is stable up to its melting point (with decomposition) at 212C, but the authors note that no actual data could be found to back this up. So they gave the compound a full safety analysis, with differential scanning calorimetry and then Yoshida correlations (a method of using DSC data to predict explosive hazards). What they found was rapid onset of decomposition at 170 degrees, with a large release of energy. Several commercial lots of the compound were tested, and almost all of them showed the same behavior, with one initiating decomposition at even lower temperatures, albeit less violently, probably due to impurities. All samples set off warnings with the Yoshida calculations for explosive propagation. Indeed, drop-hammer tests showed that these TMZ samples decompose suddenly with smoke on impact.

You can get even more information on such substances with a technique called “accelerated rate calorimetry”, which is especially useful to get an idea of how heat propagates through solid samples under decomposition conditions and how much pressure is likely to be generated when that happens. ARC showed decomposition coming on at about 145 C, even lower than the DSC experiments had indicated. The accompanying rise in pressure indicated that TMZ has a risk of detonation. They put this suspicion to empirical testing through the UN Test Series 2 and 3 methods, a set of tests developed for evaluating the transport of explosive materials. You have to really be into explosions to be familiar with some of these. Test Series 2, for example, involves detonations under various conditions in steel tubing with rating scales to assess the damage. Was this piece of steel perforated or not? Did this other tube just bulge after the detonation, or was it fragmented into pieces? Large pieces or small ones? That sort of thing.

TMZ failed one of these as well, and is tentatively assigned as a Class 1 explosive. It’ll take more work to figure out just where it fits inside that category, but it’s safe to say that it’s a lot more dangerous than anyone realized. I have personally worked with compounds that are this hazardous, but at least I knew up front that they were! The companies that are making this material on scale should especially be made aware of these data, and I find it very odd that TMZ’s explosive properties hadn’t been realized until now. The compound, though, was first disclosed in the 1970s and took quite a while to be developed, so it may well have been a case that everyone knew that it had been around for a long time and assumed that someone else had taken a look long before. Not so.

55 comments on “Temozolomide Is Explosive”

  1. David Young says:

    We probably used Dacarbazine more often as the “D” in the ABVD regimen for Hodgkin’s Lymphoma.

  2. Simon says:

    Anything with that proportion of N doesn’t look happy.

    What percentage of compounds with 3 N’s in a row are stable?

    1. Grant Seiler says:

      How many high-molecular weight organic azides have been prepared? How many of their corresponding CuAAC products have been prepared? How many derivatives of benzotriazole have been prepared? That many.

  3. ezra abrams says:

    D – fab post, thanks but don’t get a swelled head !!

  4. An Old Chemist says:

    Temozolimide has got 8 hetero-atoms and 6 carbon atoms, and so by the rule of thumb it is supposed to be explosive. The rule of thumb says that in a compound when the number of hetero-atoms exceeds the number of carbon atoms the risk of explosion increases. Of course, there are a few exceptions, e.g. metformin has got 5 nitrogen and 4 carbons but is not explosive.

    1. Peter Kenny says:

      Was having difficulty commenting so apologies if similar comment emerges later. I think the problem is more about single bonds between elements in the top right corner of the periodic table. Here’s a quote from Pierre Dulong’s wikipedia page:

      “Another example of Dulong’s indifference to danger amid scientific pursuit came about in his studies into nitrogen trichloride. Despite losing two fingers and one eye in his initial experiments, Dulong continued to research the unknown substance. His inquiry led to more injuries, after which he turned over the results of his studies to Sir Humphry Davy.”

      1. MAMO says:

        In the spirit of Pierre Dulong, the seminal work that you cite made my head explode. After 20 pages, 11 figures, and 8 tables, the Conclusion: “physicochemical property space of recent drugs predominantly reflects the constraints imposed by their biological targets.” Eureka!

      2. Bannem says:

        Indeed . . .
        From Wiki :-

        https://en.wikipedia.org/wiki/Nitrogen_trichloride

        The pure substance (rarely encountered) is a dangerous explosive, being sensitive to light, heat, even moderate shock, and organic compounds. Pierre Louis Dulong first prepared it in 1812, and lost two fingers and an eye in two explosions.[7] In 1813, an NCl3 explosion blinded Sir Humphry Davy temporarily, inducing him to hire Michael Faraday as a co-worker. They were both injured in another NCl3 explosion shortly thereafter.

    2. Stan Bundy says:

      Quote: “. Of course, there are a few exceptions, e.g. metformin has got 5 nitrogen and 4 carbons but is not explosive.”

      Unless you count the explosive diarrhea you get from taking Metformin…….

      1. Vader says:

        I guess I was lucky. I never experienced this side effect. Just some loose stools that lasted about two days.

        YMMV

    3. Barry says:

      Freons certainly don’t fit this simple “rule”

  5. Eugene says:

    Ok, not a chemist but just breaking down the terminology “accelerated rate calorimetry” suggests an excuse to play with things that go bang.

  6. KazooChemist says:

    Should be omide, not imide in the title.

  7. David E. Young, MD says:

    I am not enough of a chemist to know if I am close or not. Any chance that Roxolitinib is explosive? https://en.wikipedia.org/wiki/Ruxolitinib

    1. myma says:

      Its been quite a while since I had to have the handy printout of rings pinned up in my cube, but I am going to say probably not because these kind of ring dings are very common in drug discovery … I don’t remember their names, but they were on that sheet. The one up at the top of this post, nope, not on it.

    2. Baltic says:

      Extremely unlikely. At a glance, the most suspicious fragment there might be the pyrazole ring, and those are stable; they don’t really have an energetically favorable way to turn that N-N fragment into nitrogen gas, which is the most common reason behind many polynitrogenated compounds being jumpy. There aren’t any “energetic” moieties (such as NO2 groups) in this molecule at all.

      1. Derek Lowe says:

        Agreed – Roxolitinib this one looks very vanilla indeed, fortunately.

  8. tally ho says:

    nitroglycerin is another orally dosed explosive, to quickly lower blood pressure (angina). Fortunately, it’s provided in a stable (non-explosive) formulation, though I’ve always wondered who had the bright idea to try it out in the first place. Did they pass out from low blood pressure, fear of realizing ingestion of a high explosive, or both?

    1. Baltic says:

      I believe the discovery of its properties comes from the days when “taste” was about as common reported property of molecules as NMR spectra are novadays.

      1. tally ho says:

        very good point. just 0.4 mg of nitro is the formulated dose (for under-the-tongue delivery). so a taste of the pure stuff would certainly have done the trick. maybe Derek will contribute a blog dedicated to “old school” drug discovery – therapeutics discovered by medicinal chemist self-dosing (which would probably get you fired these days).

        1. Thomas says:

          I think I read that the CEO of one the German Covid vaccine developers dosed themselves first while proclaiming “so, that saves us a few months”.
          But then, a CEO doesn’t get himself fired.

        2. Mel says:

          A post along these lines, and the recommended reads that would surely come out in the comments, would be a terrific read!!

    2. CB says:

      Nitroglycerin plasters are used for trans dermal delivery and there is an warning that a cardioverter/defibrillator should not be used if a Nitro-Dur patch is applied on the chest….as explosions may happen……better have a quick look first in emergency cases

    3. William J. Jackson says:

      Way back, nitroglycerine was noted for the way it affected the heart rate of dynamite workers as free nitro would often migrate to the surface of the wrapped stick = better wraps.
      more data and references here https://en.wikipedia.org/wiki/Nitroglycerin

      1. Randall Morris says:

        A college roommate had worked at one of America’s bomb storage “campuses.” This was many years ago. Some of the old bombs leaked and the workers hated to move them because they produced “nitro headaches.” “They were leaking nitroglycerine?!” I exclaimed. My roomie grinned and shrugged.

    4. “ That’s how I was elected to the dynamite, which made me sick. Before I had started the job I had heard stories that if you touch dynamite and then your face you will get a headache. Maybe I was carried away by the story, because as long as I worked on the powder I always had headaches.”
      Norman Maclean, “USFS 1919: The Ranger, The Cook, and a Hole in the Sky”

      Perhaps anecdotes like this led to looking at the physiological effects of nitroglycerin

      1. Aidan Chappuis says:

        I could’ve sworn I saw something about how headaches and drops in blood pressure in factory workers, combined with workers with angina feeling better, were actually why we looked at it

    5. Sarah says:

      Nitroglycerin readily absorbs through the skin. You wouldn’t have to taste it to dose yourself with enough to drop your blood pressure and get a nice headache. If I recall correctly, much of the sublingual dose is absorbed directly through the mucus membranes of the mouth rather than the rest of the GI system.

  9. M says:

    This shouldn’t come as a surprise. Its inventor Malcolm Stevens has approximately 9.5 fingers due to his interest in nitrogen-rich heterocycles – specifically, I’ve heard it was triazine 2,4,6-triazide (C3N12) that caused the digital deficit.

  10. Ammar Hasan says:

    It’s fair to say when I first saw this headline I thought it was figurative …

  11. Athaic says:

    “I find it very odd that TMZ’s explosive properties hadn’t been realized until now”

    That’s the sort of realization one wishes to happen in a lab, and not in a producing factory or a cargo ship…

  12. David A. Van Baak says:

    I seem to recall that the explosive properties of picric acid also lay hidden for many decades after its discovery . . .

    1. 이웅견 says:

      Iirc, in an interesting compendium for 1920s drugstore owners, among many other fascinating facts, it was mentioned that people would apply picric acid to their hair, I forgot what for. Otoh they also used hair grease made from cattle marrow, so I feel real pity for peoples’ hair back then, what a job!

      1. Isidore says:

        “I feel real pity for peoples’ hair back then:
        Hey, don’t knock it until you’ve tried it! 😉

  13. TallDave says:

    science demands we explore the possibility of spontaneous human combustion when combined with hard liquor

  14. Mark Foote says:

    TallDave,
    I’m not a chemist, but I found the whole comment section very entertaining reading, and arriving at your post I just exploded with laughter.
    Mark

  15. Aylons says:

    There’s a typo in the 3rd paragraph: tetratogenic should be teratogenic.

    1. Derek Lowe says:

      Thanks – fingers on autopilot there.

      1. TallDave says:

        well I for one enjoyed the visual of small colorful characiform fish spilling from an improperly handled container

  16. Chiffed says:

    So you are saying that shrapneliferousness is an issue? Was that your term from TIWWW?

  17. Peter Kenny says:

    One way to reduce carboaromaticity (apparently performs the vital function of differentiating drugs from random actives in ChEMBL according to the seminal contribution to the MedChem literature that I’ve linked in as the URL for this comment) and even the aromatic rings themselves.

  18. li zhi says:

    I’m not an organic chemist, but I wonder why that 4 nitrogen ring (is there a ‘parent structure’ for a 6-membered triaza cyclohexylamino ring?) wouldn’t be a clear red flag for potential rapid decomposition. My question is how many compounds with similar natures are in commerce? When I used it, way back, DSC required a high skill level to do right. (I recall my last job, the tech director had some equipment budget to use up and was talked into buying a DSC (or was it a TGA, shmaybe?), despite my cautioning that it was difficult to do right. The enthusiast with the golden tongue tried and failed to get it to work for him, and, seeing that the time commitment would be high (duh!) abandoned it after a couple of months of part-time effort. So, I wonder if part of the problem is the efficiency of modern machines has replaced accuracy. Trade-offs are usually made when a machine replaces an artist…) I wonder how many chemists synthesizing analogs sent them for DSC. Of course, you have to get an “adequate” purity before it’d be worth anything. And I wonder who to “blame” for the error – claiming 212 C mp when it decomposes at 170 is blameworthy in my book. Of course, after millions spent on drug dev., who is gonna want to look for trouble? Wonder what Malcolm Stevens has to say about it… Derek, follow-up on that might be enlightening.

    1. li zhi says:

      Is the Org.Proc.R&D paper directly applicable in the real world? I hit the good-old ACS pay-wall. I’d assume they did their work on the pure compound, but they might have checked the formulated commercial products as well.

      1. J Sperry says:

        We did indeed look at various commercial lots of TMZ. This work began because of the claim it was a safe alternative to diazomethane so we did not undertake the examination of formulated drug product. I’d be happy to send you a copy of the paper if you like!

  19. David Edwards says:

    I’ve read enough of Derek’s TIWWW articles on compounds with lots of weirdly bonded nitrogen atoms in them, to think to myself “That looks like a Klapötke compound” on seeing the structure. Indeed, upon seeing that ChemDraw rendition, I’m surprised it wasn’t found to be explosive much earlier than this.

    Perhaps that’s how it deals with glioblastomas – it blows the cells to bits … though given how nasty that disease is, anyone diagnosed with it would probably want this molecule to blow the cells to pieces …

    That’s a strange one all right, and I don’t even have Derek’s level of med-chem learning to think this.

  20. Radioactive Man says:

    So is dacarbazine explosive too? That has an even higher percentage nitrogen content than temozolomide.

  21. Thomas says:

    News about AZBT (5-(4’-(azidomethyl)-[1,1’-biphenyl]-2-yl)-1H-tetrazole) impurities in irbesartan, losartan and valsartan.
    AZBT is also rather nitrogen-rich – a 5-N ring like the Sartans have, and a 3-N stick poking out from the other end.

    1. A Nonny Mouse says:

      Interestingly, I have just seen a check-sheet from a contractor that we are using (for materials purchase from third parties) and there is now a list of chemicals which could potentially result in formation of these impurities.

  22. Clearasil says:

    Pure benzoyl peroxide is also explosive, but 5-10% pastes are used topically for acne. No nitrogens.

    1. So Smart says:

      And elemental nitrogen, with nothing else than nitrogen, is not an explosive either. So what do we learn from it?

      1. Thomas says:

        I prefer my nitrogen as N2, not elemental. I suppose the atomic N variety would be interesting to say the least.

        1. aairfccha says:

          An N4 molecule would probably have interesting properties as well.

  23. An Actual Dragon says:

    Reading this immediately reminded me of a quip from the TIWWW on nitrotetrazole oxides: “the FDA takes a dim view of exploding pharmaceuticals (nitroglycerin notwithstanding; that one was grandfathered in)”.
    I should assume that one, too, will stick around for a while for its mentioned usefulness. Not that I’d mind, as a patient – sudden explosion beats comparatively slow and almost certainly more painful cancer in my book.

    1. Pedantic Speaker says:

      Just try not to accidentally breath fire on the pills.

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