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

Strahinja Kovačević; Milica Karadžić Banjac; Jasmina Anojčić; Sanja Podunavac-Kuzmanović; Lidija Jevrić; Andrea Nikolić; Marina Savić; Ivana Kuzminac

doi:10.1016/j.chroma.2022.463197

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

J Chromatogr A. 2022 Jun 21:1673:463197. doi: 10.1016/j.chroma.2022.463197. Epub 2022 Jun 3.

Authors

Strahinja Kovačević¹, Milica Karadžić Banjac², Jasmina Anojčić³, Sanja Podunavac-Kuzmanović¹, Lidija Jevrić¹, Andrea Nikolić³, Marina Savić³, Ivana Kuzminac³

Affiliations

¹ University of Novi Sad, Faculty of Technology Novi Sad, Department of Applied and Engineering Chemistry, Bulevar cara Lazara 1, 21000 Novi Sad, Serbia.
² University of Novi Sad, Faculty of Technology Novi Sad, Department of Applied and Engineering Chemistry, Bulevar cara Lazara 1, 21000 Novi Sad, Serbia. Electronic address: mkaradza@uns.ac.rs.
³ University of Novi Sad, Faculty of Sciences, Department of Chemistry, Biochemistry and Environmental Protection, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia.

PMID: 35688017
DOI: 10.1016/j.chroma.2022.463197

Abstract

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.

Keywords: Biologically active steroids; Chemometrics; Lipophilicity; Molecular modeling; Quantitative structure retention relationship analysis.

MeSH terms

Androstanes / pharmacology
Chemometrics*
Chromatography, High Pressure Liquid / methods
Chromatography, Reverse-Phase / methods
Quantitative Structure-Activity Relationship*
Steroids / chemistry

Substances

Androstanes
Steroids