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Inclusion Complexes of Gold(I)-Dithiocarbamates with β-Cyclodextrin: A Journey from Drug Repurposing towards Drug Discovery.

ABSTRACT: The gold(I)-dithiocarbamate (dtc) complex [Au(N,N-diethyl)dtc]₂ was identified as the active cytotoxic agent in the combination treatment of sodium aurothiomalate and disulfiram on a panel of cancer cell lines. In addition to demonstrating pronounced differential cytotoxicity to these cell lines, the gold complex showed no cross-resistance in therapy-surviving cancer cells. In the course of a medicinal chemistry campaign on this class of poorly soluble gold(I)-dtc complexes, >35 derivatives were synthesized and X-ray crystallography was used to examine structural aspects of the dtc moiety. A group of hydroxy-substituted complexes has an improved solubility profile, and it was found that these complexes form 2 : 1 host-guest inclusion complexes with β-cyclodextrin (CD), exhibiting a rarely observed "tail-to-tail" arrangement of the CD cones. Formulation of a hydroxy-substituted gold(I)-dtc complex with excess sulfobutylether-β-CD prevents the induction of mitochondrial reactive oxygen species, which is a major burden in the development of metallodrugs.

SUBMITTER: Morgen M

PROVIDER: S-EPMC8456977 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundIn this study we investigated the predictability of three thermodynamic quantities related to complex formation. As a model system we chose the host-guest complexes of beta-cyclodextrin (beta-CD) with different guest molecules. A training dataset comprised of 176 beta-CD guest molecules with experimentally determined thermodynamic quantities was taken from the literature. We compared the performance of three different statistical regression methods - principal component regression (PCR), partial least squares regression (PLSR), and support vector machine regression combined with forward feature selection (SVMR/FSS) - with respect to their ability to generate predictive quantitative structure property relationship (QSPR) models for DeltaG degrees, DeltaH degrees and DeltaS degrees on the basis of computed molecular descriptors.ResultsWe found that SVMR/FFS marginally outperforms PLSR and PCR in the prediction of DeltaG degrees, with PLSR performing slightly better than PCR. PLSR and PCR proved to be more stable in a nested cross-validation protocol. Whereas DeltaG degrees can be predicted in good agreement with experimental values, none of the methods led to comparably good predictive models for DeltaH degrees. In using the methods outlined in this study, we found that DeltaS degrees appears almost unpredictable. In order to understand the differences in the ease of predicting the quantities, we performed a detailed analysis. As a result we can show that free energies are less sensitive (than enthalpy or entropy) to the small structural variations of guest molecules. This property, as well as the lower sensitivity of DeltaG degrees to experimental conditions, are possible explanations for its greater predictability.ConclusionThis study shows that the ease of predicting DeltaG degrees cannot be explained by the predictability of either DeltaH degrees or DeltaS degrees. Our analysis suggests that the poor predictability of TDeltaS degrees and, to a lesser extent, DeltaH degrees has to do with a stronger dependence of these quantities on the structural details of the complex and only to a lesser extent on experimental error.

Dataset Information

Inclusion Complexes of Gold(I)-Dithiocarbamates with β-Cyclodextrin: A Journey from Drug Repurposing towards Drug Discovery.

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