Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt.
Department of Chemistry, Faculty of Applied Science, Umm Al-Qura University, Makkah 24230, Saudi Arabia.
Med Chem. 2024;20(1):63-77. doi: 10.2174/1573406419666230810124855.
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 (IC = 2.81-17.61 μM) and MDA-MB-231 (IC = 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 (IC = 0.157- 0.618 μM) compared to palbociclib (IC = 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.
由于 CDKs 在广泛的人类恶性肿瘤中被证明过度表达，因此抑制 CDK 已被引用为开发抗癌药物的有效技术。
在这种情况下，本工作中产生了具有潜在 CDK4 抑制作用的新型双-氧吲哚/螺-三唑-氧吲哚抗乳腺癌药物。新的双-氧吲哚/螺-三唑-氧吲哚系列是由双-氧吲哚与苯胺衍生物反应，然后通过腙酰氯的 1,3-偶极环加成合成的。
这些双-氧吲哚/螺-三唑-氧吲哚系列的结构基于它们的光谱分析得到证实。大多数双-氧吲哚和双-螺-三唑-氧吲哚化合物有效地抑制 MCF-7（IC = 2.81-17.61 μM）和 MDA-MB-231（IC = 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。而参考阿霉素对 MCF-7 的 IC50 值为 7.43 μM，对 MDA-MB-231 细胞系的 IC50 值为 5.71 μM。此外，与 palbociclib（IC = 0.071 μM）相比，化合物 3b、3c、6b 和 6d 显示出显著的抗 CDK4 活性（IC = 0.157-0.618 μM）。随后的机制研究表明，3c 通过诱导细胞凋亡来触发肿瘤细胞死亡。此外，它还能刺激癌细胞在 G1 期停滞。此外，Western blot 揭示，3c 诱导的细胞周期停滞可能是通过 p21 的上调介导的。
根据所有的发现，双-氧吲哚 3c 有望成为针对 CDK4 的癌症治疗药物。
