Martin Havlík

In‐Flight Epimerization of a Bis‐Tröger Base

In 1887, Julius Tr ger reported the synthesis of a nitrogen base, whose structure was determined only about 50 years later. In “Tr ger bases”, nitrogen atoms serve as chiral centers because the otherwise rapid nitrogen inversion is prevented by conformational strain. After Prelog and Wieland separated the enantiomers, the chirality and the rigid V-shape of Tr ger bases led to widespread applications in chemistry. A fundamental question in the chemistry of Tr ger bases concerns the mechanism of their pseudoepimerization, for which either a proton-catalyzed ring opening or a retro-Diels–Alder (RDA) sequence has been proposed (Scheme 1).

One-pot reaction as an efficient method for rigid molecular tweezers.

Rigid molecular tweezers are compounds of increasing scientific interest. As the structural requirements for such compounds are highly specific, few types of these tweezers are thus far known. The preparation of examples of rigid large-pincered molecular tweezers based on bis Trogers bases derived from 1,4-benzenediamine is described. In addition, evidence is presented of the different binding abilities of the diastereoisomers of such compounds.

Synthesis and biological activity evaluation of hydrazone derivatives based on a Tröger’s base skeleton

We report the design and synthesis of novel anticancer agents based on bis-hydrazones separated by a rigid Trögers base skeleton. This novel approach combines a biologically active moiety (hydrazone) with this scaffold (Trögers base) to construct DNA intercalators. Evaluation of the anticancer activity of these agents using seven cancer cell lines and two healthy cell lines found that several derivatives had potent anticancer activity and excellent selectivity indexes toward cancer cells. The antimicrobial activities were tested on a set of thirteen bacterial stains, but the prepared compounds were not active. Complexation studies using biologically important metal ions demonstrated that these compounds are able to bind Cu(2+), Fe(3+), Co(2+), Ni(2+) and Zn(2+). DNA intercalation studies showed that the compounds themselves do not interact with DNA, but their metallocomplexes do interact, most likely via intercalation into DNA.

Caffeine-hydrazones as anticancer agents with pronounced selectivity toward T-lymphoblastic leukaemia cells.

We report design and synthesis of set of novel anticancer agents based on caffeine-hydrazones bearing 2-hydroxyaryl- or 2-N-heteroaryl moiety. Anticancer activity evaluation using seven cancer cell lines and two non-malignant cell lines demonstrated that several derivatives display significant anticancer activity and great selectivity index toward T-lymphoblastic leukaemia cells. In general, hydrazones bearing 2-N-heteroaryl moiety are more active and selective than those with 2-hydroxyaryl moiety. Tested compounds exhibit dose-dependent inhibition of both RNA and DNA synthesis, with some exceptions. Antimicrobial activities were tested on set of twelve bacterial and yeast strains, however prepared compounds were not active, suggesting for a molecular target specific for eukaryotic cells.

Synthesis of Highly Functionalized Fluorinated Porphyrins

Highly functionalized fluorinated porphyrins were synthesized by a convergent strategy. Nucleophilic substitution using fluorinated branched unit and 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin afforded highly functionalized fluorinated porphyrin 8 containing 24 fluorinated chains in the peripheral region.

Identification and interconversion of diastereomeric oligo-Tröger bases probed by ion mobility mass spectrometry

Oligo-Tröger bases are auspicious scaffolds of molecular engineering, which motivates studies on the mechanism of their interconversion and on the facile determination of the relative configuration of their diastereoisomers. Protonated, sodiated, and argentated species of those compounds were therefore studied via ion-mobility mass spectrometry (IM-MS), allowing differentiation on the basis of the shapes of the ions. First, the isomerization was confirmed to be acid-catalyzed as it takes place readily in the case of protonated Tröger bases, whereas the metallated bases are configurationally stable. Second, the corrected arrival times of the various isomers of the cationized bases were found to show distinct differences in IM-MS, and their excellent correlation with the cross sections obtained from quantum chemical calculations paves the way toward the easy identification of diastereoisomers.

Nonaqueous Capillary Electrophoretic Enantioseparation of Water Insoluble Tröger's Base Derivatives Using β-Cyclodextrin as Chiral Selector

Racemic mixtures of six Trögers base derivatives were separated by chiral nonaqueous capillary electrophoresis. The separation protocol was optimized first for suitable solvents. Then the applicability of various salts dissolved in organic solvents and their mixtures was evaluated. As chiral selectors β-cyclodextrin and heptakis(2,6-di-O-methyl)-β-cyclodextrin at various concentrations were used. The best enantioselectivity for the studied analytes was obtained utilizing formamide as organic nonaqueous solvent containing a mixture of sodium citrate and tris(hydroxymethyl)aminomethane acetate as electrolytes, and β-cyclodextrin as chiral additive. The experimental results demonstrated the feasibility of nonaqueous capillary electrophoresis for enantioseparation of Trögers base derivatives. This technique represents a suitable alternative to more commonly used capillary electrophoresis in aqueous environment.

Enantioseparation of Tröger's base derivatives by capillary electrophoresis using cyclodextrins as chiral selectors.

The enantioseparation of seven Trögers base derivatives (TBs) was carried out by capillary electrophoresis using α-, β-, and γ-cyclodextrins as chiral selectors and phosphate at 20 mmol/l concentration, pH 2.5, as background electrolyte. The method was optimized with respect to the concentration of chosen chiral selectors (0-50 mmol/l) and the amount of organic solvent (acetonitrile, 0-25 % (v/v)) in the electrolyte. The results indicate that all the studied variables, i.e., type of chiral selector, its concentration, and the amount of the added organic solvent, have a significant impact on the enantioseparation of the studied TBs. The best results for the majority of the separated TBs were obtained utilizing β-cyclodextrin at 5 mmol/l concentration and with various amounts of acetonitrile added ranging from 5 to 15% (v/v) in the background electrolyte. For the two smallest studied TBs, γ-cyclodextrin with 10% (v/v) acetonitrile also provided good resolution.

A new synthetic strategy to prepare throne and calix diastereoisomers of parallel tris-Tröger's bases

The calix diastereoisomers of the parallel tris-Trögers base (tris-TB) derivatives were suggested as potential cavitands in 2002, and the first members of this cavitand family were introduced in 2007. The synthetic strategy enabling the preparation of naphthalene and anthracene derivatives of parallel tris-TBs, i.e. preparation without any reduction step, is introduced. Naphthalene calix-tris-TB derivative having a cavity volume of about 0.113 nm3 (65% of α-CD cavity) is prepared by isomerisation in various acid conditions.

Sensitivity of Diamond-Capped Impedance Transducer to Tröger’s Base Derivative

Sensitivity of an intrinsic nanocrystalline diamond (NCD) layer to naphthalene Trögers base derivative decorated with pyrrole groups (TBPyr) was characterized by impedance spectroscopy. The transducer was made of Au interdigitated electrodes (IDE) with 50 μm spacing on alumina substrate which were capped with the NCD layer. The NCD-capped transducer with H-termination was able to electrically distinguish TBPyr molecules (the change of surface resistance within 30-60 kΩ) adsorbed from methanol in concentrations of 0.04 mg/mL to 40 mg/mL. An exponential decay of the surface resistance with time was observed and attributed to the readsorption of air moisture after methanol evaporation. After surface oxidation the NCD cap layer did not show any leakage due to NCD grain boundaries. We analyzed electronic transport in the transducer and propose a model for the sensing mechanism based on surface ion replacement.