Discovery of 4H-chromeno[2,3-d]pyrimidin-4-one derivatives as senescence inducers and their senescence-associated antiproliferative activities on cancer cells using advanced phenotypic assay

Current research suggests therapy-induced senescence (TIS) of cancer cells characterized by distinct morphological and biochemical phenotypic changes represent a novel functional target that may enhance the effectiveness therapy. In order to identify small-molecule inducers cellular determine potential be used for treatment melanoma, new method high-throughput screening (HTS) high-contents (HCS) based on detection was designed. This image-based whole cell-based technology applied screen select class antiproliferative agents cells, 4H-chromeno[2,3-d]pyrimidin-4-one derivatives, which induced senescence-like in human melanoma A375 without serious cytotoxicity against normal cells. To evaluate structure-activity relationship (SAR) study scaffold starting from hit 3, focused library containing diversely modified analogues constructed led identification 38, compound have remarkable anti-melanoma activity vitro with good metabolic stability.