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May 11, 2019

Discovery of Membrane Permeability, Pharmacokinetics Properties and Mechanism of Action for Analogs of Ethylenediamine-N,N′-di-2-(3-Cyclohexyl)Propionic Acid and 1,3-Propandiamine-N,N′-di-2-(3-Cyclohexyl)Propionic Acid with Antiproliferative Activity Using In Vitro and In Silico Methods

Abstract

In previously in vitro studies on different cell lines and in vivo on melanoma and 4T1 murine breast cancer and metastasis it was shown antiproliferative activity for ester derivatives of (S,S)-ethylenediamine-N,N′-di-2-(3-cyclohexyl)propanoic acid, and (S,S)-1,3-propanediamine-N,N′-di-2-(3-cyclohexyl)propanoic acid. The aim of this study was to predict membrane permeability by parallel artificial membrane permeability assay (PAMPA), molecular mechanism of action, metabolites and absorption, distribution, metabolism, toxicity—ADMET properties for observed substances using in vitro and in silico methods. Obtained results of PAMPA show the best membrane permeability of ethyl esters analogs (DE-EDCP and DE-PDCP) and refer to the hypothesis that the retention in cell membrane is important for cytotoxic activity of investigated substances. Prediction of main metabolic pathways was performed by the Metabolizer software and it was obtained that the major metabolic reactions were the hydrolyses of ester and subsequently intramolecular cyclization. Toxicity of investigated substances and their potential metabolites are lower than toxicity of observed official cytotoxic drugs. Based on the results obtained by the Molecular docking, it can be assumed that the antiproliferative effects of the investigated substances were realized through the multiple mechanisms by potential metabolites: acids, lactam carboxylate and lactam alkyl esters, while the esters are probably a prodrug substance with favorable properties to provide sufficient bioavailability at the target of action. Based on obtained results it can be proposed there to be investigated the existence of the metabolites: lactam carboxylate and lactam alkyl esters in biological materials.

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