RESUMO
We describe here the design and antitumor evaluation of benzofuroxan-based nitric oxide (NO)-donor hybrid derivatives targeting human carbonic anhydrases (hCAs) IX and XII. The most effective compounds, 27 and 28, demonstrated potent dual action, exhibiting low nanomolar inhibition constants against hCA IX and significant NO release. Notably, compound 27 showed significant antiproliferative effects against various cancer cell lines, particularly renal carcinoma A-498 cells. In these cells, it significantly reduced the expression of CA IX and iron-regulatory proteins, inducing apoptosis via mitochondrial caspase activity and ferroptosis pathways, as evidenced by increases in ROS, nitrite, and down-regulated expression of ferritin-encoding genes. In three-dimensional tumor models, compound 27 effectively reduced spheroid size and viability. In vivo toxicity studies in mice indicated that the compounds were well-tolerated, with no significant alterations in kidney function. These findings underscore the potential of benzofuroxan-based CA inhibitors for further preclinical evaluations as therapeutic agents targeting renal cell carcinoma.
Assuntos
Antineoplásicos , Anidrase Carbônica IX , Inibidores da Anidrase Carbônica , Óxido Nítrico , Humanos , Inibidores da Anidrase Carbônica/farmacologia , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/uso terapêutico , Animais , Anidrase Carbônica IX/antagonistas & inibidores , Anidrase Carbônica IX/metabolismo , Óxido Nítrico/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Camundongos , Linhagem Celular Tumoral , Benzoxazóis/farmacologia , Benzoxazóis/síntese química , Benzoxazóis/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Doadores de Óxido Nítrico/farmacologia , Doadores de Óxido Nítrico/química , Doadores de Óxido Nítrico/síntese química , Doadores de Óxido Nítrico/uso terapêutico , Antígenos de Neoplasias/metabolismo , Relação Estrutura-Atividade , Ensaios de Seleção de Medicamentos Antitumorais , OxidiazóisRESUMO
A novel nanoconstruct based on poly(lactic-co-glycolic acid) nanoparticles loaded with a tetrathiahelicene molecule conjugated to a fluorescent rhodamine probe was prepared and characterized. Because helicenes are known to be very promising DNA intercalators, the tetrathiahelicene was selected for this study as a model therapeutic cytotoxic molecule. The ability of the nanoconstruct to internalize the tetrathiahelicene and deliver it intracellularly in a safe manner has been investigated by means of cytotoxicity and cell uptake tests on Balb/3T3 cloneâ A31 fibroblasts. The outcomes of this study suggest the suitability of the developed nanoconstruct to act as a vector for the intracellular delivery of hydrophobic small molecules, such as helicenes, thus contributing to their possible future exploitation as novel therapeutics.