Kabir Abbas, Tilekar Kalpana, Upadhyay Neha, Ramaa C S
Bharati Vidyapeeth's College of Pharmacy, Department of Pharmaceutical Chemistry, Sector 8, C. B. D. Belapur, Navi Mumbai 400614, Maharashtra, India.
Anticancer Agents Med Chem. 2018;18(11):1551-1562. doi: 10.2174/1871520618666180423111309.
Cancer being a complex disease, single targeting agents remain unsuccessful. This calls for "multiple targeting", wherein a single drug is so designed that it will modulate the activity of multiple protein targets. Topoisomerase 2 (Top2) helps in removing DNA tangles and super-coiling during cellular replication, Casein Kinase 2 (CK2) is involved in the phosphorylation of a multitude of protein targets. Thus, in the present work, we have tried to develop dual inhibitors of Top2 and CK2.
With this view, in the present work, 2 human proteins, Top2 and CK2 have been targeted to achieve the anti-proliferative effects.
Novel 1-acetylamidoanthraquinone (3a-3y) derivatives were designed, synthesized and their structures were elucidated by analytical and spectral characterization techniques (FTIR, 1H NMR, 13C NMR and Mass Spectroscopy). The synthesized compounds were then subjected to evaluation of cytotoxic potential by the Sulforhodamine B (SRB) protein assay, using HL60 and K562 cell lines. Ten compounds were analyzed for Top2, CK2 enzyme inhibitory potential. Further, top three compounds were subjected to cell cycle analysis.
The compounds 3a to 3c, 3e, 3f, 3i to 3p, 3t and 3x showed excellent cytotoxic activity to HL-60 cell line indicating their high anti-proliferative potential in AML. The compounds 3a to 3c, 3e, 3f, 3i to 3p and 3y have shown good to moderate activity on K-562 cell line. Compounds 3e, 3f, 3i, 3x and 3y were found more cytotoxic than standard doxorubicin. In cell cycle analysis, the cells (79-85%) were found to arrest in the G0/G1 phase.
We have successfully designed, synthesized, purified and structurally characterized 1- acetylamidoanthraquinone derivatives. Even though our compounds need design optimization to further increase enzyme inhibition, their overall anti-proliferative effects were found to be encouraging.
癌症是一种复杂的疾病，单一靶向药物一直未取得成功。这就需要“多重靶向”，即设计一种单一药物，使其能够调节多个蛋白质靶点的活性。拓扑异构酶2（Top2）有助于在细胞复制过程中消除DNA缠结和超螺旋，酪蛋白激酶2（CK2）参与多种蛋白质靶点的磷酸化。因此，在本研究中，我们试图开发Top2和CK2的双重抑制剂。
基于此观点，在本研究中，针对两种人类蛋白质Top2和CK2以实现抗增殖作用。
设计、合成了新型1-乙酰氨基蒽醌（3a - 3y）衍生物，并通过分析和光谱表征技术（傅里叶变换红外光谱、1H核磁共振、13C核磁共振和质谱）对其结构进行了阐明。然后使用HL60和K562细胞系，通过磺酰罗丹明B（SRB）蛋白质测定法对合成的化合物进行细胞毒性潜力评估。分析了10种化合物对Top2、CK2酶的抑制潜力。此外，对排名前三的化合物进行了细胞周期分析。
化合物3a至3c、3e、3f、3i至3p、3t和3x对HL - 60细胞系显示出优异的细胞毒性活性，表明它们在急性髓系白血病中具有较高的抗增殖潜力。化合物3a至3c、3e、3f、3i至3p和3y对K - 562细胞系表现出良好至中等的活性。发现化合物3e、3f、3i、3x和3y比标准阿霉素更具细胞毒性。在细胞周期分析中，发现细胞（79 - 85%）停滞在G0/G1期。
我们成功设计、合成、纯化并对1-乙酰氨基蒽醌衍生物进行了结构表征。尽管我们的化合物需要进行设计优化以进一步提高酶抑制作用，但发现它们的总体抗增殖效果令人鼓舞。
