Predicting Pharmacokinetic Properties of Potential Anticancer Agents via Their Chromatographic Behavior on Different Reversed Phase Materials

Abstract

The Quantitative Structure-Activity Relationship (QSAR) methodology was used to predict biological properties, i.e., the blood–brain distribution (log BB), fraction unbounded in the brain (fu,brain), water-skin permeation (log Kp), binding to human plasma proteins (log Ka,HSA), and intestinal permeability (Caco-2), for three classes of fused azaisocytosine-containing congeners that were considered and tested as promising drug candidates. The compounds were characterized by lipophilic, structural, and electronic descriptors, i.e., chromatographic retention, topological polar surface area, polarizability, and molecular weight. Different reversed-phase liquid chromatography techniques were used to determine the chromatographic lipophilicity of the compounds that were tested, i.e., micellar liquid chromatography (MLC) with the ODS-2 column and polyoxyethylene lauryl ether (Brij 35) as the effluent component, an immobilized artificial membrane (IAM) chromatography with phosphatidylcholine column (IAM.PC.DD2) and chromatography with end-capped octadecylsilyl (ODS) column using aqueous solutions of acetonitrile as the mobile phases. Using multiple linear regression, we derived the statistically significant quantitative structure-activity relationships. All these QSAR equations were validated and were found to be very good. The investigations highlight the significance and possibilities of liquid chromatographic techniques with three different reversed-phase materials and QSARs methods in predicting the pharmacokinetic properties of our important organic compounds and reducing unethical animal testing.

Anti-Tumor Active Isopropylated Fused Azaisocytosine-Containing Congeners Are Safe for Developing Danio rerio as Well as Red Blood Cells and Activate Apoptotic Caspases in Human Breast Carcinoma Cells

“…In general, the higher the drug score, the higher the probability that the compound will be a drug in the future [28]. All the investigated isopropylated congeners (I-VI) revealed favorable physico-chemical and pharmacokinetic properties and they were devoid of undesired side effects, such as mutagenicity, tumorigenicity, irritating and reproductive effects, as previously reported [2]. It was found that a drug score for compound VI was almost the same as that of pemetrexed.…”

“…Due to the remarkable in vitro antiproliferative effect against human tumors of the breast, cervix and lung-even stronger than that of an anticancer agent pemetrexed-and a lower toxicity to normal cells, the title compounds are of particular pharmacological importance. In addition, most of these isopropylated congeners show the protective effect on oxidatively-stressed erythrocytes, better or comparable to that of ascorbic acid and Trolox, and they are characterized by lipophilicity indices ensuring the optimal absorption and effective permeability in body compartments [1,2]. It is hoped that the most selective molecules of this class will find application in cancer chemotherapy in the future.…”

“…It is hoped that the most selective molecules of this class will find application in cancer chemotherapy in the future. Taking into account the significant pharmacological activities, selectivity as well as favorable pharmacokinetic and physico-chemical properties of novel isopropylated fused azaisocytosine-containing congeners-recently patented [3] and published [1,2]-further studies on these compounds were fully justified. As the development of highly safe drugs is desirable, each newly synthesized potential drug candidate should be carefully assessed for its toxicity/safety in an animal model already at an early stage of its preclinical development, before entering the clinical trials [4][5][6].…”

Assessment of Lipophilicity Parameters of Antimicrobial and Immunosuppressive Compounds

“…Among other separation techniques, micellar liquid chromatography (MLC) or micellar electrokinetic chromatography (MEEKC), respectively, in which the mobile phase comprises surfactants that allow better mapping of penetration of molecules through biomembranes can be also be used for lipophilicity determination [ 7 ]. The literature review shows that numerous publications have dealt with the subject of determining the lipophilicity of various bioactive compounds using chromatographic methods [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ].…”

Experimental Studies on the Thermal Properties and Decomposition Course of a Novel Class of Heterocyclic Anticancer Drug Candidates

“…The anticancer active annelated asymmetrical triazines ( 1 – 5 , Figure 1 ), that have been synthesized in our laboratory, belong to antimetabolite-type molecules that may be irreversible inactivators of specific enzymes [ 1 ]. The molecular structures of these innovative heterocycles have previously been established, whereas their experimental lipophilicities (derived from the retention behavior in reversed-phase high-performance liquid chromatography on different columns, including those imitating biosystems), structural and electronic descriptors have been correlated strongly with important pharmacokinetic descriptors, resulting in highly predictive QSAR relationships suggesting their high bioavailability [ 1 , 2 ]. A three-dimensional (3D) structure of compound 2 has recently been established by X-ray crystallography.…”