[zippy5]

I used to work on DNA dyes. Typically when you see a 6 carbon ring with a chain of carbons attached, there is high probability of that molecule interfering with DNA replication.

Basically the mechanism works because the hexagon ring slides between the base pairs and this leads to a lowest energy state due to a phenomenon call pi orbital stacking resulting in the molecule getting stuck there. The carbon chain is mostly valuable in the sense that it distances the rest of molecule from interfering with the stacking process.

Take a look at ethidium bromide or pretty much any other intercalating dna stain and you’ll see similar characteristics. It’s also extremely carcinogenic.

https://en.m.wikipedia.org/wiki/Pi-Stacking_(chemistry)

It’s analogous to getting some cloth stuck in your zipper. Sometimes you can zip and unzip easily enough but sometimes it’ll get stuck. My understanding is that really DNA replication issues tend to be the root cause of some, possibly many cancers but really that’s outside my expertise.

So I would say that it is internally consistent with my limited knowledge of biochemistry that aspartame is carcinogenic.

I would strongly caveat this with saying that these structures occur in pretty high frequency across many forms of plant and animal life. Chemists in my lab used to joke about how potatoes contain 17 or so know carcinogenic compounds so why buy organic. My point is, if you go looking for correlations with cancer in many forms of food, you will find them.

I think for most people, aspartame is not likely to be major risk factor unless you are consuming it in extreme quantities and otherwise live a very healthy life.

[tptacek]

The biochemist I raised and who is sitting next to me drinking beers I paid for so that he would not drink all my expensive whiskey says that ethidium bromide doesn't even pass the Ames test except with liver homogenates, and its actual carcinogenicity is unproven. Your body produces similar carbon rings --- phenylalanines --- constantly. You can't simply derive carcinogencity axiomatically.

(I'm butchering this and mostly just having fun with it.)

Edit

He is correcting me and saying that at the moment he is technically working as a veterinary immunologist. But the point about 6-carbon thingies stands.

[dctoedt]

> The biochemist I raised and who is sitting next to me drinking beers I paid for so that he would not drink all my expensive whiskey

Ah, the joys of having young-adult offspring! I was recently surprised and delighted when the high-school history teacher that I raised brought home a bottle of the not-expensive whisky that we drink (Famous Grouse) to replace the bottle that magically empties so much faster since he started coming over for dinner now and then. He hasn't brought whiskey yet (Jameson's Port Cask) because we don't drink that up as quickly ....

[kortex]

If that hypothesis were true, it would implicate not just phenylalanine, but dopamine, epinephrine, diphenhydramine, ibuprofen, paracetamol, limonene, vanillin, cinnamaldehyde, and literally thousands of other different molecules, natural and synthetic, we constantly interact with. Heck, most polyphenols have pi-conjugation, and those are widely thought to have antioxidant and anticancer effects. Oh and I completely forgot about the indole moiety (tryptophan).

Intercalation is way more complicated than just some flat pi-bonded moieties. If that's all it took, we'd see everyone getting cancer like...rats...oooohhhh, I wonder...

Maybe rodents (especially Sprague rats) are way more vulnerable to intercalation? That would explain why so many things cause cancer - weak recovery mechanisms for DNA replication errors. I need to look into this further.

Anyway... the pattern I see across known intercalators is large, multi-ring (3 or more) fused flat structures. Like PAHs.

[zippy5]

It’s not really a comprehensive interpretation of intercalation but I think a geometric interpretation can help some non-chemists understand how intercalating molecules bind to dna.

From the purely geometric model, some of the molecules you proposed have pretty large functional groups adjacent to rings which I think may make the intercalation process less efficient. That being said, if you took those molecules and gave massive doses to rats, some may comeback as carcinogenic.

I think that your multi-ring point is fair. The multi ring structure to me suggests that the more the pi orbitals are able to delocalize their electrons the higher the binding efficiency. I have tested 1-2 molecules where non-fused rings showed some affinity but not near the potency of fused ring structures. I would also say two rings with a carbon-carbon link seem to be potent binding as well. I presume that it’s also related to delocalizing pi orbitals and extra degrees of freedom in the intercalation process but I suppose that’s just speculative.

[nate_meurer]

> some of the molecules you proposed have pretty large functional groups adjacent to rings

And many more do not.

> if you took those molecules and gave massive doses to rats, some may comeback as carcinogenic.

Luckily we don't have to guess. For example, look at the hundreds of terpenoids that saturate traditional diets, many of which and are widely believed to prevent cancer. If you have any actual evidence, put it up.

> The multi ring structure to me suggests...

All this is interesting, but it has exactly nothing to do with in vivo carcinogenicity. You don't have to look far to see this is true. Healthy diets are chock full of polyphenols that exhibit significant DNA binding affinity, but lack evidence of carcinogenicity. And it's not for lack of looking.

You appear to have some specialized knowledge, but when you try to extrapolate it to a wider field where you're out of your depth, these hand-waving guesses can easily turn into fearmongering.

[zippy5]

I want to apologize, I definitely don’t intend to fear monger and most definitely not want to imply that I have expertise. Roughly my level of understanding is mostly that of a low level undergrad and you should treat my naiveness as such.

I recognize that what I’m engaging in is entirely wild speculation based on limited experience and data, likely very error prone and that really I’m just having fun without considering how it may impact other readers.

I understand that for many this an important issue of health and research. I did not intend to detract from these more legitimate forms of discussion.

[nate_meurer]

I doubt there are many graduate students who would readily understand what you wrote about fused rings. It's going to take me some time to digest it.

[tptacek]

Bah! It was a fun argument to read and you clearly seem to have been participating in good faith.

[kortex]

> I think a geometric interpretation can help some non-chemists understand how intercalating molecules bind to dna.

Absolutely, geometry of electric fields is the primary factor in biochemical interactions. "The electron is where its at" as my o-chem teacher always said.

But that's exactly why aspartame is totally different than intercalators like EthBr, doxorubicin, and PAHs. That phenyl moeity has a rotational degree of freedom, and the whole peptide backbone is floppy. EthBr has a Ph but it's stabilized in-plane by the tri-ring. Intercalators typically have 300-500 daltons worth in a "planar greasy brick" regime, with very little in the way of bulky or floppy steric groups. On paper, aspartame looks pretty flat, but you gotta think about thermal molecules in solution.

E: just noticed this

> I would also say two rings with a carbon-carbon link seem to be potent binding as well.

Oh yeah, like biphenylyl, -Ph-Ph? So that's actually much more planar than a single Ph. The conjugation (any time you see carbon chains with alternating double bonds) of the pi-orbitals stabilizes the rings in-plane. Also it's rather unnatural, there's not a lot of reactions which forge a sigma bond between two aromatics like that.

https://en.m.wikipedia.org/wiki/Biphenyl

[ncmncm]

While you're here... what is a Ph ring with an O substituted, and an N opposite it, called?

[kortex]

If it's fully unsaturated, 1,4-oxazinane. If it's 2 double bonds, 1,4-oxazine, or more commonly oxazinone if it's part of a larger fused structure (eg nile red). If you fully aromatize it, it becomes oxazinium. That's a weird one, probably unstable. I think there are some peroxo species with a 1,4-oxazin-1-ium but it's a bit wacky.

The meta (1,3) oxazinium is more stable, but it still needs 3 big electron-withdrawing groups to stabilize it in the case of 2,4,6-Triphenyl-1,3-oxazine-1-ium.

https://en.m.wikipedia.org/wiki/Oxazines

https://chemdrawdirect.perkinelmer.cloud/js/sample/index.htm...

[ncmncm]

Thank you. I was looking at a vermicide that had what looked like a complicated nitrogen cage, empty, with a pair of those hanging off, and I realized I had no idea what to call them.

[nate_meurer]

> Take a look at ethidium bromide or pretty much any other intercalating dna stain and you’ll see similar characteristics. It’s also extremely carcinogenic.

This is a myth. This is actually a good example of a plausible biological effect that doesn't apply to living organisms:

https://blogs.sciencemag.org/pipeline/archives/2016/04/18/th...