The present study seeks to describe the design and synthesis of six new Michael adducts of (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-dithiocarbamate with nitrostyrenes and their in vitro antiproliferative activity against human cervical cancer cell lines [HeLa (HPV 18 positive), CaSki (HPV 16 positive) and ViBo (HPV negative) cervical cancer cell lines]. Virtual screening of the physicochemical properties of all compounds have also been presented. All the compounds exploited significant antiproliferative activity on the three cervical cancer cell lines. Compound 8a was found to be most potent, displaying in vitro antiproliferative activity against HeLa, CaSki and ViBo cervical cancer cell lines superior to Cisplatin and Paclitaxel with IC₅₀ values 0.99 ± 0.007, 2.36 ± 0.016 and 0.73 ± 0.002 μM respectively. In addition, compound 8a did not trigger the necrosis cell death to the test cancer cell lines. Further mechanistic study revealed that compound 8a could inhibit the cancer cell proliferation by inducing apoptosis through caspase-3 activation. Moreover, cell cycle analysis indicated that compound 8a could arrest the cell cycle at the G1 phase for HeLa and CaSki cancer cells. At the predetermined IC₅₀ values on cancer cells, compound 8a did not induce any necrotic (cytotoxic) death to the normal human lymphocytes. In the present design, (1S,4S)-2,5-diazabicyclo[2.2.1]heptane system was found to be superior than the piperazine counterpart 11.

本研究旨在描述（1 S，4 S）-2,5-二氮杂双环[2.2.1]庚烷-二硫代氨基甲酸酯与硝基苯乙烯的六种新迈克尔加合物的设计与合成及其对人宫颈癌细胞的体外抗增殖活性细胞系[HeLa（HPV 18阳性），CaSki（HPV 16阳性）和ViBo（HPV阴性）宫颈癌细胞系]。还提出了对所有化合物的理化性质进行虚拟筛选的方法。所有化合物对三种宫颈癌细胞系均具有显着的抗增殖活性。发现化合物8a最有效，在体外对HeLa，CaSki和ViBo宫颈癌细胞系表现出优于顺铂和紫杉醇的IC ₅₀，具有抗增殖活性值分别为0.99±0.007、2.36±0.016和0.73±0.002μM。另外，化合物8a没有触发测试癌细胞系的坏死细胞死亡。进一步的机理研究表明，化合物8a可通过caspase-3激活诱导细胞凋亡来抑制癌细胞的增殖。此外，细胞周期分析表明，化合物8a可以将HeLa和CaSki癌细胞的细胞周期阻滞在G1期。在癌细胞上的预定IC ₅₀值下，化合物8a对正常人淋巴细胞没有诱导任何坏死性（细胞毒性）死亡。在本设计中，（1 S，4 S）-2,5-二氮杂双环[2.2.1]庚烷系统被发现优于哌嗪对应物11。