Sabarubicin Hydrochloride

Studies on the intercalation of anticancer compounds with DNA can provide useful suggestions and guidance for the design of new and more efficient anticancer drugs.A quant. structure-property relationship (QSPR) study of a series of anticancer and candidate anticancer drugs with calf thymus DNA (ct-DNA) was performed.Constitutional, Topol., and WHIM descriptors, as well as GETAWAY, 3D-MoRSE, and Aromaticity Indexes descriptors generated from Dragon, were selected to describe the mols.The resampling by half-means method was used to detect the outlier mols.Self-organizing map was used to split the original dataset into training and test set.Genetic algorithm-multiple linear regression technique was used to establish QSPR model for training set.Finally, the best four-mol. descriptor model was developed on a training set of mols. and the external validation was performed on test set of mols.The stability and predictability of QSPR model were determined with the leave-one-out cross-validated variance and the external-validated variance.This QSPR approach can contribute to a better understanding of structural factors of the compounds responsible for drug-DNA intercalations, and be useful in predicting the binding affinity of other compounds with DNA.

We studied the binding of two anthracycline drugs, Doxorubicin and Sabarubicin, to a model telomeric sequence 5'-d[GGG(TTAGGG)(3)]-3' (21-mer), assuming the basket G-quadruplex (G4) conformation in Na(+)-rich aqueous solution. We used an approach that combines spectroscopic and microcalorimetric techniques to obtain information about ground and excited state properties of the most stable complexes. Both drugs bind to the 21-mer in basket conformation and complexes of 1:1 and 2:1 drug : 21-mer stoichiometry coexist in solution. Binding constants were determined from fluorescence and isothermal titration calorimetry experiments. For both drugs association is driven by enthalpy and disfavoured by entropy in the case of two sequential binding events to different sites. The drug fluorescence is completely quenched in the 1:1 complex, most likely by electron transfer from the guanine system to the anthraquinone moiety, while part of the emission survives in the 2:1 complex. Circular dichroism (CD) of the individual complexes is dominated by the G-quadruplex signal in the UV and by the anthracycline signal in the near-UV and Vis region. The experimental CD spectra combined with conformational calculations at MM level and quantum mechanical calculation of the rotational strength of the electronic transitions afforded information on the binding geometries.