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

• 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.

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.Figure optionsDownload as PowerPoint slide