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Diamondoid ammonium salts (DAS) are known guest molecules capable of realizing extremely tight binding within cucurbituril (CB[n]) hosts in aqueous environment, with binding constants reaching up to 1015 mol–1 dm3. [1] Inspired by these properties, we broadened the scope of our research concerning the binding between DAS and other hydrophobic cavities, i.e., cyclodextrins (CDs).[2] Herein we present binding capabilities of various DAS regioisomers and evaluate the effect of different nitrogen-based functionalities on complex stabilities with CDs. Stability constants were determined by ITC and 1H NMR titrations in aqueous solutions. Additionally, we used a diffusion NMR 1H DOSY method to estimate the percentage of complexation based on the calculated diffusion coefficients. The structural features of the complexes were assessed by the 1H- 1H NOESY NMR experiments, and computational studies revealed key interactions acting within the inclusion complexes

Two newly synthesized coumarin–palladium(II) complexes (C1 and C2) were characterized using elemental analysis, spectroscopy (IR and1H-13C NMR), and DFT methods at the B3LYP-D3BJ/6-311+G(d,p) level of theory. The in vitro and in silico cytotoxicity of coumarin ligands and their corresponding Pd(II) complexes was examined. For in vitro testing, five cell lines were selected, namely human cervical adenocarcinoma (HeLa), the melanoma cell line (FemX), epithelial lung carcinoma (A549), the somatic umbilical vein endothelial cell line (EA.hi926), and pancreatic ductal adenocarcinoma (Panc-1). In order to examine the in silico inhibitory potential and estimate inhibitory constants and binding energies, molecular docking studies were performed. The inhibitory activity of C1 and C2 was investigated towards epidermal growth factor receptor (EGFR), receptor tyrosine kinase (RTK), and B-cell lymphoma 2 (BCL-2). According to the results obtained from the molecular docking simulations, the inhibitory activity of the investigated complexes towards all the investigated proteins is equivalent or superior in comparison with current therapeutical options. Moreover, because of the low binding energies and the high correlation rate with experimentally obtained results, it was shown that, out of the three, the inhibition of RTK is the most probable mechanism of the cytotoxic activity of the investigated compounds.

To achieve the desired biological activity of synthetically produced peptides, several properties are important, such as peptide hydrophobicity, net charge, amphipathic nature, and secondary structure. [1] The secondary structure of ferrocene-derived peptidomimetics can be tuned by the number and type of constitutive amino acids, modification of their chirality, and bulkiness of C- and N-protecting groups, starting from the choice of ferrocene backbone: ferrocene amino acid (Fca) or symmetrically disubstituted ferrocene diacid (−OC−Fn−CO−) and diamine (−NH−Fn−NH−). Our study of ferrocene diamine derived peptides started with Y-Ala-NH-Fn-NH-Ala-Y (Ia, Y=Ac, Boc) and was extended by the preparation of their homologues Ac-AA-NH-Fn-NH-AA- Boc (Ib, AA=Val, Leu, Phe). [2-5] To find out how the side chain of amino acids affects the pattern of hydrogen bonding, we decided to replace an Ala residue with hydrophobic L- and D-amino acids (Leu, Val and Phe) to generate peptidomimetics II (Fig. 1). To investigate whether the dipeptides II adopt ordered conformations supported by IHBs in solution, we performed IR, NMR and CD spectroscopic studies.

The biological activity, conformational stability, and therapeutic application of peptides depend on their secondary structure. Therefore, the main goal in the design and preparation of synthetic peptides is to nucleate the formation of secondary structure elements. It has been shown that various ferrocene templates, when incorporated into peptides, induce the formation of hydrogen bonds, which allows the formation of turn- and -sheet- like structures [1, 2]. Here, we provide an overview of hydrogen-bonding patterns in ferrocene peptides based on detailed spectroscopic, DFT and crystallographic analyses.

Hydrazone derivatives of vitamin B6, pyridine-4- carbaldehyde and 2-quinolinecarbaldehyde (1-15) were synthesized. Phenyl-hydrazine and substituted phenyl-hydrazines were used for the synthesis: 2, 4-dinitrophenyl-hydrazine, 4- chlorophenyl- hydrazine, 4-fluorophenylhydrazine, 4- methylphenyl-hydrazine. The reactions were performed in two different solvents, acetone and ethanol, to examine the effect of solvent polarity and absorption power on the reaction yield. The structures of the synthesized compounds were confirmed by 1H and 13C NMR spectroscopy and mass spectrometry. The syntheses were carried out under the influence of microwave radiation, a more environmentally friendly method by which the desired product can be obtained in a much shorter time. The research investigates how microwave radiation, as one of the alternative synthesis methods, and the choice of solvent affect the chemical yields compared to conventional synthesis methods of hydrazone derivatives. The obtained results were compared with the research results of other authors who obtained similar or same hydrazones by classical organic synthesis. [1-3]

The temperature and solvent effect on the complexation of adamantane and diamantane alcohols by cyclodextrins (β-CD and γ-CD) in water, formamide, and ethylene glycol was investigated by means of ITC and NMR spectroscopy. The predominantly exothermic binding of all guests by β-CD in water was observed at 298 K, whereas the inclusion within γ-CD was entirely entropy-driven, with the exception of diamantan-1-ol. β-CD was a better receptor for explored guests, especially for adamantan-1-ol and apical diamantane alcohols. In the case of both receptors, the complex stability increased with the size of included hydrophobic surface. A pronounced decrease of ΔrH° and ΔrS° with temperature, resulting in weak ΔrG° (T) dependence, was observed for all studied systems. The effect is predominantly due to the disordering of the guest-hydrating water, which gradually shifts from classical to non-classical as the temperature increases. Unlike in water, the binding of alcohols with β-CD in organic solvents was exothermic and accompanied with negative entropy changes over the explored temperature range.

Diamondoid ammonium salts are an intriguing class of compounds capable of forming ultra-stable complexes with cucurbituril (CB[n]) hosts in aqueous environment.[1] The host–guest chemistry of diamantane derivatives with different hydrophobic cavities, i.e., cyclodextrins (CDs), has not been explored as much.[2] We have therefore embarked on a study of inclusion complexes consisting of cage ammonium salts and CDs.[3] Herein we present the synthesis of a new series of diamantane amine derivatives and showcase the results of their binding with β- and γ-CDs. We used a diffusion NMR 1H-1H DOSY method to estimate the percentage of complexation based on the calculated diffusion coefficients. The binding strength of complexation was revealed by 1H NMR titrations, and the structural features of the complexes were assessed by the 1H-1H NOESY NMR experiments. Equilibrium constants and other thermodynamic parameters were additionally confirmed by ITC whereas computational studies revealed key interactions within the inclusion complexes.

Cyclodextrins (CDs) are important host macrocycles in supramolecular chemistry that possess deep, centrally positioned cavity, a structural feature essential for accommodation of hydrophobic guest molecules via their non-polar parts. Because of their properties and bioavailability, CDs have found application in pharmacology, biotechnology, catalysis, nanotechnology, etc.[1] Adamantane derivatives are known guest molecules that fit well into a CD cavity.[1] However, permethylated ammonium salts of adamantane have not been explored so far with this respect. Note that this class of compounds shows excellent binding abilities for cucurbituril hosts (CBs).[2] Inspired by these properties, we decided to broaden the scope of research regarding the binding between 1-substituited adamantane ammonium salts and CDs.[3] As a continuation of our study, herein we evaluated the binding capability of other regioisomers and the effect of other nitrogen-based functionalities on the complex stabilities. Various NMR spectroscopic techniques and ITC measurements were employed to determine the stability constants and explore host-guest interactions. Computational methods were used to gain more insight into structural features of formed complexes.

Ferrocene peptides are often used as peptidomimetics because it is known that the conjugation of ferrocene core (Fcd, Fca, Fcda) and different amino acids leads to the formation of intramolecular hydrogen bonds that induce the formation of several elements of secondary structure. [1, 2] Addition of L- or D-leucine to antimicrobial peptide brevinin-1OS can affect improvement of antibacterial and anticancer activity to be ten times stronger than parent peptide. [3] To examine the influence of ferrocene synthone itself, the chirality of leucine (D- / L-) and the influence of protecting groups on the chiral arrangement and biological activity of prepared peptides, we decided to prepare homochiral and heterochiral ferrocene dipeptides Ac-L(D)-Leu-NH- Fn-NH-L(D)-Leu-Boc (1-4). The prepared dipeptides were examined by spectroscopic analysis (IR, NMR, and CD spectroscopy), followed by biological evaluation which included determination of antimicrobial activity (disk-diffusion method and nutrient broth dilution method with determination of MIC values) and determination of antioxidant activity (DPPH and FRAP methods).

Functionalized diamondoid ammonium salts are an intriguing class of compounds capable of forming ultra-stable complexes with cucurbituril hosts (CB[n]) in aqueous environment with binding constants up to 1015 mol–1 dm3.1 Inspired by these properties, we decided to broaden the research scope of inclusion complexes stabilized by hydrophobic interactions between various cage ammonium salt guests and cyclodextrin (CD) as a different macrocycle host molecule.2 Herein we present the synthesis of a continued series of diamondoid ammonium salts and a detailed thermodynamic study of their complexation with β- and γ-CDs. The complex stability constants were determined by ITC and 1H NMR titrations in aqueous solutions. Additional NMR spectroscopic techniques (1H-1H NOESY, 1H DOSY) along with computational methods were employed to provide a deeper insight into the thermodynamics of hydrophobically driven complexations and structural features of the formed supramolecules. The binding strength was assessed as a function of diamondoid salt size, functional group position and cyclodextrin cavity size and by varying these parameters, a structure- selectivity relationship can be determined in order to facilitate the design of next generation of suitable guests.

Adamantane and diamantane derivatives are used as guest molecules in supramolecular inclusion complexes due to their unique structure.Cucurbituril hosts (CBs) bind diamondoid ammonium salts very strongly, with binding constants up to 1015 mol–1dm3 . [1] The next step was to broaden the scope of the research to a new series of guest compounds as well as other host molecules like cyclodextrins (CDs). [2a] Namely, CDs are important host macromolecules in supramolecular chemistry with broad applications in pharmacology, biotechnology, catalysis, nanotechnology, etc. [2b] Herein we present the synthesis of a continued series of diamondoid ammonium salts, and a detailed thermodynamic study of their complexation with β- and γ-CDs. The complex stability constants were determined by ITC and 1H NMR titrations in aqueous solutions. Structures of the complexes and relevant interactions that occur between host and guest species were examined by 1H1H NOESY NMR experiments. The obtained results provided a deeper insight into the thermodynamics of hydrophobically driven complexation and structural characteristics of the corresponding supramolecules as well as a useful tool for the design a next generation of guest compounds.

In plant biochemistry and physiology, coumarins are known as antioxidants, enzyme inhibitors and precursors of toxic substances. Nuclear magnetic resonance (NMR) spectra are primary sources of molecular structural data. NMR provides detailed information about the local environment of the atom which can be used to determine the atomic connectivity, stereochemistry, and molecular conformation. For many years the molecular structure has been determined by NMR spectroscopy and chemical shifts are determined manually with the help of computer programs. However, recent progress in computational chemistry and chemo/bioinformatics opened the possibility for the prediction of chemical shifts (especially those of 1H and 13C nuclei) of new chemicals. We analyzed the accuracy of three available chemoinformatics methods developed for the prediction of 1H and 13C chemical shifts based on deep neural networks CASCADE [1], an older prediction method based on classical neural networks NMRshiftDB [2, 3], and group-contribution method in ChemDraw [4]. The mean absolute errors (MAEs) in the prediction of NMR shifts of four newly synthesized coumarins [5] by CASCADE, NMRshiftDB and ChemDraw are (respectively) 0.39, 0.65 and 0.32 ppm for 1H, and 1.5, 6.5 and 2.3 ppm for 13C atoms, shoving relatively big differences between these prediction methods.

Research on macrocyclic host molecules capable of encapsulating small guest molecules can inspire supramolecular architectures that mimic biological systems and can have useful technological applications.1 We have recently shown that functionalized diamondoid ammonium salts are suitable guests for cucurbituril (CB[n]) hosts in aqueous environment. Especially strong binding was found for the complex of 4, 9-diammonium diamantane derivative with CB[7], having an attomolar dissociation constant that rivals the interaction between avidin-biotin.2 As a continuation of our work, we explored complexation of diamondoid ammonium salts with β and γ cyclodextrins (CDs) in water (Figure 1). The key step in the synthesis of these permethylated diamondoid ammonium salts was selective functionalization of diamantane scaffold via nitroxylation and subsequent hydrolysis3 that was optimized in detail in the scope of this study. When assessing the binding strength, we considered the size of the diamondoid salts, substitution type and number of functional groups as well as the cyclodextrin cavity size. Equilibrium constants and other thermodynamic parameters for the complexation of diamondoid ammonium salts with CDs were determined by ITC, conductometric and/or 1H NMR titrations. Additional NMR spectroscopic techniques (1H-1H NOESY, 1H DOSY) were employed to elucidate specific interactions of guest encapsulated within host molecules, along with the corresponding computational analysis.

Conjugates of different ferrocene scaffolds and amino acids are recognized as peptidomimetics because they are able to adopt different elements of peptide secondary structure (turns, coils, sheets) based on intramolecular hydrogen bonding. [1-3] Peptide sequences rich in hydrophobic amino acids have desirable properties (high solubility, stability and bioavailability) that allow them to enhance the biological activity of the corresponding peptidomimetics. [4] To investigate the influence of the chirality of the hydrophobic amino acid and protecting groups (Ac or Boc) on the conformational properties and biological activity, we prepared ferrocene dipeptides Ac (Boc)L(D)AANHFnCOOMe (I) [Fn=ferrocenylene, AA= valine, leucine or phenylalanine, (Figure 1)] by the standard HOBt/EDC method. Dipeptides I are subjected to detailed spectroscopic analysis (IR, NMR and CD) in order to determine their conformational properties. Their preliminary biological evaluation is carried out by measuring the antimicrobial and antioxidant activity (DPPH and FRAP methods).

The amide conjugates of 1, n-disubstituted ferrocenes and amino acids are well known for their ability to adopt the turn or -sheet-like structures [1-5], owing to the turn-inducing capacity of ferrocene scaffolds. Amide-to-ester substitutions in the peptide backbone have proven to be a good tool for evaluating of backbone hydrogen-bonding behaviour of the so-derived depsipeptides [6-7]. Herein, we describe the synthesis of depsipeptide analogue of the previously reported ferrocene peptides [2, 4]. The influence of the amide-to-ester substitution on the conformational properties of the depsipeptide 1 is explored by IR, NMR and CD spectroscopy.