Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Poznan, Poland.
Department of Organic Chemistry, Poznan University of Medical Sciences, Poznan, Poland.
J Physiol Pharmacol. 2017 Apr;68(2):201-207.
Pyrazoles and their derivatives belong to a class of compounds that demonstrate a great potential in design of anticancer, antiangiogenic, and antimetastatic drugs. Our earlier studies showed that pyrazole derivatives TOSPYRQUIN and TOSIND diminished viability of colorectal adenocarcinoma cells HT-29. Here we demonstrated for the first time in human mammary gland adenocarcinoma cell lines MCF7 and MDA-MB-231 cells the cytotoxic effects of four pyrazole derivatives: TOSIND, PYRIND, METPYRIND, and DIPYR. Three pyrazoles: PYRIND, METPYRIND, and one novel unpublished derivative DIPYR were tested for the first time in living cells. Viability of MCF7 did not significantly change in the presence of TOSIND but it decreased after 72 hours of treatment with PYRIND (IC-50 39.7 ± 5.8 μM). In the presence of METPYRIND the viability was also diminished, while DIPYR increased MCF7 viability after 24 hours of incubation. The viability of MDA-MB-231 cells was strongly decreased by TOSIND (IC-50 17.7 ± 2.7 μM 72 h), and was not influenced by PYRIND and METPYRIND, while DIPYR increased the viability and stimulated the growth of MDA-MB-231 cells. PYRIND, METPYRIND and DIPYR caused a gradual decrease of caspase-3 and caspase-7 activities in MDA-MB-231 cells and there was no influence of TOSIND on the activity of both caspases. Our results open the way to search for other compounds with pendant pyrazole residues in order to increase their cytotoxic activity; especially with regard to its anti-breast cancer activity. It appears that the pyrazoles synthesized by us diminish cell viability in a cell-specific manner. This observation might be useful in designing 'off-DNA' anticancer drugs, compounds which are not harmful to the healthy cells.
吡唑及其衍生物属于一类化合物，在设计抗癌、抗血管生成和抗转移药物方面具有巨大潜力。我们之前的研究表明，吡唑衍生物 TOSPYRQUIN 和 TOSIND 降低了结肠直肠腺癌 HT-29 细胞的活力。在这里，我们首次在人乳腺腺癌细胞系 MCF7 和 MDA-MB-231 细胞中证明了四种吡唑衍生物：TOSIND、PYRIND、METPYRIND 和 DIPYR 的细胞毒性作用。三种吡唑：PYRIND、METPYRIND 和一种新的未发表的衍生物 DIPYR 首次在活细胞中进行了测试。TOSIND 存在时 MCF7 的活力没有明显变化，但在 72 小时的 PYRIND 处理后活力下降（IC-50 为 39.7±5.8μM）。METPYRIND 存在时，活力也降低，而 DIPYR 在孵育 24 小时后增加 MCF7 的活力。TOSIND 强烈降低 MDA-MB-231 细胞的活力（IC-50 为 17.7±2.7μM 72 小时），PYRIND 和 METPYRIND 对其活力没有影响，而 DIPYR 增加 MDA-MB-231 细胞的活力并刺激其生长。PYRIND、METPYRIND 和 DIPYR 导致 MDA-MB-231 细胞中 caspase-3 和 caspase-7 的活性逐渐降低，而 TOSIND 对两种半胱天冬酶的活性没有影响。我们的结果为寻找其他具有侧挂吡唑残基的化合物开辟了道路，以提高其细胞毒性活性；特别是在乳腺癌的抗癌活性方面。我们合成的吡唑似乎以细胞特异性的方式降低细胞活力。这一观察结果可能有助于设计“非 DNA 结合”抗癌药物，即对健康细胞无害的化合物。
