University of Novi Sad, Faculty of Technology Novi Sad, Department of Applied and Engineering Chemistry, Bulevar cara Lazara 1, 21000 Novi Sad, Serbia.
University of Novi Sad, Faculty of Technology Novi Sad, Department of Applied and Engineering Chemistry, Bulevar cara Lazara 1, 21000 Novi Sad, Serbia.
J Chromatogr A. 2022 Jun 21;1673:463197. doi: 10.1016/j.chroma.2022.463197. Epub 2022 Jun 3.
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.
甾族化合物在治疗各种类型癌症中的应用研究已有 50 多年的历史。许多甾族化合物衍生物表现出显著的抗癌活性，但在将其应用于临床之前，需要对其理化性质和毒理学性质进行全面分析。本研究主要集中在应用反相超高效液相色谱（RP-UHPLC）系统在等度条件下和化学计量学工具对一系列先前合成的具有抗癌活性的新型雄烷衍生物（16E-羟亚氨基衍生物、D-同型内酯和 D-去甲二腈）的理化性质进行表征，包括通过计算机模拟测定其吸收、分布、代谢、排泄和毒性（ADMET）性质。采用两种两元溶剂和一种三元溶剂的流动相进行色谱分析，其中包括质子性（水和甲醇）和非质子性（乙腈）溶剂。进行的定量构效关系建模得到了两个单变量和九个多变量线性数学模型，成功地将保留参数（logk）与分子极性/亲脂性描述符（tPSA、REF、平均 LogP、ClogP、ALOGP、LogS-SILICOS-IT、AClogS）、主要依赖于分子间相互作用的描述符（BP、CP、CT、DE、HL）和 ADMET 描述符（SWISSLogKpSP、GPCR、HIA、EI）相关联。通过内部和外部验证证明了模型的质量，通过 Y 随机化检验证明了模型的稳健性。考虑到理化性质/ADMET 性质和保留参数之间建立的有意义关系，可以认为所分析的甾体衍生物系列的确定的 logk 参数从亲脂性的角度来看是一种生物制药性质。
