Novel 2-amino-1,4-naphthoquinone hybrids: Design, synthesis, cytotoxicity evaluation and in silico studies.

Albumin is an abundant protein in nature with several biological functions. In the human body, both in health and in illness, its transport function is highlighted by the binding to medicinal drugs and consequent distribution in the bloodstream to the site of action. This is particularly relevant for anticancer treatments, since this protein accumulates in the tumor microenvironment to supply the energetic demands of cancer cells. Different spectroscopy, thermodynamic and in silico studies techniques can be employed to verify how albumin binds to ligands by using either human serum albumin (HSA) or bovine serum albumin (BSA) due to their structural similarity. There is an increasing tendency to use albumin in analyses of absorption, distribution, metabolism and excretion (ADME) properties of anticancer molecules, which further demonstrated the promising character of this investigation for proposing new drugs.

Albumin roles in developing anticancer compounds

In this study, we report the synthesis of twenty new acridine–thiosemicarbazone derivatives and their antiproliferative activities. Mechanisms of action such as the inhibition of topoisomerase IIα and the interaction with DNA have been studied for some of the most active derivatives by means of both in silico and in vitro methods, and evaluations of the non-clinical toxicities (in vivo) in mice. In general, the compounds showed greater cytotoxicity against B16-F10 cells, with the highest potency for DL-08 (IC50 = 14.79 µM). Derivatives DL-01 (77%), DL-07 (74%) and DL-08 (79%) showed interesting inhibition of topoisomerase IIα when compared to amsacrine, at 100 µM. In silico studies proposed the way of bonding of these compounds and a possible stereoelectronic reason for the absence of enzymatic activity for CL-07 and DL-06. Interactions with DNA presented different spectroscopic effects and indicate that the compound CL-07 has higher affinity for DNA (Kb = 4.75 × 104 M−1; Ksv = 2.6 × 103 M−1). In addition, compounds selected for non-clinical toxicity testing did not show serious signs of toxicity at the dose of 2000 mg/kg in mice; cytotoxic tests performed on leukemic cells (K-562) and its resistant form (K-562 Lucena 1) identified moderate potency for DL-01 and DL-08, with IC50 between 11.45 and 17.32 µM.

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Synthesis and Evaluation of Antiproliferative Activity, Topoisomerase IIα Inhibition, DNA Binding and Non-Clinical Toxicity of New Acridine–Thiosemicarbazone Derivatives

The potential of acridines (amsacrine) as a topoisomerase II inhibitor or poison was first discovered in 1984, and since then, a considerable number of acridine derivatives have been tested as topoisomerase inhibitors/poisons, containing different substituents on the acridine chromophore. This review will discuss a series of studies published over the course of the last decade, which have investigated various novel acridine derivatives against topoisomerase II activity.

Francivaldo Araújo da Silva Filho

Papers

Topoisomerase inhibition and albumin interaction studies of acridine-thiosemicarbazone derivatives.