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Simple Summary  Sulfonate derivatives have limited application in pharmacology. Only few examples of small-molecule alkylating agents used as DNA poisons are known. This is the first report presenting strong anticancer activity of aromatic sulfonates based on quinazolines. The screening revealed that compounds expressed good submicromolar activity exceeding imatinib against a panel of cancer cell lines, including leukemia, colon, pancreatic cancers and glioblastoma, and minimal effect on proliferation of non-cancer cells. This activity corresponds with strong cell cycle arrest and mitotic inhibition similar or higher than that of paclitaxel. Further investigation revealed a more multitargeted mechanism of action. This structure may be an effective, novel scaffold for drug design.    Abstract  Sulfonates, unlike their derivatives, sulphonamides, have rarely been investigated for their anticancer activity. Unlike the well-known sulphonamides, esters are mainly used as convenient intermediates in a synthesis. Here, we present the first in-depth investigation of quinazoline sulfonates. A small series of derivatives were synthesized and tested for their anticancer activity. Based on their structural similarity, these compounds resemble tyrosine kinase inhibitors and the p53 reactivator CP-31398. Their biological activity profile, however, was more related to sulphonamides because there was a strong cell cycle arrest in the G2/M phase. Further investigation revealed a multitargeted mechanism of the action that corresponded to the p53 protein status in the cell. Although the compounds expressed a high submicromolar activity against leukemia and colon cancers, pancreatic cancer and glioblastoma were also susceptible. Apoptosis and autophagy were confirmed as the cell death modes that corresponded with the inhibition of metabolic activity and the activation of the p53-dependent and p53-independent pathways. Namely, there was a strong activation of the p62 protein and  GADD44 . Other proteins such as cdc2 were also expressed at a higher level. Moreover, the classical caspase-dependent pathway in leukemia was observed at a lower concentration, which again confirmed a multitargeted mechanism. It can therefore be concluded that the sulfonates of quinazolines can be regarded as promising scaffolds for developing anticancer agents.

Novel Benzenesulfonate Scaffolds with a High Anticancer Activity and G2/M Cell Cycle Arrest