GLYCOSYL ISOXAZOLES AS NOVEL LEADS FOR A TARGETED CANCERTHERAPY

LE PORS, MACARENA S.; VASQUEZ, IVANA R.; RIAFRECHA, LEONARDO E.; COLINAS, PEDRO A.; AZNAR, IGNACIO

San Pablo

Simposio; 30th International Carbohydrate Symposium; 2022

UFS

In 1930’s Otto Warburg had demonstrated that cancer cells show high rates of uptake of glucose and secretion of lactic acid, a unique feature of cancer cells, even in the presence of oxygen.1 Due to these metabolic properties latter known as the Warburg effect, tumors show an increased intracellular pH, and a more acidic extracellular pH compared to the corresponding values in normal cells. An anticancer strategy has focused on the acidic extracellular pH, which is regulated by several mechanisms such as the Na+/H+ exchanger (NHE-1), the proton-linked monocarboxylate transporter, the Cl-/HCO3- exchangers and carbonic anhydrases (CAs) IX and XII in many tumors.2We report the synthesis of twelve O-glycosylmethyl isoxazoles incorporating the phenoxyaryl moiety, that were designed to selectively target the cancer-related human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms (Figure 1). The O-glycosides have been prepared by cycloaddition of nitrile oxides to O-propargyl glycosides in green chemistry environment.3 Compounds were assessed as inhibitors of the physiologically dominant isozymes hCA I and II and the tumor-associated isozyme hCA IX and hCA XII. In this study several glycosides have been identified as highly selective inhibitors of hCA IX and XII. As a consequence of their conformation, the O-glycosides could also be preferentially uptaken by cancer cells due to the overexpression of GLUT-1 transporter. The most active compounds were assessed as antiproliferative agents against osteosarcoma cells, which overexpress hCA IX and GLUT-1. The results show that these O-glycosyl isoxazoles selective tumor-related CA inhibitors will be a promising step in the strategy for an effective targeted cancer therapy.