Avaliação da atividade anticâncer e imunomoduladora de derivados da ftalimida : abordagens in vitro e in silico

Cancer remains a major cause of death worldwide and was the cause of 8.8 million deaths in 2015, and colorectal cancer is the third most prevalent. Thalidomide is a synthetic compound most known for its involvement in a big pharmacological disaster, after its use for morning sickness by pregnant women. Despite this notorious episode involving teratogenesis, thalidomide was rediscovered, and now is used for the treatment of many diseases. Notably, thalidomide structure may serve as an interesting scaffold for development of new phthalimide derivatives that may present a diverse amount of pharmacologic effects, including anti-neoplastic, epigenetic, anti-angiogenic and anti-inflammatory properties. The aim of this work was to evaluate a series of thalidomide analogs for its antitumor effects and immunomodulatory properties through in vitro and in silico approaches. The series concerns 14 molecules, which have a common phthalimide core and vary in some substituents. Cytotoxic effects were assessed with three colon cancer cell lines and Vero cells. Compounds selectivity for colon cancer cell was also determined. Cytometric Bead Array (CBA) was used to detect Th1, Th2 and Th17 cytokine profiles in supernatants of mice splenocytes stimulated with each compound at CC₅₀ after 24h, 48h, 72h and six days of incubation. Compounds tested revealed toxicity and selectivity to tumor cells when compared to thalidomide, with CC₅₀ values between 25 μL e 274.9 μL. Compounds also shown remarkable immunomodulatory effects, specialy in the modulation of TNF and IL-10, key cytokines in development and progression of colorectal cancer. In order to evaluate a possible correlation between in vitro effects and the IKKβ protein, an important player in NF-κB signaling pathway, we performed molecular docking calculations with IKKβ as target. Through molecular docking was possible to describe the molecular interactions between compounds from AS series and aminoacid residues in the active site of the protein IKKβ, which demonstrated good correlaction with in vitro results. After analyzing all results, compound AS-11 stood out, with the better toxicity, high selectivity and high induction of decrease TNF production when compared to the other series compounds. Results corroborate the expected anticancer and immunomodulatory activities of thalidomide analogs, with a possible interaction with IKKβ protein.