A new model to determine lipophilicity of 1,2-ethanediamine-N,N'-di-2-(3-cyclohexyl)propanoic acid and 1,3-propanediamine-N,N'-di-2-(3-cyclohexyl)propanoic acid derivatives with antiproliferative activity by combining shake flask procedure and UHPLC-MS method.

Fourteen compounds representing ester derivatives of (S,S)-1,2-ethanediamine-N,N'-di-2-(3-cyclohexyl) propanoic and (S,S)-1,3-propanediamine-N,N'-di-2-(3-cyclohexyl)propanoic acids, expressing antiproliferative activity in vitro were examined. The objective of this study was to determinate their lipophilicity data, and also to ensure a mathematical model for prediction lipophilicity data of potential in vivo metabolites and new derivatives of (S,S)-1,2-ethanediamine-N,N'-di-2-(3-cyclohexyl)propanoic acid, based on chromatographic parameters. Experimentally, lipophilicity data were obtained by a traditional shake flask procedure and an ultra-high performance liquid chromatographic tandem mass spectrometry (UHPLC-MS) method. A correlation between the partition coefficient n-octanol/water (logD7,4) and chromatographic data (CHI, 0), and also, between logD7,4 and retention time was investigated. A very good correlation (r2=0.8969) was found between lipophilicity parameters 0 and logD7,4 obtained using UHPLC-MS and shake flask methods: logD7,4 = (0.11±0.01)×0 + (1.25±0.20)×Nc - (9.19±1.18); statistical parameter F=47.84; significance of F = 3.74×10-6, Nc=number of C atoms between two amino groups (Nc=2 for 1,2-ethanediamine derivatives and Nc=3 for 1,3-propanediamine derivatives). The model predictivity power was determined by cross validation leave one out (LOO) technique, and expressed by the term Q2, was 0.89. The developed model has good predictivity power for prediction lipophilicity data of potential in vivo metabolites of the investigated compounds, such as novel 1,2-ethanediamine and 1,3-propanediamine N,N'-di-2-(3-cyclohexyl)propanoic acid derivatives. Also, the lipophilicity data obtained in the present study correlated with the antiproliferative activity of the investigated substances shown previously in in vitro studies.