Estudo in sílico de derivados semissintéticos da estemodina e obtenção de um composto mais ativo no controle de linhagem de células de carcinoma de cólon humano (HCT-116)

Abstract

The species Stemodia maritima Linn (Plantaginaceae), popularly known as matruz-bravo or melosa, has the diterpene stemodine as its main chemical constituent, for which antibiotic, antitumor, antimitotic, antiviral and anti-inflammatory properties are reported. Oximic analogues of stemodin have demonstrated anticancer potential, including for human colon carcinoma cell lines (HCT-116). According to the World Health Organization (WHO), colorectal cancer is the third most common type of cancer in the world and the second leading cause of death from cancer. Faced with this problem, a in silico study of the anticancer activity of the oximic derivatives of stemodin was carried out in comparison with the in vitro results, with the aim of developing an analogue of stemodin with greater bioactive potential. This study analyzed the metabolic pathway of PI3K enzymes as a therapeutic strategy for controlling cancer cells. Inhibition of PI3K helps regulate cell growth and induces programmed death of cancer cells. The presence of regions of alkyl, pi-alkyl and pi-pi T-shaped interactions and aromaticity analysis in the active site of the macromolecule made it possible to design a benzoylated stemodane derivative (STEM-Bz). The anticancer activity of STEM-Bz was simulated in silico through molecular docking, showing the formation of a more stable, low-energy complex (-9.32±0.03 kcal.mol-1). The simulated IC50 for the benzoylated derivative was 14.69 µM, revealing no toxicity. The pharmacokinetic profile showed ideal absorption, distribution, metabolism and excretion properties in the human body. In this way, the semi-synthetic derivative STEM-Bz was obtained from in silico approach applied to Computational Medicinal Chemistry and will have its in vitro activity evaluated.