DTNQ-based anticancer derivatives as selective glucose penetration inhibitors

The quinones are a widely diffused group of natural products with well recognized cytotoxicity against tumour cells.[1] The clinical use of quinone-based anti-cancer drugs is nowadays widely debated due to the rapid onset of drug resistance mechanisms and to severe side-effects, as myelosuppression and cardiotoxicity.[2, 3] In the last years, our research group has been deeply involved in investigating the potentiality of the dihydrithieno[2,3-b]naphto-4,9-dione scaffold (1, figure 1) as anti-tumour agents. [4] With the aims of broadening the structure-activity relationship of this class of compounds and designing synthetic pathways to build up pharmacologically active naphthoquinone-based libraries, we focused on the chemical modifications of the 3’-amino and 3’-ester moieties of the DTNQ system (Figure 1). The synthesized DTNQ analogues were tested on different tumour cell lines (HuH7, MCF7, LN222 and BxPC3) for the assessment of potency and on cardiomyocyte cell line (H9C2) for the determination of cardiotoxicity. They showed a remarkable cytotoxicity against the selected tumour cell lines, with comparable or higher potency than doxorubicin. In particular, derivative 14 showed high potency and a strongly reduced cardiotoxicity. Thus, further investigations were done to highlight the molecular mechanism underlying these differences with classical quinones. Confocal microscopy analysis highlighted a prevalent cytoplasmatic distribution of 14 in glioblastoma cells, whereas doxorubicin accumulates mainly in nucleus. Moreover, a reduction of both cellular glucose uptake and serine/threonine kinase AKT expression was evidenced. These findings suggest the use of synthesized DTNQ analogues as useful tool for the development of novel anticancer molecules with improved pharmacological profile