Ladislav Habala

{(1R,2R,4R)-4-Methyl-1,2-cyclohexanediamine}oxalatoplatinum(II): A Novel Enantiomerically Pure Oxaliplatin Derivative Showing Improved Anticancer Activity in Vivo

Novel derivatives of the clinically established anticancer drug oxaliplatin were synthesized. Cytotoxicity of the compounds was studied in six human cancer cell lines by means of the MTT assay. Additionally, most promising complexes were also investigated in cisplatin- and oxaliplatin-resistant human cancer cell models. The therapeutic efficacy in vivo was studied in the murine L1210 leukemia model. Most remarkably, {(1R,2R,4R)-4-methyl-1,2-cyclohexanediamine}oxalatoplatinum(II), comprising an equatorial methyl substituent at position 4 of the cyclohexane ring, was as potent as oxaliplatin in vitro but distinctly more effective in the L1210 model in vivo at the optimal dose. The advantage observed in the in vivo situation was mainly based on a more favorable therapeutic index. The maximum tolerated dose of the novel analogue was higher than that of oxaliplatin and caused a greater increase in life span (>200% versus 152%), with more animals experiencing long-term survival (5/6 versus 2/6). These data support further (pre)clinical development of the methyl-substituted oxaliplatin analogue with improved anticancer activity.

Complexes of N-hydroxyethyl-N-benzimidazolylmethylethylenediaminediacetic acid with group 12 metals and vanadium—Synthesis, structure and bioactivity of the vanadium complex

Four new complexes of group 12 metals [Zn(II), Cd(II) and Hg(II)], along with vanadyl bound to the ligand N-hydroxyethyl-N-benzimidazolylmethylethylenediaminediacetic acid, have been synthesized and characterized. The structure of the complexes with Zn(II), Hg(II) and V(IV) was determined by X-ray structural analysis. In all observed cases, the symmetry of these complexes was found to be distorted octahedral. The inhibition of protein tyrosine phosphatase 1B by the vanadium(IV) complex was demonstrated. The cytotoxicity of the vanadium(IV) complex was tested in vitro against three cancer cell lines, with a comparison of the activity of the free ligand and of vanadyl acetylacetonate and sodium orthovanadate. The IC50 values of the complex were in the range of 9 to 21μM. Remarkably, cytotoxic potency in the multidrug-resistant non-small cell lung cancer cell line A549 was at least as high as in the broadly chemosensitive ovarian teratocarcinoma cell line CH1(PA-1).

Antimicrobial Activity and Urease Inhibition of Schiff Bases Derived from Isoniazid and Fluorinated Benzaldehydes and of Their Copper(II) Complexes

In order to evaluate the influence of substitution on biological properties of Schiff bases and their metal complexes, a series of differently substituted fluorine-containing Schiff bases starting from the drug isoniazid (isonicotinylhydrazide) were prepared and their structures were established by single-crystal X-ray diffraction. Also, four copper(II) complexes of these Schiff bases were synthesized. The prepared compounds were evaluated for their antimicrobial activity and urease inhibition. Two of the Schiff bases exerted activity against C. albicans. All copper(II) complexes showed excellent inhibitory properties against jack bean urease, considerably better than that of the standard inhibitor acetohydroxamic acid.

DART – LTQ ORBITRAP as an expedient tool for the identification of synthetic cannabinoids

Synthetic cannabinoids as designer drugs constitute a major problem due to their rapid increase in number and the difficulties connected with their identification in complex mixtures. DART (Direct Analysis in Real Time) has emerged as an advantageous tool for the direct and rapid analysis of complex samples by mass spectrometry. Here we report on the identification of six synthetic cannabinoids originating from seized material in various matrices, employing the combination of ambient pressure ion source DART and hybrid ion trap - LTQ ORBITRAP mass spectrometer. This report also describes the sampling techniques for the provided herbal material containing the cannabinoids, either directly as plant parts or as an extract in methanol and their influence on the outcome of the analysis. The high resolution mass spectra supplied by the LTQ ORBITRAP instrument allowed for an unambiguous assignment of target compounds. The utilized instrumental coupling proved to be a convenient way for the identification of synthetic cannabinoids in real-world samples.

Synthesis and In Vitro Pharmacological Evaluation of 5-(Alkoxymethyl)-2-(3-alkylamino-2-hydroxypropoxy)phenylethanones Related to Acebutolol and Celiprolol

The structure–activity relationships of 13 analogs of aryloxyaminopropanol type derived from 2‐hydroxyphenylethanone as potential β‐blockers are described. The synthesized compounds possess an isopropyl or a tert‐butyl group in the hydrophilic part of the molecule and an alkoxymethyl substitution in the lipophilic moiety. The target compounds were prepared by an established four‐step method and their structures were confirmed by interpretation of their UV, IR, 1H NMR and 13C NMR spectra, and by elemental analysis. The β‐adrenolytic efficacy of the prepared racemic compounds was determined on isolated guinea pig atria (β1) and trachea (β2) and expressed as pA2 values against isoprenaline tachycardia. The assumed cardioselectivity was expressed as β1/β2 ratio and the values of compounds with an alkoxy group (CH3O, iC3H5O, C5H11O, CH2CHCH2O, CH3OCH2CH2O) in the lipophilic part and with tert‐butyl in the hydrophilic part of the molecule were found to be comparable or higher than those of the standards acebutolol and celiprolol. All evaluated substances at a concentration of 10−7 mol/dm3 showed also negative chronotropic effects.

Chromatographic separations based on tartaric acid and its derivatives

The enormous importance of chirality in chemistry, biology, and pharmacology is well established today. In particular, the often considerably different bioactivities of individual enantiomers of chiral drugs necessitate their separation and independent evaluation. Tartaric acid played an eminent role in the evolution of stereochemistry as well as in the development of enantioseparation techniques. This brief survey deals with the application of tartaric acid and its derivatives in various chromatographic separation methods, such as HPLC, GC, and TLC, with focus on the more recent literature. It is based on a contribution presented at the 46th EuroCongress on Drug Synthesis and Analysis, 2017 in Bratislava, Slovakia.Graphical abstract

REVIEW: metal complexes as urease inhibitors

Abstract Urease plays a significant role in the pathogenesis of several diseases and also has practical implications in other fields, such as agriculture or chemical analysis. Among the multitude of chemical species known to inhibit urease, metal complexes stand out as a special category due to their specific mechanism of action, distinct from purely organic substances. Their inhibitory activity seems to depend on the type of metal and its oxidation state as well as on the coordination environment of the central atom. Furthermore, the study of the interaction between metal ions and their complexes with urease renders valuable insights into detailed catalytic mechanisms of this enzyme. This brief survey attempts to provide an overview of the published research on urease inhibition by metal complexes.