RESUMO
Bioprospecting contributes to the discovery of new molecules with anticancer properties. Compounds with cytolytic activity and the ability to induce immunogenic cell death can be administered as intratumoral injections with the aim to activate anti-tumor immune responses by causing the release of tumor antigens as well as damage-associated molecular patterns (DAMPs) from dying cancer cells. In the present study, we report the cytolytic and DAMP-releasing effects of a new natural product mimic termed MPM-1 that was inspired by the marine Eusynstyelamides. We found that MPM-1 rapidly killed cancer cells in vitro by inducing a necrosis-like death, which was accompanied by lysosomal swelling and perturbation of autophagy in HSC-3 (human oral squamous cell carcinoma) cells. MPM-1 also induced release of the DAMPs adenosine triphosphate (ATP) and high mobility group box 1 (HMGB1) from Ramos (B-cell lymphoma) and HSC-3 cells, as well as cell surface expression of calreticulin in HSC-3 cells. This indicates that MPM-1 has the ability to induce immunogenic cell death, further suggesting that it may have potential as a novel anticancer compound.
Assuntos
Alarminas , Produtos Biológicos , Carcinoma de Células Escamosas , Neoplasias Bucais , Trifosfato de Adenosina/metabolismo , Alarminas/efeitos dos fármacos , Alarminas/metabolismo , Antígenos de Neoplasias , Produtos Biológicos/farmacologia , Calreticulina/metabolismo , Carcinoma de Células Escamosas/tratamento farmacológico , Linhagem Celular Tumoral , Proteína HMGB1/efeitos dos fármacos , Proteína HMGB1/metabolismo , Humanos , Neoplasias Bucais/tratamento farmacológicoRESUMO
A practical and efficient methodology for the preparation of 2-aminoethyl α,α-disubstituted ß-amino amides in three steps from methyl cyanoacetate has been developed. The key step in the synthesis was the chemoselective reduction of the nitrile group in presence of an amide and aryl halide functionalities. Reduction with RANEY® Nickel catalyst, either with molecular hydrogen (8-10 bar) or under transfer hydrogenation conditions, necessitated in situ protection of the resulting amines with Boc2O, whereas aryl bromide containing nitriles could be chemoselectively reduced with ZnCl2/NaBH4 without debromination. The developed protocol involved only one chromatographic purification step and can be performed at gram scale.