It’s not too common to encounter a compound as one above in a paper tagged ‘medicinal chemistry’. But the team of Spanish and French chemists seems not to care too much about rule of 5 or any other rules of thumb that constrain their creativity. Especially when the rationale for compound design was:
it is difficult to make compounds of an adequate size and multivalency to mimic natural systems such as viruses
The ligands dubbed ‘superballs’ are targeting dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN). And the multivalency of ligand-receptor interaction is the key factor of viral infection. Previous state-of-the-art ligands were virus-like particles with 1620 mannoses displayed on their surface. So I guess in this study authors significantly optimized ligand efficiency.
As one can expect, structure confirmation for the final compounds was not straightforward. Authors used IR spectroscopy to confirm absence of azides and alkyne groups (it’s certainly easier than to confirm presence of anything else by IR). They couldn’t detect the molecular ion in MALDI-MS. But 13C NMR saved the day and the structure was successfully assigned. The molecules were so big (~60 kDa) that they gave single-molecule peaks in dynamic light scattering and were observable by tunneling electron microscopy!
The compound 17c inhibited the entry of Ebola-like viral particles into the model DC-SIGN-expressing cells with subnanomolar IC50. There was even some sort of SAR (compound with shorter linker showed 30-fold reduced potency, different saccharides showed no activity). So it’s a valid medchem paper after all. And for the dessert, a nice conclusion:
the compounds reported here pave the way to […] the
use of disaccharides to improve significantly the scope of the biological applications of tridecafullerenes
Well, this kind of pharmacophore has been certainly overlooked up to now.
Sarcasm aside, it’s a really nice piece of work!