Development of novel selenocompounds as antitumor agents

Resumo

In this work, innovative series of novel selenadiazole compounds, seleno- nonsteroidal anti-inflammatory drug (NSAID) analogs and acylselenourea derivatives, comprising a total of eighty seven novel compounds, have been designed, synthesized and biologically evaluated. Regarding the series of twenty seven novel selenadiazole compounds, a novel selenadiazole with outstanding inhibition of cell viability on breast cancer cells while sparing the non-tumoral 184B5 cells was found. Remarkably, its mechanism of action is independent of induction of apoptosis and modulation of cell cycle. This unique behavior warrants further investigation of the in-depth mechanism of action. The series of twelve novel seleno-NSAID analogs were designed by incorporating methylseleno-, ethylseleno- and benzylseleno- moieties into NSAIDs structures, including aspirin, diflunisal, naproxen, indomethacin, mefenamic acid and sulindac. Three methylseleno analogs exhibited a significant increase on cytotoxic potency as compared to methylselenilic acid and parent NSAID scaffolds (aspirin, indomethacin and sulindac, respectively) alone or in combination in colorectal cancer (CRC) cells. Interestingly, these analogs showed completely different activity profiles on the National Cancer Institute’s (NCI) Developmental Therapeutics Program (DTP) panel of 60 cancer cell lines. Of particular interest is the compound with sulindac which exhibited potent cytotoxicity against the 6 most drug-resistant cells of the DTP panel, with cytotoxic parameter values of 47, 410 and 3900 nM for GI50, TGI and LC50, respectively, in the most resistant cancer cell line (OVCAR-5 from ovarian cancer). Hence, these seleno-NSAID analogs are under the protection of an intellectual disclosure issue by Penn State University [PSU 2020-5106]. Furthermore, one of these hybrids was encapsulated with cyclodextrins (β- and HP-β-CDs) and copolymer micelles (Pluronic F127). Water solubility and antitumoral efficacy towards CRC cells of this analog was enhanced. The improvement of their antitumoral efficacy might be due to a controlled release of analogs or its active volatiles. Besides, a novel and efficient method of intramolecular cyclization with hydrides to obtain lactam was developed. Besides, an unexpected and unprecedented Vilsmeier reagent application was reported to afford a 2-seleno functionalized indole with potent antitumoral activity in the most resistant breast cancer cell line of NCI panel (BT-549). Finally, benzodioxyl derivatives from a series of forty seven acylselenoureas have aroused as new agents with antioxidant and selective cytotoxic activity. Overall, these results reinforce that incorporation of a selenium atom into small organic molecules is a valid approach to design more active and selective antitumor compounds.