Prodrugs derived from triterpenoids with cytotoxic activity.

Introduction

The current trend of cancer pharmacotherapy is targeted approach and possibly with a minimised toxicity. One way how to prevent adverse effects is a drug application in the form of a pro-drug which can lead to limited systemic toxicity and improved activity because of the drug activation directly in tumour tissue. Betulinic acid is a well-known representative of triterpenes, which posses a moderate cytotoxic activity and high selectivity towards the tumor cells. However, its pharmacological properties, particularly solubility and bioavailability, are poor. Therefore, we are continuously working to develop active derivatives with improved bioavailability and high therapeutic index. In our recent work we have focused on the promising approach to convert the betulinic acid derivatives to pro-drugs.

Materials/methods

About 40 synthetic pro-drugs of biologically active betulinic acid derivatives were prepared and biological activities in vitro were analysed. We have developed methods for activation of „prodrug“ derivatives of betulinic acid by primary rat hepatocytes. Cytotoxicity of pro-drugs and activated metabolites on tumor cell line CCRF-CEM (human lymphoblastic leukemia) was measured.

Results and conclusions

We have observed that metabolized derivatives compared to the intact parental substance are showing significantly higher cytotoxic activity. Our concept and predicted mechanism of pro-drug activation was analysed and verified by HPLC-MS/MS. For most active derivatives we have tested ADME parameters and pharmacokinetics. Based on the data we are designing pharmacodynamic experiments under in vivo conditions.

This work was supported by grants LF_2015_031 and by the National Sustainability Programme (LO1304).