Design and synthesis of novel soluble 2,5-diketopiperazine derivatives as potential anticancer agents

• Published in: European journal of medicinal chemistry 2014-08, Vol.83, p.236-244
• Main Authors: Liao, Shengrong, Qin, Xiaochu, Li, Ding, Tu, Zhengchao, Li, Jinsheng, Zhou, Xuefeng, Wang, Junfeng, Yang, Bin, Lin, Xiuping, Liu, Juan, Yang, Xianwen, Liu, Yonghong
• Format: Article
• Language: English
• Subjects: 2,5-Diketopiperazine derivative; Anticancer agent; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Cell Survival - drug effects; Chemistry Techniques, Synthetic; Diketopiperazines - chemical synthesis; Diketopiperazines - chemistry; Diketopiperazines - pharmacology; Drug Design; Humans; Inhibitory Concentration 50; Protective group; Solubility
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2014.06.030

Non-protected 2,5-diketopiperazine derivatives have poor solubility thus with negative impact on their bioavailability. In the present study, twenty-one novel soluble mono-protected, and three non-protected 2,5-diketopiperazine derivatives were designed and synthesized. Their anticancer activity to ten cell lines were evaluated by using CCK8 assay, and the results showed that about half of the mono-protected derivatives had broad-spectrum anticancer activity. Among allyl-protected derivatives, compound 4m had strong activity to all the cell lines (IC50 = 0.5–4.5 μM), especially to the cancer cell lines U937 (IC50 = 0.5 μM) and K562 (IC50 = 0.9 μM). Compound 4m could become a lead compound for further development for anticancer agents. Non-protected 2,5-diketopiperazine derivatives have had poor solubility thus with negative impact on their bioavailability. A novel series of soluble derivatives were synthesized and had strong and broad-spectrum anticancer activity. [Display omitted] •Solubility is a problem in some previous studies of diketopiperazine derivatives.•Novel soluble protected 2,5-diketopiperazine derivatives were synthesized.•Many soluble derivatives showed high and broad-spectrum anticancer activity.•Substituents, solubility, and protective groups had different effects on activity.•Allyl-protected compound 4m could be a lead compound as an anticancer agent.