Laskar Sujay, Sánchez-Sánchez Luis, Flores Sebastián M, López-Muñoz Hugo, Escobar-Sánchez María L, López-Ortiz Manuel, Hernández-Rodríguez Marcos, Regla Ignacio
Lab. de Síntesis de Fármacos, Laboratorio 9 UMIEZ, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Ejercito de Oriente, Iztapalapa 09230, Ciudad de México, Mexico.
Lab. Biología Molecular del Cáncer, Laboratorio 2 PB UMIEZ, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Ejercito de Oriente, Iztapalapa 09230, Ciudad de México, Mexico.
Eur J Med Chem. 2018 Feb 25;146:621-635. doi: 10.1016/j.ejmech.2018.01.020. Epub 2018 Jan 10.
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 IC 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 IC 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(1S,4S)-2,5-二氮杂双环[2.2.1]庚烷-二硫代氨基甲酸盐与硝基苯乙烯的六种新型迈克尔加合物的设计与合成，以及它们对人宫颈癌细胞系[HeLa（HPV 18阳性）、CaSki（HPV 16阳性）和ViBo（HPV阴性）宫颈癌细胞系]的体外抗增殖活性。还展示了对所有化合物物理化学性质的虚拟筛选。所有化合物对三种宫颈癌细胞系均表现出显著的抗增殖活性。发现化合物8a最具活性，对HeLa、CaSki和ViBo宫颈癌细胞系的体外抗增殖活性优于顺铂和紫杉醇，IC值分别为0.99±0.007、2.36±0.016和0.73±0.002μM。此外，化合物8a未引发受试癌细胞系的坏死性细胞死亡。进一步的机制研究表明，化合物8a可通过激活caspase-3诱导凋亡来抑制癌细胞增殖。此外，细胞周期分析表明，化合物8a可使HeLa和CaSki癌细胞的细胞周期停滞在G1期。在对癌细胞的预定IC值下，化合物8a未对正常人淋巴细胞诱导任何坏死性（细胞毒性）死亡。在本设计中，发现(1S,4S)-2,5-二氮杂双环[2.2.1]庚烷体系优于哌嗪类似物11。
