Prediction of in vivo Bioavailibility by in vitro Characterization of Ethylenediamine Dipropanoic Acid Derivatives with Cytotoxic Activity

Abstract

O, O'-diethyl-(S,S)-ethylenediamine-N,N'-di-2-(3-cyclohexyl)propanoate (DE-EDCP) is novel substance with cytotoxic activity in human leukemic cells. The aim of this study has been to predict in vivo bioavailability of the DE-EDCP and its potential metabolite (S,S)-ethylenediamine-N,N'-di-2-(3-cyclohexyl)propanoic acid (EDCP) by in vitro characterization which includes determination of lipophilicity and passive membrane permeability. There has also been evaluated inter-laboratory reproducibility of the bio-analytical method which was previously developed and validated for non-clinical study of the DE-EDCP and EDCP.Distribution coefficient n-octanol/water was 1.68 and 0.03, and apparent permeability coefficient was 4 × 10 -4 cm/s and 20 × 10 -4 cm/s, for the DE-EDCP and EDCP, respectively.Observed results have shown that the DE-EDCP is more lipophilic with better membrane retention, but the EDCP has better pass through the membrane. Also, there has been demonstrated a reproducibility and robustness of the proposed bio-analytical method.

Feedback Regulation of Cathepsin C by the Propeptide Dipeptides of Granzymes A and B

“…One possible explanation for this increased cytotoxicity would be polymerization of the released dipeptides by cathepsin C into membranolytic forms, as seen for Leu-Leu-OMe, 24 acting as substance with cytotoxic activity. 35 However, cathepsin C failed to polymerize any of the two N-terminal dipeptides of granzymes A and B (Figure 2).…”