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, φ0 ), and also, between logD7,4 and retention time was investigated. A very good correlation (r2 =0.8969) was found between lipophilicity parameters φ0 and logD7,4 obtained using UHPLC-MS and shake flask methods: logD7,4 = (0.11±0.01)×φ0 + (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.