鉴于CDK在人类多种恶性肿瘤中已被证明过度表达，因此抑制CDK已被引证为一种有效的抗癌药物开发技术。在这个背景下，本文制备了具有潜在CDK4抑制效应的新型双吲哚/螺环三唑吲哚抗乳腺癌药物。这种新型双吲哚/螺环三唑吲哚系列化合物是通过双吲哚与苯胺衍生物的反应，然后随后通过 1,3-二极体环加成反应合成的。通过光谱分析证明了这些双吲哚/螺环三唑吲哚系列化合物的结构。大部分双吲哚和双螺环三唑吲哚化合物能有效抑制MCF-7（IC50 = 2.81-17.61 μM）和MDA-MB-231（IC50 = 3.23-7.98 μM）乳腺癌细胞系的生长，对正常WI-38细胞的抑制活性较低。而参考药物多柔比星（doxorubicin）在MCF-7和MDA-MB-231细胞系中的IC50值分别为7.43 μM和5.71 μM。此外，化合物3b、3c、6b和6d在抗CDK4活性方面表现出显著的活性（IC50 = 0.157-0.618 μM），与帕博西尼（palbociclib，IC50 = 0.071 μM）相比。随后的机制研究表明，化合物3c能够通过诱导凋亡诱导肿瘤细胞死亡。此外，它还能促使癌细胞在G1期停滞。此外，Western blotting显示，3c诱导的细胞周期停滞可能通过上调p21进行介导。根据所有的发现，双吲哚3c显示出作为针对CDK4的治疗癌症的前景。版权所有© Bentham Science Publishers；如有任何疑问，请发送电子邮件至epub@benthamscience.net。

Since CDKs have been demonstrated to be overexpressed in a wide spectrum of human malignancies, their inhibition has been cited as an effective technique for anticancer drug development.In this context, new bis-oxindole/spiro-triazole-oxindole anti-breast cancer drugs with potential CDK4 inhibitory effects were produced in this work. The novel series of bis-oxindole/spirotriazole- oxindole were synthesized from the reaction of bis-oxindole with the aniline derivatives then followed by 1,3-dipolar cycloaddition of hydrazonoyl chloride.The structure of these bis-oxindole/spiro-triazole-oxindole series was proven based on their spectral analyses. Most bis-oxindole and bis-spiro-triazole-oxindole compounds effectively inhibited the growth of MCF-7 (IC50 = 2.81-17.61 μM) and MDA-MB-231 (IC50 = 3.23-7.98 μM) breast cancer cell lines with low inhibitory activity against normal WI-38 cells. While the reference doxorubicin showed IC50 values of 7.43 μM against MCF-7 and 5.71 μM against the MDA-MB-231 cell line. Additionally, compounds 3b, 3c, 6b, and 6d revealed significant anti-CDK4 activity (IC50 = 0.157- 0.618 μM) compared to palbociclib (IC50 = 0.071 μM). Subsequent mechanistic investigations demonstrated that 3c was able to trigger tumor cell death through the induction of apoptosis. Moreover, it stimulated cancer cell cycle arrest in the G1 phase. Furthermore, western blotting disclosed that the 3c-induced cell cycle arrest may be mediated through p21 upregulation.According to all of the findings, bis-oxindole 3c shows promise as a cancer treatment targeting CDK4.Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.