A simple stochastic approach, designed to model the movement of electrons throughout chemical bonds, is introduced. This model makes use of a Markov matrix to codify useful structural information in QSAR. The self-return probabilities of this matrix throughout time ((SR)pi(k)) are then used as molecular descriptors. Firstly, a calculation of (SR)pi(k) is made for a large series of anticancer and non-anticancer chemicals. Then, k-Means Cluster Analysis allows us to split the data series into clusters and ensure a representative design of training and predicting series. Next, we develop a classification function through Linear Discriminant Analysis (LDA). This QSAR discriminates between anticancer compounds and non-active compounds with a correct global classification of 90.5% in the training series. The model also correctly classified 86.07% of the compounds in the predicting series. This classification function is then used to perform a virtual screening of a combinatorial library of coumarins. In this connection, the biological assay of some furocoumarins, selected by virtual screening using the present model, gives good results. In particular, a tetracyclic derivative of 5-methoxypsoralen (5-MOP) has an IC50 against HL-60 tumoral line around 6 to 10 times lower than those for 8-MOP and 5-MOP (reference drugs), respectively. Finally, application of Iso-contribution Zone Analysis (IZA) provides structural interpretation of the biological activity predicted with this QSAR.
Four new benzo- and tetrahydrobenzo-psoralens have been examined in their reversible interaction toward DNA and in their DNA-photobinding properties. These compounds were also examined for their ability to produce singlet oxygen and in vivo skin photosensitization reaction. Fluorescence and equilibrium dialysis measurements show that the complexation ability of benzoderivatives is remarkably high. Binding is less effective in the case of the tetrahydrocongeners. All compounds photoreact quite effectively to DNA. The photoadducts were obtained by enzymatic hydrolysis of drug-modified DNA and were characterized by high performance liquid chromatographic elution techniques. The 3,4 position represents the unique photoreactive site for benzopsoralens. Denaturation-renaturation experiments confirm that the benzoderivatives are purely monofunctional, while the tetrahydrocongeners form interstrand cross-links, even though to a remarkably lesser extent than 8-methoxypsoralen (8-MOP). The new compounds, in the presence of long-wavelength ultraviolet radiation, are very moderately effective in forming reactive oxygen species; they are ineffective in promoting oxidation of tyrosine and 3-(3,4-dihydroxyphenyl)alanine to dopachrome and melanin. Skin photosensitizing experiments on guinea pigs indicate that benzo- and tetrahydrobenzopsoralen derivatives are almost devoid of any phototoxic effects. Thus, this class of compounds appears to be interesting for the development of new, less phototoxic chemotherapeutic agents that interact with DNA better than 8-MOP.
Vascular Endothelial Growth Factor (VEGF) pathway has emerged as one of the most important positive modulators of Angiogenesis, a central process implicated in tumour growth and metastatic dissemination. This led to the design and development of anti-VEGF monoclonal antibodies and small-molecule ATP-competitive VEGFR-inhibitors. In this study, we describe the synthesis and the biological evaluation of novel 2-aryl substituted benzothiopyrano-fused pyrimidines 1a-i, 2a-i and 3a-i. The ability of the compounds to target the VEGF pathway was determined in vitro exploiting the compounds' antiproliferative efficacy against HUVEC cells. The VEGFR-2 inhibition was confirmed by enzymatic assays on recombinant human kinase insert domain receptor (KDR), by cell-based phospho-VEGFR-2 inhibition assays, and by ex vivo rat aortic ring tests. The selectivity profile of the best performing derivatives belonging to series 2 was further explored combining modeling studies and additional assays in a panel of human cell lines and other kinases.
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