Investigação do potencial antitumoral do carbapterocarpano

Abstract

Several drugs have been developed in order to fight cancer, many of them derived from natural products. In recent years, target-specific anticancer therapies have been intensified, including those aimed at preventing cell proliferation. Microtubules stand out in the antimitotic scenario, due to interference with cell replication. The class of pterocarpans has been showing promise with cytotoxic activity and antimitotic potential. In this sense, the present study seeks to synthesize and perform screening of different analogs of pterocarpans, to determine the structure-activity relationship and validation of antimitotic properties. The compound LQB 507 was pre-selected as the analogue of the best profile and proceeded to characterize the cytotoxic activity against the prostate cancer cell line (PC3). Chapter 1 presents a survey of the biological properties of pterocarpans and their respective molecular targets under study. Scientific and technological monitoring was also carried out indicating that Brazil is among the countries with the largest number of publications related to pterocarpans, however studies on anticancer activity and patent filings of this class are still scarce. Chapter 2 deals with the process of synthesis and evaluation of the cytotoxicity pattern, through the MTT assay, with the indication of the analogue with the best profile (LQB507 IC 50 in the value of 11.85 µM). Through the analysis of the cell cycle, the analog showed antimitotic property with stop in G2/M. Chapter 3, evaluates the concentration / time dependence pattern of the compound LQB507, through MTT and SRB tests, by metabolic and structural inferences, respectively. Different changes induced by the compound LQB507 were observed, including pattern of cell death, mitochondrial depolarization, pattern of interference in structures of the mitotic spindle, in addition to some pharmacological characteristics, such as intestinal absorption profile and ability to penetrate the blood-brain barrier in silico (pkADMETox) and in vitro (PAMPA). A survey of the expression profile of possible targets in the PC3 cell was evaluated. Taxol (Tx) was used as a positive control. The substance LQB 507 has a cytostatic profile, with discrete cytotoxic activity found in higher concentrations. Changes in the pattern of mitochondrial polarization, with induction of apoptosis were verified. The morphology indicated that the cells treated with LQB 507 showed a transition in the fusiform (Control) and lobulated (treated) format, in addition, confocal microscopy indicated disorganization of the centrosomes in the cells treated with LQB 507, and this phenotype was similar to PT +. In addition, in silico prediction had its in vitro results corroborated. Since the PAMPA test of the substance LQB 507 indicated that the substance is permeable to the gastrointestinal tract and impermeable to the blood-brain barrier. In silico studies showed that the genes with the highest expression were TUBG1, AURKA and CEP57, being characterized as possible targets for the class. LQB 507 and PT+ presented similar pharmacological and biological profiles, and it is interesting to continue the study with LQB 507 as it is a synthetic substance that showed good performance and favorable biological activity in relation to the prostate cancer line. In this sense, the studied molecule has high potential for the development of antitumor drugs for the treatment of prostate cancer.