Planejamento e síntese de Aril-guanilidrazonas p-substituídas como potenciais protótipos antitumorais

Abstract

Cancer consists of a group of more than 100 diseases characterized by uncontrolled cell growth. It represents a serious public health issue and is considered the second death cause worldwide with 9.6 million reported cases in 2018. In Brazil, 300,000 and 280,000 new cases were reported for men and women respectively in 2018; however, although more than 150 drugs were approved between 1949 and 2014, cancer treatment is still limited by factors including lack of specificity, resistance, toxicity, and high cost, which make pharmaceutical research for drug development highly relevant. For that reason, guanylhydrazones represent coumpounds with medicinal value, especially because they have antitumor activity through effects on the cell cycle, apoptosis induction, mitochondrial function and targets like the ribonucleotide reductase enzyme. Therefore, after identifying the hit compound LQM14 in recent studies of the research group on medicinal chemistry, new analogs with modifications on the biphenyl of the prototype LQM14 were designed and synthesized in this study. To achieve that aim, the synthesis method consisted of the synthesis of p-functionalized benzaldehydes and condensation reactions to obtain guanylhydrazone derivatives, which were characterized by 1H NMR, 13C NMR, and IR. SNAr reactions (reaction yield of 40-82%), cross coupling of Buchwald-Hartwing (yield of 40-53%), and Suzuki Miyaura (yield of 26%) were developed which enabled the production of 9 p-substituted benzaldehydes. The method applied to obtain the planned guanylhydrazones was successful, in which 7 guanylidrazones were obtained with high purity (>95%) and reactional yields between 40-92%. The guanylidrazones were characterized through 1H NMR and IR in which the characteristic imine signal of the formation of these compounds was identified between 7.98 and 8.04 ppm and through the stretching bands between 1668-1659 cm -1. Finally, the developed guanylhydrazones will be further evaluated for their antitumor effect and the aim is that these compounds may contribute to research related to antitumor therapy.