Modeling Cellular Pharmacokinetics of 14- and 15-Membered Macrolides with Physicochemical Properties

Stepanić, Višnja; Koštrun, Sanja; Malnar, Ivica; Hlevnjak, Mario; Butković, Kristina; Ćaleta, Irena; Dukši, Marko; Kragol, Goran; Makaruha-Stegić, Oresta; Mikac, Lara; Ralić, Jovica; Tatić, Iva; Tavčar, Branka; Valkó, Klára; Zulfikari, Selvira; Munić, Vesna

doi:10.1021/jm101317f

Cited by 43 publications

(40 citation statements)

References 48 publications

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“…[22,33] Furthermore, it was previously shown that positively charged terminal groups are responsible for accumulation into cells. [34,35] Here presented pairs of acyclic and cyclic amidine derivatives have shown almost identical activities against all examined bacterial species. The lipophilic character of compounds has been found to be important parameter for the observed activity of the tested benzoimidazole derivatives against Moraxella catarrhalis.…”

Section: In Silico Analysis Antibacterial Activity and Structure Actmentioning

confidence: 82%

Synthesis and SAR Study of Novel Amidino 2-substituted Benzimidazoles as Potential Antibacterial Agents

Perin¹,

Starčević²,

Perić³

et al. 2017

Croat. Chem. Acta

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A series of novel 2-substituted benzimidazole derivatives were synthesized and their antibacterial activity was assessed against selected Gram-positive and Gram-negative bacteria. The specific moiety at the 2-position of the benzimidazole was extensively modified with several fused heterocyclic functional groups containing nitrogen and sulfur heteroatoms. In addition, the influence of different amidino groups at the position 5 of benzimidazole scaffold was evaluated. The values of clogP (a partition coefficient) and clogD7.5 (calculated distribution coefficient, pH 7.5) were determined and the lipophilic character of compounds has been found to be important parameter for the observed activity of the tested benzimidazole derivatives against Moraxella catarrhalis. The indolo 2-substituted benzimidazole 13a demonstrated solid activity against Staphylococcus aureus (MICs 16 µg/mL) and Moraxella catarralis (MICs 2 µg/mL) and represents promising lead molecule for further optimization.

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Section: In Silico Analysis Antibacterial Activity and Structure Actmentioning

confidence: 82%

Synthesis and SAR Study of Novel Amidino 2-substituted Benzimidazoles as Potential Antibacterial Agents

Perin¹,

Starčević²,

Perić³

et al. 2017

Croat. Chem. Acta

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“…Azithromycinaglycon (AZAG) and telithromycin (TEL) were a kind gift from Fidelta, and 33 macrocyclic compounds, derivatives of azithromycin and clarthromycin were a kind gift from GlaxoSmithKline. Test macrocycles are numbered according to the previous publication, 18 where all structures and synthesis procedures were reported.…”

Section: Test Compoundsmentioning

confidence: 99%

“…In our previous work, we have used different physicochemical and 3D structural approaches to expand the chemical space of predictable structures to the area of macrocycles. 17,18 The models are mainly aimed for preselection of the compounds for the measurement of intracellular accumulation, rather than as a replacement for it.…”

Section: Introductionmentioning

confidence: 99%

“…In this project, we aimed to see whether any of the effects on cellular processes reported for some of the lysosomotropic compounds could be used in a quantitative manner to determine the intracellular accumulation and retention of these compounds in cells. We used a unique set of 47 compounds 17,18 consisting of 39 macrocycles, together with 8 nonmacrocyclic compounds, specifically designed to cover the entire feasible range of cellular accumulation intensities, as reported for pharmaceuticals so far ( Fig.1). By using the data on their intracellular accumulation and retention measured by liquid chromatography with tandem mass spectrometry (LC-MS/MS), we aimed to evaluate how well these PK parameters can be predicted from the biological endpoints related to the changes in the lysosomes.…”

Section: Introductionmentioning

confidence: 99%

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Quantification of Intracellular Accumulation and Retention of Lysosomotropic Macrocyclic Compounds by High-Throughput Imaging of Lysosomal Changes

Easwaranathan

Inci

Ulrich

et al. 2019

Journal of Pharmaceutical Sciences

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Many marketed pharmaceuticals reach extremely high tissue concentrations due to accumulation in lysosomes (lysosomotropism). Quantitative prediction of intracellular concentrations of accumulating drugs is challenging, especially for macrocyclic compounds that mainly do not fit in current in silico models. We tested a unique library of 47 compounds (containing 39 macrocycles) specifically designed to cover the entire range of accumulation intensities observed with pharmaceuticals so far. For the first time, we show that intracellular concentration of compounds measured by liquid chromatography with tandem mass spectrometry correlates with the induction of phospholipidosis and inhibition of autophagy, but the highest correlation was observed with the increase of lysosomal volume (R ¼ 0.95), all measured by high-throughput imaging assays. Based only on imaging data, we developed a 5-class in vitro model for the prediction of compound accumulation with the accuracy of 81%. The measured change of total lysosomal volume can thus be used in high-throughput screening for determination of the actual intensity of intracellular accumulation of new macrocyclic compounds. The models are largely based on macrocycles, greatly improving the screening and prediction of intracellular accumulation of this challenging class. However, all tested nonmacrocyclic compounds fitted well in the models, indicating potential use of the models in broader chemical space.

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“…We showed previously on a different set of compounds that uptake into cells is mainly governed by lipophilicity and basicity of compounds. [31] Statistical models for the 3D cells are in general somewhat less accurate with similar descriptor contribution. Weaker ability to distinguish between active and non-active compounds indicates some additional underlying features that also play important role in antiproliferative activity on the 3D cell, but were not used in .…”

Section: Influence Of Physico-chemical Properties On Anti-proliferatimentioning

confidence: 99%

Comparison of Antitumor Activity of Some Benzothiophene and Thienothiophene Carboxanilides and Quinolones in 2D and 3D Cell Culture System

et al. 2017

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One of the main reasons for the high drug attrition rate in oncology is the poor clinical predictive power of 2D cancer cell lines cultures in vitro which are the standard assay used as screening assay to select new chemical entities (NKE) with potent anticancer activity. Therefore, there is increasing interest in developing 3D in vitro cell culture systems, as a primary screening assays which would represent a biologically more relevant assay system, due to similarity to physiological conditions in which tumors growth in living organism. Very important is to develop reproducible 3D cell line culture in vitro assays, feasible for the primary screening of NKEs platforms. Within this manuscript we have tested small platform of selected benzo [b]thieno, thieno [2,3-b]thiophene, and thieno[3,2-b]thiophene 2-carboxanilides, as well as their cyclic derivatives [2,3-c]quinolones, which already showed anti-proliferative activity on other cancer cell lines in 2D system. Platform was tested in 2D and 3D cancer cell culture assays on three human breast cancer cell lines (SK-BR-3, MDA-MB-231, T-47D). Those cell lines were selected on the basis of ability to growth and form cell spheres and also on different sensitivity to chemotherapeutic agents. We used doxorubicin as control compound due similar mode of action, (specific intercalation with the DNA double helix), as tested compound probably have.Obtained results in some cases showed significant disagreement, indicating that in early screening selection of active compounds only on 2D activity basis we could pick up false positive compounds (active only on 2D cell culture lines and not on 3D cell lines for which it is clamed that are more similar to real physiological conditions for tumor growth). One possibility for obtained discrepancy of results obtained on 2D and 3D cell cultures could be physico-chemical properties of compounds. Therefore, we analyzed some physico-chemical properties of active compounds as chrom logD values and calculated structural parameters: number of hydrogen bond donors and acceptors, calculated logP and logD values, molecular weight, ionization constants (pKa), number of aromatic rings, number of rotatable bonds and polar surface area. Association of physico-chemical descriptors with observed anti-proliferative activity has been investigated. Basicity, molecular weight and number of H-bond donors are found to be main factors contributing to the anti-proliferative effect of investigated compounds for both 2D and 3D cell cultures.

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Modeling Cellular Pharmacokinetics of 14- and 15-Membered Macrolides with Physicochemical Properties

Cited by 43 publications

References 48 publications

Synthesis and SAR Study of Novel Amidino 2-substituted Benzimidazoles as Potential Antibacterial Agents

Synthesis and SAR Study of Novel Amidino 2-substituted Benzimidazoles as Potential Antibacterial Agents

Quantification of Intracellular Accumulation and Retention of Lysosomotropic Macrocyclic Compounds by High-Throughput Imaging of Lysosomal Changes

Comparison of Antitumor Activity of Some Benzothiophene and Thienothiophene Carboxanilides and Quinolones in 2D and 3D Cell Culture System

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