Synthesis, screening and nanocrystals preparation of rhein amide derivatives

Abstract

Rhein (RH) has many bioactivities, but the application was limited of its poor solubility. The present study aimed to establish an efficient method for the synthesis of rhein amide derivatives (RAD) to increase the solubility and anti-tumour activity. RAD exhibited stronger anti-tumour activity than RH in MTT assay. The solubility and oil/water partition coefficient results indicated that rhein-phenylalanine and rhein-isoleucine have better absorption effect, which was consolidated in pharmacokinetic study. Then, rhein-phenylalanine and rhein-isoleucine were prepared into nanocrystals via the precipitation high-pressure homogenisation method. Additionally, the nanocrystals both displayed much higher dissolution profiles than the bulk drugs. Pharmacokinetics study indicated that the AUC_0–∞ and C_max of nanocrystals increased markedly (p < 0.01). However, the concentration of RH-Phe-NC was far less than RH-Ile-NC in plasma. Consequently, RH-Ile-NC was validated to be an applicable way to improve the bioavailability of RH, which owns a promising future in clinical application.

Keywords:

• Rhein
• rhein amide derivatives (RAD)
• bioavailability
• nanocrystals
• pharmacokinetics

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by Innovation Team Project [no. LT2015011] and Innovation Talents Project [no. LR2017065] from the Education Department of Liaoning Province, the Liaoning Provincial Education Department Project of China [no. L2015192], and the Shenyang Science and Technology Program of China [no. F16–205-1–44].