I love a good mystery, most scientists do. Whether it’s JFK being killed by a poison arrow or secret CIA Cold War poisons, I’m all in. And for me, the older the better. When I’m searching for poisons I like to start with the oldest references, which for me are usually in the mid to late 1800’s. There’s a certain flair in Victorian Era scientific literature that’s sorely missing today: flowery language, bravado, and hyperbole….but I can live without the overt racism and sexism. So when I encountered an 1800’s reference to a mysterious poison and mass murder, I was hooked, and so began my journey down the rabbit hole, not knowing where it would take me.

It starts in the wild plains, the Llanos, of Venezuela. In 1862, Don Ramon Paez, a Venezuelan native that documented the geography, flora, and fauna of South America writes in his book, “Wild Scenes in South America,” about a plant known locally as Guachamacan (1):

“So virulent is this poison, that meat roasted on spits made from the Guachamacan, absorbs sufficient poison to destroy all who partake of it. (They) make use of it to kill without trouble the cranes and herons on the borders of the lagoons. For this they procure a number of sardines, besmear them with the juice of the plant, and spread them among the places frequented by those birds. The moment one of them seizes the fish, and before it is fairly swallowed, the bird drops dead; then the indolent hunter, issuing from his hiding-place, cuts off the parts affected by the poison, usually the head and neck, and feels no scruple in eating the remainder.”

Interesting, so this is where the legend of a troop of Boy Scouts dying after roasting hot dogs on oleander sticks started, but I digress. The part that really caught my attention though was homicide. Senor Paez regales us with the story of a woman who felt slighted when her man made googly-eyes at another woman. And what better way to avenge your honor than by poisoning him? She prepared him a bowl of masato – a fermented corn beverage – in which she soaked chips of Guachamacan, and offered it to him “with smiling grace.” Not to be rude, the dude invited his neighbors over – including his side-chick – to share it with him. Senor paez writes:

“Out of the eleven persons there assembled, amongst them several children, not one escaped except the wicked perpetrator of this wholesale murder, nor even the donkeys and fowl of the household, as their attentive master had thrown them the remains of the deadly mixture.”

Nice lady we’ve got here. As for the accuracy of this tale? Who knows, it sounds sensational. But Senor Paez’s guides were certainly afraid of Guachamacan, as they threatened to desert him if he even carried a specimen of it in his baggage.

Guachamacan leaf, by M.A. Ernst (CC 0)

Fortuneately Mr. Ernst, a pharmacist in Caracas, had more amenable guides, and was able to procure a branch and two roots (2). Wanting in on the excitement, Sir Joseph Hooker* declared the plant to be of the genus Prestonia, sight unseen. Bad idea. Once he actually saw the plant, however, he changed his mind and decided upon Malouetia nitida (3). Good idea. Analysis of the plant revealed the roots to be harmless, but the leaves contained a fast-acting poison. Aqueous extracts of this poison had a paralyzing effect on muscles, yet left consciousness intact, much like curare. Not only was the mode of action was surprisingly like that of curare, but the chemical analysis as well (4). So similar that many proposed guachamacine – the name coined by Dr. Kobert of the Pharmaceutical Institute of the University of Strassburg – to be identical to curare. The icing on the cake for that theory was that the best curare came from the Orinoco and Rio Negro areas of Venezuela, where Guachamacan was also located. Alas, guachamacine can’t possibly be one in the same as curare, because, as you readers know, curare has no oral bioavailability. This is how curare could be used as an arrow poison to hunt wild game, yet allow the hunter to feast on the flesh, and why it’s a rookie move to try to poison someone with a curare laced steering wheel.

* Sir Joseph Hooker was a badass. A friend of Charles Darwin, he was to botany what Darwin was to evolution, only better. He collected plant specimens from all over the world, even Antarctica, and fought hard for science and the famed Kew gardens. Check out his bio, here.

With the plant now firmly entrenched as a member of the genus Malouetia, a name change for the poison was in order: malouetine. But just what the heck was malouetine? No one knew, this was the 1880’s after all, and structural elucidation of complex natural compounds could take years. Or 80. In 1960, Prof. Francoise Laine, of the University of Paris, isolated malouetine from the bark of an African Malouetia species, Malouetia bequaertiana. His experiments in cats showed the same neuromuscular-blocking activity as d-tubocurarine, but only one-third as toxic. The structure of malouetine? A steroid! (5)

When the bisquaternary steroid structure of malouetine was discovered, steroid chemistry was the hot topic of the day, and medicinal chemists speculated that malouetine, or analogs, could offer an alternative to d-tubocurarine. The race was on, but malouetine itself was scrapped due to profound hypotension in dogs. But in 1964, a related drug, pancuronium, was synthesized. Pancuronium has up to 10-times the potency of d-tubocurarine, and is still in use today, not only as a neuromuscular blocker, but also as one of the drugs in the “three drug cocktail” for lethal injections in the United States. If not for the discovery of malouetine, there would likely be no pancuronium, rocuronium, or vecuronium today.

The potential lethality of malouetine isn’t in question, but this mystery is far from over. There’s still the question of oral activity and the legend of the spiteful and pissed off princess. Pancuronium, as a reference, has poor oral bioavailability, but is active nonetheless. What about malouetine? Even with marginal oral activity, it seems doubtful that enough malouetine could be extracted from bark, wood chips, or leaves, that would be lethal when drunken. And second, malouetine has only been extracted from African malouetia species, not South American (5). There are many, many chemical present in South American species, but none so far that could account for Senor Paez’s legend.

Am I bummed that I don’t have an answer to this mystery poison? Nah. Maybe not all mysteries are meant to be solved, and besides, science exists because there are questions left to be answered. And who knows, maybe some young reader will use this as motivation to travel to Venezulea, find some specimens, and do some fancy structural elucidation. Send me a postcard.

** Homepage featured image of Venezuelan Llanos (plains) by Hochgeladen von Araujojoan96 (CC BY 2.0) **

References:
1. Páez, Ramón. Wild Scenes in South America, Or, Life in the Llanos of Venezuela. New York: C. Scribner, 1862.
2. Ernst, M.A. “On the Guachamaccan, a Poisonous Plant growing in the Llanos (Plains) of Venezuela.” Transactions of the Botanical Society of Edinburgh 10 (1870): 448-451.
3. “Guachamaca.” American Journal of Pharmacy (1885): 560-562.
4. “On Guachamaca and its Relation to Curare.” American Druggist (1885): 188.
5. Bisset, N.G. “Uses, Chemistry and Pharmacology of Malouetia.” Journal of Ethnopharmacology 36 (1992): 43-50.
6. Buckett, W. R., Christine E. B. Marjoribanks, Fiona A. Marwick, and Marion B. Morton. “The Pharmacology Of Pancuronium Bromide (Org.na97), A New Potent Steroidal Neuromuscular Blocking Agent.” British Journal of Pharmacology and Chemotherapy 32.3 (1968): 671-82.