Synthesis and antiproliferative evaluation of 5-oxo and 5-thio derivatives of 1,4-diaryl tetrazoles

A series of 1,4-diaryl tetrazol-5-ones were synthesized by copper mediated N-arylation of 1-phenyl-1H-tetrazol-5(4H)-one with aryl boronic acids, o-R1C6H4B(OH)2 where R1 = H, OMe, Cl, CF3, Br, CCH. The 1,4-diaryl tetrazol-5-ones substituted with OMe, Cl, CF3, Br underwent thionation with Lawesson’s reagent to yield the corresponding 5-thio derivatives. The 1-(2-bromophenyl)-4-phenyl-1H-tetrazole-5(4H)-thione so obtained was subjected to lithiation/protonation and Sonogashira coupling to produce 1,4-diphenyl-1H-tetrazole-5(4H)-thione and 1-(2-ethynylphenyl)-4-phenyl tetrazole-5-thione, respectively. The title compounds were found to be stable to strong Lewis acid conditions. Three of these novel compounds were found to inhibit L1210 leukemia cell proliferation and SK-BR-3 breast cancer cell growth over several days in culture in vitro. Shorter tetrazole derivative treatments also reduced the expression of the Ki-67 marker of cell proliferation in SK-BR-3 cells and the rate of DNA synthesis in L1210 cells.

We report the synthesis of a series of 1,4-diaryl tetrazol-5-ones and tetrazole-5-thiones that inhibit the proliferation of L1210 and SK-BR-3 tumor cells in vitro.Figure optionsDownload as PowerPoint slide