Extensive and adaptable polycyclic ring structures can effectively invert themselves, leading to a neglected phenomenon known as ‘homeomorphic isomerisation’. This conformational change allows configurations to transition between various forms and may have implications for metal extraction and pharmaceutical delivery, in addition to significant consequences for intellectual property.
The arrangement of the bridgehead atoms in interconnected ring structures is vital in establishing the overall spatial configuration of the molecules. In smaller bridged bicyclic structures, the inflexibility of the connecting chains frequently results in conformational fixation, causing limited structures like norbornane or bicyclo[2.2.2]octane to be locked into one orientation. Conversely, the pliability of larger configurations provides a wider scope of freedom, allowing some to completely invert at their bridgehead atoms. ‘Essentially, we require two bridgehead components and three tethers, with a minimum of 10 atoms in these tethers being necessary. That’s the baseline requirement,’ remarks John Gladysz, an organometallic chemist from Texas A&M University in the US.
With proper activation, one tether moves through the loop formed by the other two, causing the entire ring structure to invert by altering the orientation of the bridgehead groups from inward to outward, or vice versa. The speed at which this process transpires varies among ring systems, and this variation holds promise for multiple applications, according to Gladysz.
For instance, Gladysz’s group anticipated that this phenomenon could facilitate the separation of metal ions. They populated the bend of a U-tube apparatus with an organic layer that contained a swiftly interchanging diphosphine macrobicycle, capping each arm with a water-based solution of either platinum chloride or potassium cyanide. Within a few hours, the diphosphine ring system had retained most of the platinum from one arm to the other, leaving other contaminating metal ions unaffected. ‘The out–out form captures the platinum from the boundary, enfolding it inside [as the in–in form] for transport,’ Gladysz explains. The reverse homeomorphic process subsequently releases the platinum at the other end, where it is captured by the cyanide.
Drug delivery
Nonetheless, what intrigues Gladysz most is the prospect of utilizing slow interconversion for drug delivery. Macrobicyclic peptides are becoming an increasingly favored pattern in drug discovery initiatives, but their architectures are often susceptible to digestive enzymes, rendering them unsuitable for oral intake. Gladysz asserts that a durable homeomorph of a specific peptide could theoretically be engineered to withstand the digestive tract’s environment and traverse the epithelium. This would then transition over several hours into an alternative active configuration that demonstrates the needed biological effect.
For Andrei Yudin, a synthetic chemist at the University of Toronto in Canada, this idea is an intriguing conceptual strategy, but numerous challenges remain before it can be deemed a practical method. ‘You desire this chameleonic feature where it alters between states, but how many distinct conformational states can be managed?’ he inquires. ‘Furthermore, sometimes a very minor portion of a specific conformation is actually key to the biological activity, so how do you identify the conformation responsible for a specific property?’
Of more immediate relevance are the ramifications of this conformational effect for intellectual property, especially where a considerable barrier to interconversion effectively establishes two completely unique ring topologies. Given the thorough coverage of enantiomerism and polymorphism in patent safeguarding, Gladysz was taken aback to find no reference to homeomorphic isomerisation in any of the documents reviewed by the team, and believes this may point to a weakness in current IP.
However, while Yudin concurs that conformation can significantly influence a compound’s characteristics, he questions whether homeomorphism could be valid grounds for a claim. ‘If you hold composition of matter coverage in a patent, I personally believe those claims should encompass all conceivable conformations, since conformation equals structure,’ he states.
Regardless of the legal resolution, Gladysz hopes this discussion will renew attention on this overlooked phenomenon and inspire researchers across various fields to seek and utilize these isomers in their respective domains.