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Citotoxicity of N-phenylmaleimide Derivatives and Inhibition ofMelanoma Growth in a Preclinical Mouse Melanoma Model

Vania Floriani Noldin, Claudriana Locatelli *, Clarissa AS Cordova, Angelo Tadeu Noldin, Francieli Vanzin, Jamin Dajal fae, Fatima Campos Buzzi, Celso Pilati, Valdir Cechinel - Filho and Tania Beatriz Creczynski-Pasa

Antitumor and antimetastatic effects of N-Phenylmaleimide derivatives (N-phenyl-maleimide (M2), 4-methyl-N-phenyl-maleimide (M5), 4-methoxy-N-phenyl-maleimide (M7 and N-phenyl-ethyl-maleimide (M9)) were assessed on mice implanted subcutaneously with B16F10 melanoma cells. With this approach, we evaluated the growth and persistence of solid tumors, lung metastasis, mesentery metastasis, biochemical and hematological parameters, thiobarbituric acid reactive substances (TBARS) and non-protein thiol substances (NPSH) present in the liver homogenates. The N-Pheneylmaleimides reduced the number of lung metastasis and inhibited tumor growth. The treatments with M5 and M7 showed low toxicity because minor alterations in hematological and biochemical parameters were observed, and only the treatment with M9 promoted intense oxidative stress as well as alterations in some hepatic enzymes. The effects of maleimides shown in this work can be related to their chemical structure features, principally by the proximity between the imide and aromatic rings, and the hydrophobic and electronic characteristics of the substituent groups on the aromatic ring, which can modify their lipophilic properties. These preclinical results indicate that treatments with M5 and M7 may be effective against melanoma suggesting that these compounds may be further used as leads to develop new anticancer agents.