School of Chemistry and Physics, University of KwaZulu-Natal, P/Bag X54001, Westville, Durban 4000, South Africa.
School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, Wits, Johannesburg 2050, South Africa.
Bioorg Med Chem. 2018 Nov 15;26(21):5612-5623. doi: 10.1016/j.bmc.2018.10.006. Epub 2018 Oct 12.
A novel library of coumarin tagged 1,3,4 oxadiazole conjugates was synthesized and evaluated for their antiproliferative activities against MDA-MB-231 and MCF-7 breast cancer cell lines. The evaluation studies revealed that compound 9d was the most potent molecule with an IC value of <5 µM against the MCF-7 cell line. Interestingly, compounds 10b and 11a showed a similar trend with lower inhibitory concentration (IC = 7.07 µM), in Estrogen Negative (ER-) cells than Estrogen Positive (ER+) cells. Structure-activity relationship (SAR) studies revealed that conjugates bearing benzyl moieties (9b, 9c and 9d) had superior activities compared to their alkyl analogues. The most potent compound 9d showed ∼1.4 times more potent activity than tamoxifen against MCF-7 cell line; while the introduction of sulfone unit in compounds 11a, 11b and 11c resulted in significant cytotoxicity against both MCF-7 and MDA-MB-231 cell lines. These results were further supported by docking studies, which revealed that the stronger binding affinity of the synthesized conjugates is due to the presence of sulfone unit attached to the substituted benzyl moiety in their pharmacophores.
合成了一个新型香豆素标记 1,3,4-恶二唑共轭物库，并对其抗 MDA-MB-231 和 MCF-7 乳腺癌细胞系的增殖活性进行了评价。评估研究表明，化合物 9d 是最有效的分子，其对 MCF-7 细胞系的 IC 值小于 5 µM。有趣的是，化合物 10b 和 11a 在雌激素阴性（ER-）细胞中比雌激素阳性（ER+）细胞具有更低的抑制浓度（IC = 7.07 µM），显示出类似的趋势。构效关系（SAR）研究表明，带有苄基部分的共轭物（9b、9c 和 9d）比其烷基类似物具有更高的活性。最有效的化合物 9d 对 MCF-7 细胞系的活性比他莫昔芬高约 1.4 倍；而在化合物 11a、11b 和 11c 中引入砜单元则导致对 MCF-7 和 MDA-MB-231 细胞系都具有显著的细胞毒性。这些结果得到了对接研究的进一步支持，该研究表明，合成的共轭物具有更强的结合亲和力，这是由于其药效团中取代的苄基部分上存在砜单元。
