Chemometrics of anisotropic lipophilicity of anticancer androstane derivatives determined by reversed-phase ultra high performance liquid chromatography with polar aprotic and protic modifiers

• Published in: Journal of Chromatography A Vol. 1673; p. 463197
• Main Authors: Kovačević, Strahinja, Karadžić Banjac, Milica, Anojčić, Jasmina, Podunavac-Kuzmanović, Sanja, Jevrić, Lidija, Nikolić, Andrea, Savić, Marina, Kuzminac, Ivana
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 21-06-2022
• Subjects: Biologically active steroids; Chemometrics; Lipophilicity; Molecular modeling; Quantitative structure retention relationship analysis; Quantitative structure retention relationship analysis; Biologically active steroids; Molecular modeling; Chemometrics; Lipophilicity
• ISSN: 0021-9673
• DOI: 10.1016/j.chroma.2022.463197

•RP-UHPLC analysis was done to define chromatographic lipophilicity of androstane derivatives.•Two ULR and ten MLR QSRR models were defined.•Comparison of experimental and in silico lipophilicity was carried out.
The research of the use of steroid compounds in the treatment of various types of cancer has a history of more than 50 years. Numerous steroid derivatives have expressed significant anticancer activity, however the thorough analysis of their physicochemical and toxicological properties is required prior to their clinical application. The present study is focused on the characterization of physicochemical properties of a series of previously synthesized new androstane derivatives (16E-hydroxyimino derivatives, D-homo lactones and D-seco dinitriles) with anticancer activity applying reversed-phase ultra high performance liquid chromatography (RP-UHPLC) system under isocratic conditions and chemometric tools, including in silico determination of their absorption, distribution, metabolism, excretion and toxicity (ADMET) properties. The chromatographic analysis was carried out applying two two-component and one ternary mobile phases with aprotic (acetonitrile) and protic (water and methanol) solvents. The conducted quantitative structure-retention relationship modeling resulted in two univariate and nine multivariate linear mathematical models that successfully correlate the retention parameters (logk) with descriptors of molecular polarity/lipophilicity (tPSA, REF, Average LogP, ClogP, ALOGP, LogS-SILICOS-IT, AClogS), descriptors that mainly depend on intermolecular interactions (BP, CP, CT, DE, HL) and ADMET descriptors (SWISSLogKpSP, GPCR, HIA, EI). The quality of the models was proved by the internal and external validation, while the robustness of the models was confirmed by Y-randomization test. Considering the established meaningful relationships between physicochemical/ADMET properties and retention parameters, the determined logk parameters of the analyzed series of steroid derivatives can be considered to be a biopharmaceutical property from the perspective of lipophilicity.