Pyrazole-based lamellarin O analogues: synthesis, biological evaluation and structure-activity relationships.

A library of pyrazole-based lamellarin O analogues was synthesized from easily accessible 3(5)-aryl-1-pyrazole-5(3)-carboxylates which were subsequently modified by bromination, -alkylation and Pd-catalysed Suzuki cross-coupling reactions. Synthesized ethyl and methyl 3,4-diaryl-1-(2-aryl-2-oxoethyl)-1-pyrazole-5-carboxylates were evaluated for their physicochemical property profiles and cytotoxicity against three human colorectal cancer cell lines HCT116, HT29, and SW480. The most active compounds inhibited cell proliferation in a low micromolar range. Selected ethyl 3,4-diaryl-1-(2-aryl-2-oxoethyl)-1-pyrazole-5-carboxylates were further investigated for their mode of action. Results of combined viability staining Calcein AM/Hoechst/PI and fluorescence-activated cell sorting data indicated that cell death was triggered in a non-necrotic manner mediated by mainly G2/M-phase arrest.