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.