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Hybrids of 4-hydroxy derivatives of goniothalamin and piplartine bearing a diester or a 1,2,3-triazole linker as antiproliferative agents
Bioorganic Chemistry ( IF 4.5 ) Pub Date : 2021-08-25 , DOI: 10.1016/j.bioorg.2021.105292
Thiago A Grigolo 1 , Carolyne B Braga 1 , Catia Ornelas 1 , Dennis Russowsky 2 , Guilherme A Ferreira-Silva 3 , Marisa Ionta 3 , Ronaldo A Pilli 1
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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.



中文翻译:


带有二酯或 1,2,3-三唑连接基的 goniothalamin 和 piplartine 的 4-羟基衍生物的杂化物作为抗增殖剂



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1222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-7MCF10 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1222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1222诱导雌激素阳性 MCF-7 细胞凋亡。

更新日期:2021-09-10
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