Synthesis and in vitro evaluation of potential anticancer activity of mono- and bis-1,2,3-triazole derivatives of bis-alkynes

In order to find new molecules with cytotoxic activity against cancer cells, we prepared bis-akyne amides derived from propiolic acid. The bis-alkynes were then transformed in their mono-1,2,3-triazole analogs onto the amide side, due to its greater reactivity, using a catalyst-free Huisgen's reaction. The mono-triazoles were then subjected to the copper (I)-catalyzed version of the previous reaction (CuAAC), using a supported catalyst, to produce bis-triazoles. All products were obtained pure after simple trituration or filtration procedures. All synthetic compounds were tested in vitro for their cytotoxic activity using B16 melanoma cells. Four compounds (7, 23, 25 and 33) showed activities in the micromolar range (<21 μM) whereas three compounds (3, 22 and 38) presented activity at low micromolar concentrations (<10 μM), and two analogs (2 and 13) were active at nanomolar levels (<1 μM).

Bis-alkynes were used to synthesize their mono- and bis-1,2,3-triazole derivatives using Huisgen's reaction (click chemistry) using a previously published procedure. Amongst the compounds tested, the bis-alkyne 2 (R = m-Ph) and the bis-triazole 13 (R = CH2, R1 = Bn, R2 = Bn) showed potent cytotoxic activity on B16 melanoma cell line, both with IC50 of 0.3 μM.Figure optionsDownload as PowerPoint slideHighlights
► The compounds were prepared by a regioselective synthesis using click chemistry.
► This was done by a solvent/catalyst free and a solid phase supported steps.
► All synthetic compounds were tested: alkynes, mono and bistriazoles.
► Some compounds reached micro to nanomolar cytotoxicities against B13 melanoma.
► We made a structure–activity relationship tentative for the series.