Abstract
A detailed NMR investigation of the chemical shifts of hydrogen and carbon atoms associated with the structure of the naturally occurring alkaloid colchicine was conducted using high field NMR. Initially, the experimental chemical shifts for colchicine in chloroform and DMSO were compared to the values calculated using density functional theory (DFT). There were significant deviations observed for the chloroform solvent, but these were only slight in the DMSO solution. Dilution of the chloroform solution changed the experimental chemical shifts and improved agreement with the DFT calculations, suggesting self-aggregation at higher concentrations. A dimeric model was proposed for which agreement with the DFT calculated chemical shifts was better than for corresponding monomeric structures. Three further solvents were studied to evaluate changes in chemical shift values at different dilutions. Chloroform, benzene and water showed significant chemical shift changes implying self-aggregation, whereas DMSO and acetone did not show significant change upon dilution.
Highlights
Colchicine is a naturally occurring alkaloid that binds to tubulin, inhibiting the formation of microtubules in mitotic spindles[1] and suppressing cell division[2]
The proton and carbon chemical shifts were confirmed by first principles using the 1H, 13C, COSY, HSQC and HMBC spectra
The chemical shifts were calculated using density functional theory (DFT) and comparisons with experimentally measured chemical shifts are shown in Tables 1 and 2
Summary
Solutions of colchicine in deuterated chloroform and DMSO were made up to ~46 mM concentration. Comparing the experimental and DFT calculated chemical shifts for the concentrated and diluted solutions of colchicine in chloroform, we observed that the diluted solution showed a reduction in the MAE from 0.19 to 0.15 ppm; the amide proton was not used in the calculation of this metric. Based on these observations, we can eliminate the first hypothesis, in which chloroform solvent was coordinating with colchicine. In using the cut down monomer 2 for calculation, we took the precaution of confirming that the chemical shifts of interest were not changed significantly from those of the parent colchicine molecule in the area of largest deviation in the experimentally measure chemical shifts between the concentrated and diluted solutions. This explanation was further supported by the observed NH chemical shift between the
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