RESUMO
Ajoene is an organosulfur compound found in crushed garlic that exerts its anti-cancer activity by S-thiolating cysteine residues on proteins. Its development is hampered due to limited bioavailability, so in this study, we synthesised analogues of ajoene to probe the significance of the ajoene vinyl disulfide/sulfoxide core with respect to cytotoxicity and blood stability. Polar side groups were also incorporated to improve aqueous solubility. It was found that derivatives containing a vinyl disulfide functional group (4-7, as in ajoene), were more cytotoxic compared to analogues in which the double bond was removed, although the latter showed superior blood stability. It was also found that the allyl-S sulfur of the disulfide was more electrophilic to S-thiolysis based on the global electrophilicity index (ω) and the condensed electrophilic Fukui function f k + ${{ f}_{\rm{k}}^{\rm{ + }} }$ . S-Thiolysis was found to be exergonic for the vinyl disulfides based on entropy and enthalpy computations with a deprotonated thiolate. Derivatisation to the dihydro (10, 12) and deoxydihydroajoenes (9, 11) produced analogues that were slightly less potent but with greatly improved blood stability. Taken together, the deoxydihydroajoenes present themselves as good candidates for further therapeutic development.
Assuntos
Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Relação Estrutura-Atividade , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Estrutura Molecular , Sulfóxidos/química , Sulfóxidos/farmacologia , Sulfóxidos/síntese química , Relação Dose-Resposta a Droga , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dissulfetos/química , Dissulfetos/farmacologia , Dissulfetos/síntese química , Linhagem Celular TumoralRESUMO
Colorectal cancer (CRC) affects both women and men living in societies with a high sedentary lifestyle. Amongst the phenotypic changes exhibited by tumor cells, a wide range of glycosylation has been reported for colon cancer-derived cell lines and CRC tissues. These aberrant modifications affect different aspects of glycosylation, including an increase in core fucosylation and GlcNAc branching on N-glycans, alteration of O-glycans, upregulated sialylation, and O-GlcNAcylation. Although O-GlcNAcylation and complex glycosylations differ in many aspects, sparse evidences report on the interference of O-GlcNAcylation with complex glycosylation. Nevertheless, this relationship is still a matter of debate. Combining different approaches on three human colon cell lines (HT29, HCT116 and CCD841CoN), it is herein reported that silencing O-GlcNAc transferase (OGT, the sole enzyme driving O-GlcNAcylation), only slightly affects overall N- and O-glycosylation patterns. Interestingly, silencing of OGT in HT29 cells upregulates E-cadherin (a major actor of epithelial-to-mesenchymal transition) and changes its glycosylation. On the other hand, OGT silencing perturbs biosynthesis of glycosphingolipids resulting in a decrease in gangliosides and an increase in globosides. Together, these results provide novel insights regarding the selective regulation of complex glycosylations by O-GlcNAcylation in colon cancer cells.