Andrew McGown

N‐acetyl‐L‐leucine (levacetylleucine, ALL) is the neuroprotective enantiomer of the racemic antivertigo drug, Tanganil (acetyl‐DL‐leucine, ADLL). ALL has recently been clinically repurposed for the treatment of Niemann Pick disease type C1, a disorder characterised by lysosomal accumulation of glycolipids and cholesterol. Isotopically labelled ALL was required, as well as its negative control, D‐enantiomer (ADL), to monitor the in vivo metabolic fate of the drug and to distinguish it from endogenous leucine and associated metabolites. Here, we describe the synthesis of N‐acetyl‐D‐ and ‐L‐leucine‐ ¹³ C ₆ , as well as N‐acetyl‐L‐leucine‐ ¹³ C ₁ , by N‐acetylation of their amino acid precursors, their spectroscopic characterisation and stereochemical and stability studies. These investigations found that formation of the products, as well as their water‐soluble sodium salt formulation, occurs without compromising stereochemical integrity.

Copper catalyzed aldehyde-alkyne-amine (A3) couplings lead to multifunctional, racemic, propargylic amines, many on a multigram scale. As part of an industrial collaboration, a selection of linkers was purified by chiral HPLC to afford single enantiomers, the absolute configuration of which was determined by vibrational circular dichroism (vCD). To show medicinal chemistry applications, selected linkers were further derivatized into potential cellular probes and (+)-JQ1 containing PROTACs (proteolysis targeting chimeras), which degraded their target protein BRD4.

The P2X purinergic receptor 7 (P2X7) has an essential role in inflammation, innate immunity, tumor progression, neurodegenerative diseases, and several other diseases, leading subsequently to the development of P2X7 modulators. AZ11645373 is a frequently studied P2X7 antagonist tool com-pound, but always as a racemic mixture. Racemic AZ11645373 can be separated, into its respective enantiomers by chiral chromatography, albeit in small batches, and these were stereochemically in-tact over a year later, by chiral HPLC analysis. On a higher scale, significant decomposition is ob-served. One of the enantiomers was crystallised as a palladium complex and its (R)-configuration was determined by single crystal X-ray diffraction, further confirmed, in solution, by vibrational circular dichroism. Biological studies demonstrated that both (S)- and (R)-forms were able to fully inhibit human P2X7, but (R)-AZ11645373 was more potent, with an IC50 of 32.9 nM. Contrary to its effect on human P2X7, (S)-AZ11645373 was ineffective on mouse P2X7, while the (R)-AZ11645373 enantiomer was a full antagonist. These results demonstrated that the antagonistic effects of racemic AZ11645373 are mainly due to its (R)-enantiomer. Site-directed mutagenesis and molecular dynam-ics simulations indicated that the (R)-enantiomer may form specific interactions with Phe95 and the antagonists bound to the other P2X7 monomers. Phe95 is situated at the channel pore and appears to be the pivotal molecular gateway between AZ11645373 allosteric binding and locking of the closed state of the P2X7 channel. All together, these structure-function relationships should be helpful for drug design of P2X7 modulators.

Functional changes in chaperone systems play a major role in the decline of cognition and contribute to neurological pathologies, such as Alzheimer’s disease (AD). While such a decline may occur naturally with age or with stress or trauma, the mechanisms involved have remained elusive. The current models suggest that amyloid-β (Aβ) plaque formation leads to the hyperphosphorylation of tau by a Hsp90-dependent process that triggers tau neurofibrillary tangle formation and neurotoxicity. Several co-chaperones of Hsp90 can influence the phosphorylation of tau, including FKBP51, FKBP52 and PP5. In particular, elevated levels of FKBP51 occur with age and stress and are further elevated in AD. Recently, the dihydropyridine LA1011 was shown to reduce tau pathology and amyloid plaque formation in transgenic AD mice, probably through its interaction with Hsp90, although the precise mode of action is currently unknown. Here, we present a co-crystal structure of LA1011 in complex with a fragment of Hsp90. We show that LA1011 can disrupt the binding of FKBP51, which might help to rebalance the Hsp90-FKBP51 chaperone machinery and provide a favourable prognosis towards AD. However, without direct evidence, we cannot completely rule out effects on other Hsp90-co-chaprone complexes and the mechanisms they are involved in, including effects on Hsp90 client proteins. Nonetheless, it is highly significant that LA1011 showed promise in our previous AD mouse models, as AD is generally a disease affecting older patients, where slowing of disease progression could result in AD no longer being life limiting. The clinical value of LA1011 and its possible derivatives thereof remains to be seen.

Chaperone systems play a major role in the decline of cognition and contribute to neurological pathologies such as Alzheimer’s disease (AD). While such a decline may occur naturally with age or with stress or trauma, the mechanisms involved have remained elusive. The current models suggest that amyloid-β (Aβ) plaque formation leads to the hyperphosphorylation of tau by a Hsp90 dependent process that triggers tau neurofibrillary tangle formation and neurotoxicity. Several co-chaperones of Hsp90 can influence the phosphorylation of tau, including FKBP51, FKBP52 and PP5. In particular elevated levels of FKBP51 occur with age and stress and are further elevated in AD. Recently, the dihydropyridine, LA1011 was shown to reduce tau pathology and amyloid plaque formation in transgenic AD mice, probably through its interaction with Hsp90 although the precise mode of action is currently unknown. Here, we present a co-crystal structure of LA1011 in complex with a fragment of Hsp90. We show that LA1011 can disrupt binding of FKBP51, which might help to rebalance the Hsp90-FKBP51 chaperone machinery and provide a favourable prognosis towards AD. Clinically, this is highly significant, as AD is generally a disease affecting older patients, where slowing of disease progression could result in AD no longer being life limiting.

A cheap, conventional, sealed heating reactor proved to be a useful alternative to a microwave reactor in the synthesis of a >20-member MIDA boronate library (MIDA = N-methyliminodiacetic acid). Reaction times were 10 min and work-ups were minimal, saving on energy and solvent usage.

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