Fluoro metabolite toxicity

[Solipsis]

Apart from compounds like fluorine gas or HF, but rather considering organic compounds such as fluoroacetate or 2-F-ATP, is the usual toxicity problem with fluoro compounds that they end up as analogues of biochemicals and inhibit enzymes those biochemicals are ligands for? Just like fluoroacetate is converted to the actual toxicity hazard fluorocitrate, I guess taken up in the citric acid cycle?

The relevance of my question for drugs is for example seen in many cannabinoids that have the indole/indazole N-fluoropentyl subsitution. But there are other compounds that we can think of that have a fluoro stuck to them somewhere as part of novel drug design.

What can be generalized? Are aromatic fluoro's like in flunitrazepam and alkyl-aromatic ones like in 2C-EF usually safe, but aliphatic fluoro substited compounds or cleavable moieties (not fixed to carbon backbones) potentially unsafe as they can get cleaved metabolically into 2-carbon bits? So from that point of view, 2C-T-21 could yield fluoroacetate as a metabolite? And in other cases it may depend on whether the group a fluoro is stuck to undergoes extensive metabolism or not i.e. whether the fluoro can just be excreted as part of complex compounds that are not active in unusual ways?

I know that I should not stare blindly at one possible heteroatom / moiety, but toxicology can often be a collection of a lot of unique subjects correct?

 

[sekio]

Rule of thumb:
Aromatic fluorines are so tightly bound to the ring that they are effectively hydrogens.
Linear carbon chains with an even amount of carbon atoms in them and a terminal fluorine could be metabolised to fluoroacetate through beta oxidation.
Linear carbon chains with an odd amount of carbon atoms in there could end up as fluoroproprionate by the same beta oxidation process.

... this is why it's always a fluoropentyl group and you don't see fluorobutyl or fluorohexyl groups, at least that's the playground rumor.

Part of the issue is that cleaving a C-F bond is basically impossible biologically. So it stays stuck on that last carbon until you're left with just the end, then it jams all your cellular machinery (assuming you make fluoroacetate) because there's this little electronegative bit that sticks to protiens' active sites.

So from that point of view, 2C-T-21 could yield fluoroacetate as a metabolite?

Well, if there was any evidence that the ether was removed, then on paper you could make fluoroacetate. But the amount of fluoroacetate generated from a sub-10mg-dose of a potent psychedelic would be probably not of concern unless you're doing the stuff every 6 hours.

Also, cleaving aromatic ethers is a tough job. Think of codeine conversion to morphine. Now imagine if the methyl ether couldn't fit into the binding pocket of CYP2D6 because someone stuck a bunch of fluorines on it....

 

[tryp2fun]

Rule of thumb:
Aromatic fluorines are so tightly bound to the ring that they are effectively hydrogens.
Linear carbon chains with an even amount of carbon atoms in them and a terminal fluorine could be metabolised to fluoroacetate through beta oxidation.
Linear carbon chains with an odd amount of carbon atoms in there could end up as fluoroproprionate by the same beta oxidation process.

... this is why it's always a fluoropentyl group and you don't see fluorobutyl or fluorohexyl groups, at least that's the playground rumor.

Part of the issue is that cleaving a C-F bond is basically impossible biologically. So it stays stuck on that last carbon until you're left with just the end, then it jams all your cellular machinery (assuming you make fluoroacetate) because there's this little electronegative bit that sticks to protiens' active sites.



Well, if there was any evidence that the ether was removed, then on paper you could make fluoroacetate. But the amount of fluoroacetate generated from a sub-10mg-dose of a potent psychedelic would be probably not of concern unless you're doing the stuff every 6 hours.

Also, cleaving aromatic ethers is a tough job. Think of codeine conversion to morphine. Now imagine if the methyl ether couldn't fit into the binding pocket of CYP2D6 because someone stuck a bunch of fluorines on it....

That's a useful generality, but sometimes aromatic fluorine can be dangerous. For example, 3-fluorotyrosine is toxic since it is metabolized to fluoroacetate through the normal pathway for tyrosine metabolism, but 2-fluorotyrosine is relatively nontoxic, since the fluorine is eliminated as fluoride during metabolism.

 

[Solipsis]

Thanks it's helpful - think I'm going to read up a bit more on toxicology and maybe also continue studying org chem / medicinal chem. And there is a Johns Hopkins course on Coursera called Chemicals and Health, sounds interesting.