In this work we report the highly efficient solvent-free and self-catalyzed three-component approach for the synthesis of pyrazolo[ 3,4-e][1,4]thiazepin-7(4H)-ones. The reaction between 5-aminopyrazoles, benzaldehydes and mercaptoacetic acid, acting both as reagent and catalyst, at 120 °C lead to the sequential formation of three new single bonds and the release of water as unique by-product, which demonstrates this to be an environmentally friendly three-component procedure. Selected products were evaluated by the NCI (USA) for their antitumor activity. Compound 16b displayed the most remarkable activity against different strains of human tumor cell lines with several GI50 values less than 1.0 µM (i.e. MDA-MB-435 (Melanoma, GI50 = 0.304 µM), A498 (Renal Cancer, GI50 = 0.353 µM) and SR (Leukemia, GI50 = 0.413 µM)), making it a promising building block for development of potential antitumor agents.