Abstract：
In a search for new anticancer agents with better activity and selectivity, the present work described the synthesis of several new series of sulfachloropyridazine hybrids with thiocarbamates 3a-e, thioureids 4a-h, 5a-e and 4-substituted sulfachloropyridazines 6a, b, 7a, b and 8. The synthesized compounds were screened in vitro against a panel of 60 cancer cell lines in one dose assay. The most potent derivatives 3a, 3c, 4c, 4d, 5e, 7a and 7b were tested for their antiangiogenic activity by measuring their ability to inhibit VEGFR-2. The most potent compounds in VEGFR-2 inhibitory assay were further evaluated for their ability to inhibit PDGFR. In addition, the ability of 4c compound to inhibit cell migration on HUVEC cells and cell cycle effect on UO-31 cells has been studied. The pro-apoptotic effect of compound 4c was studied by the evaluation of caspase-3, Bax and BCl-2. Alternatively, the IC50 of compounds 3a, 3c, 4c, 5e, 7a and 7b against certain human cancer cell lines were determined. Re-evaluation in combination with γ-radiation was carried out for compounds 4c, 5e and 7b to study the possible synergistic effect on cytotoxicity. Docking studies of the most active compounds were performed to give insights into the binding mode within VEGFR-2 active site.
摘要：
在寻找具有更好活性和选择性的新抗癌剂时，本工作描述了几个新系列的硫磺氯吡啶杂化物与硫代氨基甲酸酯3a-e的合成，硫脲类4a-h，5a-e和4-取代的磺胺氯吡啶6a，B,7a,B和8在一个剂量测定中针对一组60个癌细胞系体外筛选合成的化合物。最有效的衍生物3a，3c,4c,4d,5e,通过测量它们抑制VEGFR-2的能力来测试7a和7b的抗血管生成活性。进一步评价VEGFR-2抑制试验中最有效的化合物抑制PDGFR的能力。此外,研究了4c化合物抑制HUVEC细胞迁移的能力以及对UO-31细胞的细胞周期影响。通过评价caspase-3、Bax和BCl-2研究化合物4c的促凋亡作用。或者，化合物3a的IC50，3c,4c,5e,确定了针对某些人癌细胞系的图7a和7b。对化合物4c进行与γ辐射结合的再评估，5e和7b研究对细胞毒性的可能协同作用。进行最具活性的化合物的对接研究以给出对VEGFR-2活性位点内的结合模式的见解。
