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Investigação de moléculas híbridas para o tratamento anticâncer
(Universidade Federal de São Carlos, 2022-07-06) Costa, Felipe Ribaldo Ferreira da; Pranchevicius, Maria Cristina da Silva; https://lattes.cnpq.br/4772148921558977; Andricopulo, Adriano Defini; https://lattes.cnpq.br/5598322661148873; https://lattes.cnpq.br/1664901084586413
Cancer is the attribution given to the uncontrolled growth and proliferation of abnormal cells capable of invading and destroying the adjacent tissue. According to the World Health Organization (WHO), the global growth in cancer cases will reach the 60% mark by 2040, totaling around 37 million cases. In Brazil, estimates released by the National Cancer Institute (INCA) project that approximately 66 thousand new individuals will be affected by prostate cancer (PC) in 2022. In the case of the metastatic and hormone-refractory type (mHRPC), the cells are not responsive to conventional treatment. In order to circumvent this situation, the use of cytotoxic therapies targeting microtubules (MTs) is a well-established option in clinical practice. MTs are structural elements constituted by the dimeric protein tubulin, which performs cellular functions through its intrinsic capacity for dynamic instability: polymerization and depolymerization. Changes in this dynamic lead to blockage of mitosis and cell migration, directing the cell to apoptosis. This behavior can be induced by the use of modulating agents in known sites of tubulin, configuring a promising conduct when it comes to the development of antitumor drugs. In this context, the union of pharmacophoric groups to generate hybrid molecules emerges as an innovative alternative. Thus, the present work brings results regarding the in vitro screening of bioactive ligands for the treatment of mHRPC. A cell line of PC (DU-145) and three non-tumor ones [human (HFF-1) and murine (FC3H) fibroblasts, and human prostate epithelial cells (RWPE-1)] were submitted to cell viability assays to evaluate the potency of 10 quinazoline-chalcone hybrids (AQCs) from their IC50 and CC50 values. For the selected samples, these values were used to determine the selectivity index (SI). Three hybrids (AQC-02, AQC-04 and AQC-08) were active in the PC cell line (IC50 ≤ 20 µM) and selective against non-tumor ones (SI ≥ 5), and therefore referred to cellular assays involving analysis of characteristics observed in the metastatic cascade. The 3 hybrids inhibited migration in qualitative wound healing assays at single concentration (≥ 50%) and concentration x effect. Furthermore, through a transwell study based on Boyden's chamber, it was possible to quantify and confirm the inhibitory effect of hybrids on tumor cell migration and invasion (both with IC50 ≤ 10 µM). Kinetic assays directed to the molecular target corroborated the classification of the hybrids as tubulin polymerization inhibitors, as well as made it possible to determine their IC50 values (5.71 ± 0.09; 9.04 ± 0.40 and 8.40 ± 0.31 µM, respectively). Competition assays suggested that the hybrids possibly interact with tubulin near or at the colchicine site itself. Additionally, fluorescence assays reinforced the action of the compounds in destabilizing cell division and promoting the nuclear fragmentation of DU-145. This work, therefore, shows promising results that, in consonance, support the identification of lead compounds eligible for in vitro and in vivo ADME (Absorption, Distribution, Metabolism and Excretion) assays, aiming at the selection of candidates for new drugs for the mHRPC chemotherapy.
Influência da geometria do inserto de fresamento sobre a integridade superficial de uma liga de titânio
(Universidade Federal de São Carlos, 2022-07-06) Rosa, Edson Bruno Lara; Ventura, Carlos Eiji Hirata; https://lattes.cnpq.br/1689198421096127; Antonialli, Armando Ítalo Sette; https://lattes.cnpq.br/4367459395417045; https://lattes.cnpq.br/2749981510366434
Titanium alloys have got features that classify them as excellent candidates for medical applications. However, they have porr machinability mainly due to their low thermal conductivity, high chemical affinity to almost every tool material and their small modulus of elasticity. Regarding commercial milling tools, inserts usually differ one to another in terms of grade (such as substrate and coating composition and microstructure) and geometric characteristics (nose radius, rake angle and chipbreaker shape), so that it is difficult to find two products differentiated by one single variable. Due to these factors, the general goal of this research is to investigate the correlation between tool nose radius and the roughness after milling of Ti-6Al-4V ELI titanium alloy. For that, it was necessary to grind carbide inserts to prepare the three different nose radii (re = 0.8 mm; 1.2 mm or 1.6 mm) as well as their characterization, besides designing, manufacturing and evaluating a customized tool holder with a single insert seat. Tools once prepared were tested through face milling experiments, keeping fixed cutting speed (vc) at 60 m/min, axial depth of cut (ap) at 1 mm, in addition to radial depth of cut (ae) at 16.8 mm and flood coolant. Five diferente levels were used for feed per tooth ( fz): 0.10 mm; 0.15 mm; 0.20 mm; 0.25 mm or 0.30 mm. After the experiments, the specimens were evaluated in terms of different roughness parameters, and all data were statistically analyzed by means of analysis of variance (ANOVA). Regarding the characterization of the ground inserts, there was no significant variation in the irregularity of the edges as a function of the different nose radii. The design of the tool holder proved out to be adequate to the operation, providing a high design safety factor. Regarding the surface integrity of the machined surfaces, results show that, in exception of one tested condition, all other values of Ra satisfy N6 roughness grade. The pass associated to re = 0.8 mm and fz = 0.15 mm probably provided higher vibrations. ANOVA indicates that, in statistical terms, only feed ( f ) and the interaction between feed and nose radius ( f x re) affect the roughness parameters Ra, Rq, Rt, Rz, and Rmax, although these effects are not obvious. There was no statistically significant difference for skewness (Rsk), which tends to zero and, therefore, expresses an approximately symmetrical surface in terms of peaks and valleys. The same for kurtosis (Rku), which remained close to three, which means a distribution close to normal.