Planejamento racional por modelagem molecular e semissíntese de derivados cardenolídeos com potencial atividade citotóxica

Abstract

The NaK enzyme is a transmembrane enzyme responsible for cellular electrochemical gradient maintenance, osmotic balance, and conductivity in nerves and muscles. Multiple experiments during the last decades have revealed the ability of this enzyme to serves as a versatile signal transducer. Thus, NaK could be an important target for the development of new antitumor drugs. Advances in the structural and functional recognition of NaK have made it possible to design new and more potential inhibitors capable of regulating the activity of this enzyme in carcinogenesis processes.Cardiotonic glycosides (GC) are special metabolites observed in the Digitalis genus and used to treat heart failure due the positive inotropic effect triggered by specific inhibition of NaK. The repositioning of GC as antiherpetic and antitumor agents has been intensively investigated. A semisynthetic derivative of 3β-OH-digitoxigenin (DG) showed potent cytotoxic activity against different tumor cell lines and an in silico structure/activity relationship study was performed to identify the most important groups for the activity. In this context, the present work aimed to the rational design of a potential NaK inhibitors series with different amino-groups coupled to the side chain at C-3, which can preserve the cytotoxic potential of AG, but in a more selective way. The key intermediate for the synthesis of these proposed derivatives (1I – 1R) was obtained by modifying the 3β-OH group of DG through sequential reactions (overall yield 87.4%). Before submitting this intermediate to conclusive reactions, a virtual screening was performed by molecular docking to select the most promising derivatives. In addition to the ten proposed derivatives and the seven synthesis intermediates, another 40 cardiotonic derivatives with antiherpetic and cytotoxic activity defined were also tested for the ability to interact with the two main isoforms (α1 e α3) of NaK associated to carcinogenesis. The three-dimensional models of these isoforms were built by homology modeling, using the crystallographic structure PDB ID 3A3Y as a template. Nine of the ten proposed derivatives were selected as possible inhibitors for both isoforms and three (1M, 1N and 1R) kept the most common interactions between the GC and the binding site. This result suggests that the proposed molecular modifications are pertinent and may effectively result in more selective cytotoxic agents.