Abstract
Tyrosine kinase inhibitors (TKIs) are a major class of drug utilised in the clinic. During transit to their cognate kinases, TKIs will encounter different pH environments that could have a major influence on TKI structure. To address this, we report UV-Vis spectroscopic and computational studies of the TKI, AG1478, as a function of pH. The electronic absorption spectrum of AG1478 shifted by 10 nm (from 342 nm to 332 nm) from acid to neutral pH and split into two peaks (at 334 nm and 345 nm) in highly alkaline conditions. From these transitions, the pKa value was calculated as 5.58 ± 0.01. To compute structures and spectra, time-dependent density functional theory (TD-DFT) calculations were performed along with conductor-like polarizable continuum model (CPCM) to account for implicit solvent effect. On the basis of the theoretical spectra, we could assign the AG1478 experimental spectrum at acidic pH to a mixture of two twisted conformers (71% AG1478 protonated at quinazolyl nitrogen N(1) and 29% AG1478 protonated at quinazolyl nitrogen N(3)) and at neutral pH to the neutral planar conformer. The AG1478 absorption spectrum (pH 13.3) was fitted to a mixture of neutral (70%) and NH-deprotonated species (30%). These studies reveal a pH-induced conformational transition in a TKI.
Highlights
Determination of acid dissociation constant of drugs gains paramount significance from the perspective of dosage form formulation, pharmaceutical analysis, and studying drug pharmacokinetics[1,2]
Spectra of AG1478 in alkaline solutions at pH 7.3–12 had relatively reduced optical densities in the 300–400 nm region compared to acidic conditions and were shifted to the blue with a λmax at 332 nm
We found that the combination of 71% of monoprotonated AG1478 (N1-LM2) and 29% of monoprotonated AG1478 (N3-LM1) accounted for the AG1478 spectrum at pH 3.2
Summary
Determination of acid dissociation constant (pKa) of drugs gains paramount significance from the perspective of dosage form formulation, pharmaceutical analysis, and studying drug pharmacokinetics[1,2]. UV-Vis spectroscopy takes advantage over other techniques since it is accurate, precise, reproducible and cost-effective using only micromolar concentrations of samples It has been used for exploring electronic properties of the ground and excited states of fluorophores[11,12]. The two prerequisites for successful determination of pKa by UV-Vis spectrophotometry are a) presence of chromophore near to ionization centre and b) change in absorbance spectrum as a function of compound ionization[2]. For this reason, optical pH probes have gained a wide range of applications in analytical and biomedicinal chemistry[18]. Studies on active pharmaceuticals which bind to cell DNA emphasised that the cationic form of a drug intercalates with DNA bases more strongly than neutral species, while the anionic form of a chromophore is a poor intercalating agent due to the columbic repulsion between negatively charged DNA backbone and drug[50,51,52]
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