The Center for Theoretical and Computational Chemistry

Oslo, Norway

The Center for Theoretical and Computational Chemistry

Oslo, Norway
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Wilson S.R.,University of Oslo | Strand M.F.,University of Oslo | Krapp A.,University of Oslo | Krapp A.,The Center for Theoretical and Computational Chemistry | And 3 more authors.
Journal of Pharmaceutical and Biomedical Analysis | Year: 2010

The effect of acid treatment of cyclopamine, a natural antagonist of the hedgehog (Hh) signaling pathway and a potential anti-cancer drug, has been studied. Previous reports have shown that under acidic conditions, as in the stomach, cyclopamine is less effective. Also, it has been stated that cyclopamine converts to veratramine, which has side effects such as hemolysis. In this study, we examined in detail the influence of acidification on structure and activity of cyclopamine. We found that of acidified cyclopamine converts to two previously unreported isomers, which we have called cyclopamine (S) and cyclopamine (X). These have likely gone undetected because cyclopamine is often analyzed with fast and hence lower resolving chromatographic methods. Compared to natural cyclopamine, these cyclopamine isomers have a significantly reduced effect on the ciliary transport of the Hh receptor smoothened, and reduced inhibition on the Hedgehog signaling pathway. The side effects of these isomers are unknown. Our findings can partly explain a reduced efficiency of cyclopamine in a gastric environment, and may help with the rational design of more pH independent cyclopamine analogues. © 2010 Elsevier B.V.


PubMed | The Center for Theoretical and Computational Chemistry
Type: Journal Article | Journal: The journal of physical chemistry. A | Year: 2012

The molecular structures of low-lying isomers of anionic and neutral sodium auride clusters have been studied computationally at the second-order Mller-Plesset perturbation theory level using quadruple- basis sets augmented with a double set of polarization functions. The first vertical detachment energies were calculated at the Mller-Plesset level as the energy difference between the cluster anion and the corresponding neutral cluster. The photodetachment energies of higher-lying ionization channels were calculated by adding electronic excitation energies of the neutral clusters to the first vertical detachment energy. The excitation energies were calculated at the linear response approximate coupled-cluster singles and doubles level using the anionic cluster structures. The obtained ionization energies for NaAu(-), NaAu(2)(-), NaAu(3)(-), NaAu(4)(-), Na(2)Au(2)(-), Na(2)Au(3)(-), Na(3)Au(3)(-), and Na(2)Au(4)(-) were compared to values deduced from experimental photoelectron spectra. Comparison of the calculated photoelectron spectra for a few energetically low-lying isomers shows that the energetically lowest cluster structures obtained in the calculations do not always correspond to the clusters produced experimentally. Spin-component-scaled second-order Mller-Plesset perturbation theory calculations shift the order of the isomers such that the observed clusters more often correspond to the energetically lowest structure, whereas the spin-component-scaled approach does not improve the photodetachment energies of the sodium aurides. The potential energy surface of the sodium aurides is very soft, with several low-lying isomers requiring an accurate electron correlation treatment. The calculations show that merely the energetic criterion is not a reliable means to identify the structures of the observed sodium auride clusters; other experimental information is needed to ensure a correct assignment of the cluster structures. The cluster structures of nonstoichiometric anionic sodium aurides have been determined by comparing calculated ionization energies for low-lying structures of the anionic clusters with experimental data.

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