设计、合成新型双噻唑衍生物作为优先的Pim1激酶抑制剂,并进行体内外和计算机模拟的细胞毒性评估。
Design, synthesis and cytotoxic evaluation of novel bis-thiazole derivatives as preferential Pim1 kinase inhibitors with in vivo and in silico study.
发表日期:2023 Dec
作者:
Mohammad M Al-Sanea, Tamer M Nasr, Samir Bondock, Aya Y Gawish, Nada M Mohamed
来源:
J Enzym Inhib Med Ch
摘要:
Bis-噻唑衍生物是依据Hantzsch缩合反应符合Pim1药效模型而合成的。Pim1在调节G1/S期中发挥主要作用,而其抑制会使细胞周期在早期阶段停止。与staurosporine的IC50 0.36µM相比,衍生物3b和8b显示出最好的Pim1 IC50分别为0.32和0.24µM。通过阻止T47D细胞周期处于G0/G1和S期来进一步确认3b和8b对Pim1的抑制作用,其中3b显示出66.5%的细胞积累在G0/G1期,而8b相对于控制组的53.9%和14.9%,则表现出26.5%的细胞在S期积累。对3b和8b的额外体内细胞毒性评估表明,它们具有强大的抗肿瘤活性,并且在8b的情况下上调了caspase-3和下调了VEGF和TNF α免疫表达,并伴随着丙二醛水平的升高。
Bis-thiazole derivatives were synthesised conforming to the Pim1 pharmacophore model following Hantzsch condensation. Pim1 has a major role in regulating the G1/S phase which upon inhibition the cell cycle stops at its early stages. Derivatives 3b and 8b showed the best Pim1 IC50 0.32 and 0.24 µM, respectively relative to staurosporine IC50 0.36 µM. Further confirmation of 3b and 8b Pim1 inhibition was implemented by hindering the T47D cell cycle at G0/G1 and S phases where 3b showed 66.5% cells accumulation at G0/G1 phase while 8b demonstrated 26.5% cells accumulation at the S phase compared to 53.9% and 14.9% of a control group for both phases, respectively. Additional in vivo cytotoxic evaluation of 3b and 8b revealed strong antitumor activity with up-regulation of caspase-3 and down-regulation of VEGF and TNF α immune expression with concomitant elevation of malondialdehyde levels in case of 8b.