Why can curcumin cross the blood-brain barrier, but not congo red?

Question

I've read that both congo red and curcumin are able to inhibit the clumping together of amyloid $\mathrm{β_{42}}$ in the brain, which would otherwise result in Alzheimer's disease.

Apparently, congo red cannot cross the blood-brain barrier (BBB) while curcumin can.

From what I learned at my biology classes, the BBB is lined by squamous, endothelial cells. Those cells are, as far as I know, the most permeable kind of cells you could come across in the human body, and if congo red doesn't pass through that, then it must be one stubborn molecule.

Now the cell membrane, itself being composed of a phospholipid bilayer, normally shouldn't have a problem transporting lipophilic molecules across the membrane. From an earlier conversation with Jan, I believe congo red is a lipohilic molecule. Yet inspite of it being lipophilic, it still isn't able to cross the BBB.

Comparing the structures wasn't particularly enlightening.

But the possibility congo red could act as a bidentate ligand, does seem to make it stand out from curcumin. Am I onto something here? Apart from that, and a somewhat larger size, I don't see why congo red shouldn't be able to cross the BBB.

Now, I'd like to know two things,

1) What enables curcumin to cross the BBB?

2) Why isn't congo red able to cross the BBB, even though it has a structure similar to that of curcumin?

Answer 1

Preface: both molecules could act as bidentate ligands but the β-diketo structure found in curcumin is typically a much better bidentate ligands — as the 2-oxophenol moieties would be. So I would expect curcumin to be a much better ligand than congo red.

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The key difference between the two molecules is comparing the extent of their lipophilicity and their hydrophilicity. Curcumin has a rather low water solubility of $3.2~\mathrm{mg/l}$, in line with the fact that it has rather little features that can enhance solubility. Basically, it boils down to the two keto-groups and the phenol moiety.

Congo red has two sulphonic acid groups and two aromatic amino groups. This means that there is a much greater relative charge present, and indeed its solubility in water is reported to be $1.16 \times 10^{2}~\mathrm{g/l}$ — notice the different unit. So congo red is already much more hydrophilic than curcuminis.

In terms of lipophilicity, the sulphonic acid groups present in congo red reduce its lipophilicity while the amino groups themselves don’t have too strong an effect. On curcumin’s side, the phenol groups can comfortably hydrogen bond to the neighbouring methoxy residues and the β-diketo fragment can tautomerise to a keto-enol form and form another intramolecular hydrogen bond. Thus, curcumin is a lot more capable of coping with low-hydrogen bond solvents and is thus expected to have a high lipophilicity.

This is the edge that curcumin has over congo red to cross the blood-brain barrier.

Answer 2

Congo Red is quite hydrophilic and not very lipophilic. Those sulfonates are extremly polar and are commonly used to make large aromatic molecules water soluble. Like for example bathophenanthroline, which would never be water soluble on it's own but if sulfonated twice you can dissolve 100mg/ml, which is a lot. Ofc the diazo groups and the anilines are polar too. Curcumin on the other hand is pretty apolar and lipophilic, those phenols and methoxy groups don't really have much influence.