Evidence for spontaneous, reversible paracyclophane formation. Aprotic solution structure of the boron neutron capture therapy drug, L-p-boronophenylalanine

Abstract

The simple, straightforward 1 H NMR spectrum of the neutron capture therapy drug, -p-boronophenylalanine (-p-BPA), in D 2 O changes to a more complex one in DMSO-d 6 in which the ratio of new species observed is highly concentration dependent. The new species detected can only be explained by an additional stereocenter being formed at the boron center by intermolecular chelation of the amino acid of another molecule of -p-BPA. This gives rise to the presence of an oligomeric species as well as another whose aromatic protons appear as a pair of sharp AB quartets centered further upfield at 6.66 and 6.84. Due to these shifts and couplings observed between the benzylic protons and the proton at the stereocenter of the amino acid, it is proposed that this species is a paracyclophane dimer of -p-BPA in which one molecule of -p-BPA chelates head-to-tail with another. This cyclophane dimer predominates in low concentrations (<50 mM) while the oligomer predominates at higher (>90 mM) concentrations. The formation of these two species is completely reversible, the addition of D 2 O completely regenerating -p-BPA. Variable temperature 1 H NMR found that the two pairs of aromatic protons of the cyclophane dimer coalesce at T c = 141 ЊC, corresponding to a ∆G ‡ = 20.6 kcal mol Ϫ1 .

Advances in alkaline earth-nitrogen chemistry

“…The presence of these agostic interactions was detected both crystallographically and spectroscopically through the use of variable low-temperature VT 1 H NMR experiments [96][97][98][99][100][101]. Upon cooling, peak splitting was observed due to hindered rotations from the presence of agostic interactions.…”

Computational Investigation of the Oxidative Deboronation of Boroglycine, H2N−CH2−B(OH)2, Using H2O and H2O2

“…In synthetic organic chemistry, the properties of boronic acids as mild Lewis acids have made them an attractive class of intermediates [25] that have been widely used in Suzuki cross-coupling reactions [3, 26], Diels-Alder reactions [27], asymmetric synthesis of amino acids [28], selective reduction of aldehydes [29], and carboxylic acid activation [30, 31]. Biochemical and medicinal applications of boronic acids include inhibitors of serine proteases and beta-lactamases [32–34], bioconjugates [35], transmembrane transporters [36–39], anti-HIV drugs [40, 41], substrates for protein immobilization [42], and agents in neutron capture therapy [43–45]. …”

Physicochemical Investigation of the Influence of Saccharide-Based Parenteral Formulation Excipients on l-p-Boronphenylalanine Solubilisation for Boron Neutron Capture Therapy

“…The original manuscripts8,9 investigating BPA–saccharide mixtures for clinical use did not report any effect on the p K a values on the addition of fructose or mannitol; however, a reduction in the p K a values of the boronic acid group (more specifically, the boronic acid–fructose complex) in phenylboronic acid from 8.8 to 4.6 on complexation with fructose has been previously reported 20. The shift in the p K a of the boronic acid group of BPA in the presence of mannitol or fructose can be explained by the formation of the previously described tetrahedral anionic complex of BPA and monosaccharide, decreasing the oxygen–boron–oxygen bond angle which increases the acidity of the boron centre 21,22. These results also illustrate that the complexation involves or influences the carboxylic acid group causing its p K a to increase, a feature which, again, has not been previously demonstrated for BPA–fructose complexes 22.…”