Radulanine A: discovery of a natural herbicide

The use of syn­thet­ic pesti­cides and herb­i­cides is a sens­it­ive sub­ject in terms of pub­lic opin­ion, who are often con­cerned about the safety of exposed pop­u­la­tions and biod­iversity. Without enter­ing too much into this debate, it must nev­er­the­less be stressed that the search for sus­tain­able solu­tions and altern­at­ives is an act­ive field in chem­istry, par­tic­u­larly focused on nat­ur­al substances.

In organ­ic chem­istry, we some­times play Lego with atoms to repro­duce small nat­ur­al molecules with inter­est­ing prop­er­ties. This is what we call total syn­thes­is. Once these molecules have been syn­thes­ised, we try to bring them to life through new applications.

Research in this field has already made it pos­sible to bring molecules of nat­ur­al ori­gin onto the mar­ket. To give an idea of the extent of the phe­nomen­on, it should be noted that about a third of the pesti­cides pat­en­ted between 1997 and 2010 are “nat­ur­al” ¹. Altern­at­ives there­fore exist, but “nat­ur­al” does not neces­sar­ily mean “safe”.

This fig­ure is much lower in the cat­egory of herb­i­cides: over the same peri­od, only 8% of pat­en­ted molecules are “nat­ur­al”. It is in this con­text that we dis­covered a nat­ur­al herb­i­cide with poten­tial applic­a­tions. Not­ably in agri­cul­ture, but also in the treat­ment of rail­way tracks, which must remain per­fectly free from weeds to run high-speed trains on them, for example. Our pro­ject is fin­anced by the innov­a­tion clusters at the CNRS ² and Insti­tut Poly­tech­nique de Par­is ³.

In May 2019 our team from the Organ­ic Syn­thes­is Labor­at­ory of École poly­tech­nique ⁴ announced that we had suc­ceeded in syn­thes­ising a nat­ur­al herb­i­cide: Rad­u­lan­in A. The story is an example of “serendip­ity” – the abil­ity to make a sci­entif­ic dis­cov­ery by chance and grasp its use­ful­ness. For it was not a new herb­i­cide that we were work­ing on at first, but rather a new meth­od of syn­thes­is, tar­get­ing com­plex molecules.

The molecules tar­geted in our research are often com­plex and require long-term work. Basic­ally, what we were aim­ing for was a molecule pro­duced by a fungus; a com­plex molecule with cer­tain motifs that inter­ested us. To repro­duce these motifs (sev­en-chain oxy­gen­ated cycles) we developed a new meth­od of syn­thes­is, using a par­tic­u­lar chem­ic­al reac­tion (for the spe­cial­ists read­ing, this was by a rearrange­ment of the retro-Clais­en type). To test the use­ful­ness of this meth­od, we there­fore chose a sim­pler molecule: Rad­u­lan­in A. And, low and behold, our meth­od of syn­thes­is worked. In the begin­ning, there­fore, Rad­u­lan­in A was not spe­cifc­ally our target.

Once syn­thes­ised, the ques­tion arose as to how this molecule is used in nature. In doing so, we dis­covered that it has sim­il­ar­it­ies with molecules known to have plant hor­mone prop­er­ties. A fel­low research­er from Sor­bonne Uni­ver­sity, Emmanuel Baudouin, then took over and showed that Rad­u­lan­in A does indeed have the abil­ity to inter­act with plants, through phyto­tox­ic prop­er­ties. Without know­ing it, we had syn­thes­ised a nat­ur­al herbicide!

At a time when we are look­ing for indus­tri­al altern­at­ives to glyphosate, this was good news. The herb­i­cid­al prop­erty of Rad­u­lan­in A has now been pat­en­ted, and industry is inter­ested in it. For the pat­ent to be exploited, it will be neces­sary to under­stand how, over time, the molecule inter­acts with the envir­on­ment, and wheth­er it can have effects on the human body. These ques­tions, cent­ral to industry, are a pre­requis­ite for approv­al. The impact of a molecule also depends on how it is used, which must remain reas­on­able to lim­it its impact on the envir­on­ment. The tox­icity of a sub­stance is almost always a mat­ter of concentration.