Estudos in silico e in vitro de novos candidatos a fármaco anticâncer

Abstract

-Cancer is a term used for a group of highly complex malignant diseases that represent an important public health problem. Glioblastoma Multiforme (GBM) is a tumor of the central nervous system, with aggressive biological characteristics and high invasiveness. It is known that GBM has biological resistance to several classes of chemotherapy agents, with the drug temozolomide (TMZ) being the most used for treatment. Another type of cancer that represents a significant challenge to global health is breast cancer as it is the most frequently diagnosed cancer in the world and the leading cause of mortality from this disease among women. The search for effective drugs for the treatment of cancer that are selective for cancer cells is a challenge for the scientific community. In this scenario, research for new anticancer drugs is necessary in order to obtain more effective therapies that present fewer adverse reactions. The general objective of this study was to select, synthesize and test new quinazoline candidates for anticancer drugs and evaluate antitumor activity in GBM (U87-MG and T98G) and breast cancer (MCF-7) tumor lines. For this, computational studies were carried out that corroborated the selection of promising molecules with good pharmacokinetic parameters to be synthesized. An initial in vitro test was carried out to screen the synthesized molecules to evaluate their ability to inhibit cell viability in glioblastoma tumor lines. Two molecules called KDY3 and KDY23 were the most promising and quinazoline KDY3 was explored in this study. The inhibition of cell viability promoted by KDY3 in GBM and breast cancer lines was significantly greater than that promoted by temozolomide (TMZ) and doxorubicin (DOXO), which are reference drugs for treatment of GBM and breast cancer. Differential expression analysis of genes involved in cell survival pathways demonstrated that KDY3 acts through different mechanisms than the drug TMZ. Therefore, KDY3 can be considered a promising drug candidate for the treatment of GBM and breast cancer.