Every so often reports appear that some synthetic compound actually turns out to be a natural product. Sometimes these make very little sense, and turn out to be analytical mistakes (as with this report of nevirapine). But sometimes they’re right.
This one looks as if it’s right, though. Nauclea latifola, known colloquially as the “African peach”, apparently has tramadol in it. That’s pretty interesting, since tramadol was previously known as a synthetic opioid agonist (among other activities), used as an analgesic since the 1970s. Fittingly, preparations from this same species show up in a number of traditional medicine mixtures in West Africa, and there have also been numerous reports that extracts of the tree’s roots have an analgesic effect.
This work was done through classic natural-products work: fractionate the root, test the fractions for activity in a rodent assay, home in on the active fraction and see what compounds are in it. It’s always good to read about this sort of thing working – a lot of natural products were discovered this way in earlier days, but it’s gotten harder over the years. Too often, there will be some extract that shows activity, which would be worth following up on if it concentrated, but none of the fractions are then particularly interesting. Here’s a writeup at Chemistry World:
Our results indicate that high amounts of the analgesic drug, tramadol, can be obtained through a simple extraction procedure from Nauclea latifolia found in Cameroon or sub-Saharan areas,’ says Michel De Waard, a neuroscientist at the Université Joseph Fourier. De Waard adds that the root of the plant could be viably used as a source of tramadol because of the significantly high concentrations of the drug – over 1% of the original dry content.
The team used NMR and HRM spectroscopy, as well as x-ray crystallography, to determine the structure and confirm it as tramadol. Further spectroscopic and isotope ratio analyses confirmed that the compound extracted was indeed natural in origin, and not a by-product of cross-contamination. This unexpected discovery supports the traditional uses of N. latifolia roots in the treatment of pain; however, although other parts of the plant are also used in traditional remedies, the team found no analgesic compounds in the rest of the plant.
It’s interesting that tramadol is made in such high concentrations, and it’s worth speculating about what benefit the tree gets by spending that much metabolic effort. The same group that reported this isolation is now looking at the biosynthesis, and that should be worth hearing about.
Some readers, especially those outside the field, might wonder why I give this work a stamp of approval while instantly rolling my eyes at the nevirapine isolation paper. There are several reasons. One is that there are most certainly natural products that target the opioid receptors, starting with morphine and moving along from there. Natural products that potently inhibit reverse transcriptase (the target of nevirapine) are unknown to me. Nevirapine is also an unusual structure to propose as a natural product. By this point, we’ve isolated enough plant-derived compounds that most of the time a natural products chemist can say “Oh yeah, that’s a terpenoid, looks related to such-and-such”, or “Oh yeah, that’s an alkaloid of the this-and-that family”. Nevirapine does not fit easily into such classifications, and complete outliers like this are becoming more and more rare. If you find one, you make a big deal out of it. The last straw about the nevirapine paper was that it blithely mentioned that the compound was optically active, which was (see that earlier link for more) unlikely enough that it also would have been worth a separate paper. The fact that it was just mentioned in passing called the whole manuscript into question. The present paper suffers from none of these defects. Tramadol has certainly never been reported as a natural product, and it’s interesting that it is one, but looking at its structure, you could imagine that sure, a plant could make that, one way or another.