The relationship between solvatochromic properties and in silico ADME parameters of new chloroethylnitrosourea derivatives with potential anticancer activity and their β-Cyclodextrin complexes.

In view of the anticancer effect of nitrosoureas a set of four new N-(2-chloroethyl)-N-nitrosourea (CENU) derivatives was synthesized. An in silico absorption, distribution, metabolism, excretion and toxicity (ADME/Tox) prediction study revealed that the CENU derivatives satisfied all the required criteria for oral administration and introduced them as remarkable anticancer candidates in the central nervous system (CNS). A comparative solvatochromic study including the Kamlet-Taft, Catalán and Laurence models indicated that the solvatochromic behavior of the CENUs depended on both, unspecific and specific solvent-solute interactions. In detail, the solvatochromic effect of the solvent polarity on the absorption and emission maxima was significant for all CENUs, whereas the solvatochromic effect of the solvent's ability to donate or accept hydrogen bonds on the absorption and emission maxima was critically dependent on the electron density of the N'-aryl group. From the solvatochromic comparison method, excellent correlations (r ≥ 0.890) were obtained between the ADME parameters and the solvatochromic regression coefficients obtained by the Catalán model. As potential stabilizers, inclusion complexes of the investigated CENU derivatives with β-cyclodextrin (β-CD) were also explored. The spectrofluorimetric host-guest experiments included double-reciprocal Benesi-Hildebrand plots as well as the molar ratio and continuous variation plots (Job's plots), which established a 1:1 β-CD to CENU binding stoichiometry and relatively high affinities of β-CD for CENU derivatives.