Promising New Inhibitors of Tyrosyl-DNA Phosphodiesterase I (Tdp 1) Combining 4-Arylcoumarin and Monoterpenoid Moieties as Components of Complex Antitumor Therapy

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is an important DNA repair enzyme in humans, and a current and promising inhibition target for the development of new chemosensitizing agents due to its ability to remove DNA damage caused by topoisomerase 1 (Top1) poisons such as topotecan and irinotecan. Herein, we report our work on the synthesis and characterization of new Tdp1 inhibitors that combine the arylcoumarin (neoflavonoid) and monoterpenoid moieties. Our results showed that they are potent Tdp1 inhibitors with IC50 values in the submicromolar range. In vivo experiments with mice revealed that compound 3ba (IC50 0.62 µM) induced a significant increase in the antitumor effect of topotecan on the Krebs-2 ascites tumor model. Our results further strengthen the argument that Tdp1 is a druggable target with the potential to be developed into a clinically-potent adjunct therapy in conjunction with Top1 poisons

Selective adhesion of tumor cells to the endothelium of the target organ in metastasis

The fragments of cell plasma membranes of two lines of metastatic tumour of A/He mice (lung adenocarcinoma--LA-cells and hepatoma HA-1--HA-cells) were used to prepare "hybrid" vesicles (LA- and HA-liposomes). Incorporation of the fragments of LA-cells into the bilayer vesicle increased the binding of LA-liposomes with lung almost by an order of magnitude, their trapping by liver being noticeably decreased. HA-liposomes were retained in the liver in larger amounts than the model phospholipid liposomes. It is assumed that the specificity of metastatic spreading into an organ is associated with the interaction of the plasma membrane of the tumour cells with the apical membrane of the target organ endothelium