Avaliação da atividade anti-inflamatória e antitumoral de novos adutos da reação de Morita-Baylis-Hillman

Abstract

Over the years, there has been a change in the population profile with a consequent reduction of infectious diseases and an increase in the prevalence of chronic noncommunicable diseases which, for the most of them, share an inflammatory pathogenesis. Inflammation is a normal reaction to disturbance of tissue homeostasis, followed by a resolution and repair phase. Among the cells that participate in the inflammatory process, macrophages have received great attention, since they are responsible for the production of a great variety of mediators, such as cytokines, chemokines, reactive species of oxygen and nitrogen as well as lipid mediators. Despite of beneficial, inflammation needs to be finely controlled since its exacerbation can result in the onset of various types of pathologies. In this context, the need to develop new compounds capable of acting in inflammatory processes and/or cancer is increasing in an effective way and with the minimum of adverse effects. Thus, the objective of the present study was to evaluate the anti-inflammatory and antitumor of new adducts of the Morita-Baylis-Hillman (MBH) reaction, verifying if this activity was related to a possible antioxidant activity, also tested. For this, the viability of RAW 264.7 and J774A.1 cells was determined after treatment with adducts using the MTT assay. The action of these adducts on the production of nitric oxide, TNF-α, IL-6, CCL2 and costimulatory molecules (CD80, CD86 and CD40) was determined in RAW 264.7 cells, while its action under IL- 1β was determined in J774A.1 cells. The best of the adducts was also submitted to in vivo tests in a murine model of ear edema. In addition, the viability of 4T1 and B16 cells treated with the compounds was assessed by the MTT method while the antioxidant action was determined by the DPPH test. The results showed that only one of the adducts presented significant cytotoxicity at the concentration of 75uM whereas at 50uM none of the adducts was cytotoxic. Concomitantly, treatment with adducts was able to reduce NO production, as well as TNF-α, IL-6, IL-1β and CCL2. The compounds also modulated the expression of CD86 and CD40 costimulatory molecules. In vivo, the 4Br adduct was effective in reducing ear edema, inflammatory infiltrate and myeloperoxidase enzyme activity. Although it was not able to reduce the production of IL-1β, IL-6 and CCL-2 in the tissue of the ears. Regarding the viability of tumor cells, five adducts were toxic to 4T1 cells, while six of them were effective in inducing the reduction of viability of B16 cells. None of the adducts presented antioxidant activity, which suggests that the anti-inflammatory and antitumor mechanisms triggered by the adducts are independent of the antioxidant potential. The result suggests a possible applicability of these adducts in new strategies to combat inflammatory diseases and/or cancer therapy.