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    Novel cytotoxic amphiphilic nitro-compounds derived from a synthetic route for paraconic acids

    Year: 2021

    Journal: Colloid Surf. A-Physicochem. Eng. Asp., Volume 626, OCT 5

    Authors: Ribeiro, Talita A.; Machado-Ferreira, Erik; Guimaraes, Lohaine F.; Cavaleiro, Jessica; Britto, Alan Messala A.; Redua, Nataly; Pereira de Souza, Lucas Miguel; Pimentel, Andre S.; Picciani, Paulo H. S.; Oliveira, Osvaldo N. Jr Jr; Barreto, Cleber Bonfim; Soares, Carlos Augusto G.

    Organizations: Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ), Brazil [APQ1 -211.337/2015]; National Council for Scientific and Technological Development -CNPq, Brazil (Conselho Nacional de Desenvolvimento Cientifico e Tecnologico); National Institute of Science and Technology for Cancer Control -INCT-PCC (INCT para Controle do Cancer) [CNPq 573806/2008-0, FAPERJ E26/170.026/2008]; Fundacao de Amparoa Pesquisa do Estado de Sao Paulo (FAPESP), Brazil [2018/22214-6]; Coordination for the Improvement of Higher Education Personnel -CAPES, Brazil (Pos-Graduacao em Genetica, UFRJ); National Postdoctoral Program (CAPES -PNPD); CNPq (INCT-PCC); CNPq [465259/2014-6, 302554/2017-3, 303001/2019-4]; CAPES (P PRIME); fellowships for technological and industrial development -DTI; Sao Paulo Research Foundation (FAPESP) [2014/50983-3, 2018/16092-5, 2017/27078-0, 001]; FAPERJ [E-26/010.000983/2019, 210.124/2018, E-26/010.101110/2018, E-26/010.001241/2016, 210.558/2015]; National Institute of Science and Technology Complex Fluids (INCTFCx); Rio Network of Innovation in nanosystems for the health Nanohealth/FAPERJ [E-26/010.000983/2019, 195785]; National Postdoctoral Program (Pos-Graduacao em Genetica, UFRJ)

    Keywords: Non-conjugated nitro compounds; Cytotoxic amphiphilic molecules; Butanolide/gamma-butyrolactone; Alkylated 2,2-dimethyl-1,3-dioxolane; Surface activity; Phospholipid Langmuir monolayers; Cancer

    A series of precursors for bioactive paraconic acids (PA) were synthesized and their cytotoxicity assessed on human cells in vitro. Two amphiphilic nitro-containing precursors, Nitro-C15-EED and the butanolide Nitro-C12GBL, were cytotoxic at the micromolar scale, with higher activity on tumor HeLa cells than on HEK-293T of non tumor origin. The structure of these molecules is simple but different from reported bioactive nitro compounds. Nitro-C12-GBL was generally more cytotoxic, but after short-term (2 h) exposure both compounds reached maximum cytotoxicity. At 72 h post-treatments of HeLa cells the final dose-response for Nitro-C12-GBL (LC50 = 21.9 mu mol L-1) was close to that for Nitro-C15-EED (LC50 = 25.3 mu mol L-1), corresponding to LC(50)s -3-3.6 times lower than those on HEK-293T. Short-term treatments with 50 mu mol L-1 of these compounds promoted comparable outcomes, reducing tumor cells viability up to 27-36% of the controls and preserving-70% of HEK293T viability at 72 h post-treatments. Reduced cytotoxicity was observed in cultures continuously exposed to the compounds for longer periods (24-72 h), especially on tumor cells, underlining short-term treatments as alternatives to antiproliferative strategies. Due to their amphiphilic nature, these compounds show spontaneous surface activity and adsorption onto Langmuir monolayers of dipalmitoyl phosphatidyl choline (DPPC), especially Nitro-C12-GBL. The effects on DPPC monolayers are indicative of a possible physiological action that depends on the interaction with the cell membranes. Coarse-grained molecular dynamics indicate that individualized molecules of Nitro-C15-EED and the less toxic PA precursors are susceptible to trapping into phospholipid films. In contrast, Nitro-C12-GBL consistently forms large aggregates with outward polar domains, which could favor interaction with phospholipid polar heads of biological membranes.
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