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.

通过使用二酯或 1,2,3-三唑的模块化合成路线制备了 4-羟基哥尼托胺 ( 2 )、4-羟基哌拉汀 ( 4 )、monastrol ( 5 ) 和 oxo-monastrol ( 6 ) 的九种杂合体的文库作为链接器。这些化合物针对一组人类癌细胞系（包括 MCF-7（乳腺癌）、HeLa（宫颈腺癌）、Caco-2（结直肠腺癌）和 PC3（前列腺癌））以及正常乳腺癌（MCF10A）进行了检测。 ）和前列腺（PNT2）细胞。一般来说，具有含有 4-羟基哌铂碱 ( 4 ) 的酯连接体的杂合体比具有 4-羟基哥尼托胺 ( 2 ) 的相应杂合体更有效。另一方面，与具有二酯连接体的相应杂化物相比，具有 1,2,3-三唑连接体的化合物表现出增强的细胞毒性和选择性。基于 4-羟基哌铂碱的杂合体12和22对所有研究的癌细胞均表现出高细胞毒性（IC ₅₀值低于 10 μM），特别是在 MCF-7 细胞中，IC ₅₀值分别为 1.7 ± 0.1 和 1.6 ± 0.9 μM。此外，4-羟基goniothalamin-monastrol杂合体（化合物21 ）和4-羟基piplartine-oxo-monastrol杂合体（化合物25 ）均带有1,2,3-三唑连接体，对乳腺癌细胞系表现出高选择性和效力（MCF-7与MCF10 细胞，选择性指数 = 15.8 和 7。1），而带有二酯接头的 4-羟基哌铂-4-羟甲基角菌素杂化物（化合物33 ）对黑色素瘤癌细胞表现出高选择性（选择性指数 = 9.6）。进一步研究了化合物12和22针对MCF-7癌细胞的抗增殖和促凋亡潜力。细胞周期研究显示，与对照组相比，MCF-7 培养物中 G2/M 群体增加，G0/G1 群体减少，表明细胞周期停滞在 G2/M 期。此外，经处理的样品中膜联蛋白 V 阳性细胞的频率较高，表明化合物12和22诱导雌激素阳性 MCF-7 细胞凋亡。