Hybrids of 4-hydroxy derivatives of goniothalamin and piplartine bearing a diester or a 1,2,3-triazole linker as antiproliferative agents

A library of nine hybrids of 4-hydroxygoniothalamin (2), 4-hydroxypiplartine (4), monastrol (5) and oxo-monastrol (6) was prepared via a modular synthetic route with a diester or a 1,2,3-triazole as linkers. The compounds were assayed against a panel of human cancer cell lines, including MCF-7 (breast adenocarcinoma), HeLa (cervical adenocarcinoma), Caco-2 (colorectal adenocarcinoma) and PC3 (prostate adenocarcinoma), as well as against normal breast (MCF10A) and prostate (PNT2) cells. In general, hybrids with an ester linker containing 4-hydroxypiplartine (4) were more potent than the corresponding hybrids with 4-hydroxygoniothalamin (2). On the other hand, compounds presenting the 1,2,3-triazole linker displayed enhanced cytotoxicity and selectivity when compared to their corresponding hybrids with the diester linker. The 4-hydroxypiplartine-based hybrids 12 and 22 displayed high cytotoxicity (IC50 values below 10 μM) against all cancer cells studied, especially in MCF-7 cells with IC50 values of 1.7 ± 0.1 and 1.6 ± 0.9 μM, respectively. Furthermore, the 4-hydroxygoniothalamin-monastrol hybrid (compound 21) and the 4-hydroxypiplartine-oxo-monastrol hybrid (compound 25), both bearing a 1,2,3-triazole linker, displayed high selectivity and potency towards breast cancer cell line (MCF-7 vs. MCF10 cells, selectivity index = 15.8 and 7.1, respectively), while the 4-hydroxypiplartine -4-hydroxymethylgoniothalamin hybrid with a diester linker (compound 33) showed high selectivity towards melanoma cancer cells (selectivity index = 9.6). Antiproliferative and pro-apoptotic potential of compounds 12 and 22 against MCF-7 cancer cells were further investigated. Cell cycle studies revealed increased G2/M population in MCF-7 cultures as well as reduced G0/G1 population compared to the control groups indicating cell cycle arrest in G2/M phase. In addition, the frequency of positive cells for annexin V was higher in treated samples suggesting that compounds 12 and 22 induce apoptosis in estrogen-positive MCF-7 cells.