Cascade Transformation of the Ansamycin Benzoquinone Core into Benzoxazole Influencing Anticancer Activity and Selectivity.

The metal-free cascade transformation of geldanamycin benzoquinone core is proposed at relatively mild conditions. This approach yields new benzoxazole ansamycin antibiotics and enables their functionalization in an atom-economic manner, irrespective of the type of amine used. The analysis of the heterocyclization course reveals the dependence of its rate on the nature of the para-substituent within the benzylamine moiety (EDG/EWG) and the strength of the base. The reduction of the ansamycin core enables an increase in anticancer potency and selectivity.

Chiral Pyrrolidinium Ionic Liquids with (-)-Borneol Fragment in the Cation - Synthesis, Physicochemical Properties and Application in Diels-Alder Reaction.

A series of chiral pyrrolidinium salts containing (1 S)-endo-(-)-born-2-yloxymethyl substituent in the structure of the cation and six different anions: chloride, tetrafluoroborate [BF4 ]- , hexafluorophosphate [PF6 ]- , trifluoromethanesulfonate [OTf]- , bis(trifluoromethylsulfonyl)imide [NTf2 ]- , bis(pentafluoroethylsulfonyl)imide [NPf2 ]- and perfluorobutanesulfonate [C4 FS]- were efficiently prepared and extensively characterized. The enantiomeric purity of them was confirmed by NMR analysis with a chemical shift reagent. All salts were characterized with the specific rotation, the solubility in commonly used solvents, thermal properties, including phase transition temperatures and thermal stability. Salts with [PF6 ]- , [C4 FS]- , [NTf2 ]- and [NPf2 ]- anions were classified as chiral ionic liquids (CILs). Moreover, salts with [NTf2 ]- and [NPf2 ]- anions were in the liquid state at room temperature and below. Therefore, density and dynamic viscosity, the surface tension and the contact angle on three different surfaces were also measured for them. Additionally, these chiral ionic liquids were tested as solvents in Diels-Alder reaction.

Structural, Thermal, and Vibrational Properties of N,N-Dimethylglycine-Chloranilic Acid-A New Co-Crystal Based on an Aliphatic Amino Acid.

The new complex of N,N-Dimethylglycine (DMG) with chloranilic acid (CLA) was synthesized and examined for thermal, structural, and dynamical properties. The structure of the reaction product between DMG and CLA was investigated in a deuterated dimethyl sulfoxide (DMSO-d6) solution and in the solid state by Nuclear Magnetic Resonance (NMR) (Cross Polarization Magic Angle Spinning-CPMAS NMR). The formation of the 1:1 complex of CLA and DMG in the DMSO solution was also confirmed by diffusion measurement. X-ray single crystal diffraction results revealed that the N,N-dimethylglycine-chloranilic acid (DMG+-CLA-) complex crystallizes in the centrosymmetric triclinic P-1 space group. The X-ray diffraction and NMR spectroscopy show the presence of the protonated form of N,N-dimethylglycine and the deprotonated form of chloranilic acid molecules. The vibrational properties of the co-crystal were investigated by the use of neutron (INS), infrared (IR), and Raman (RS) spectroscopies, as well as the density functional theory (DFT) with periodic boundary conditions. From the band shape analysis of the N-CH3 bending vibration, we can conclude that the CH3 groups perform fast (τR ≈ 10-11 to 10‒13 s) reorientational motions down to a temperature of 140 K, with activation energy at ca. 6.7 kJ mol-1. X-ray diffraction and IR investigations confirm the presence of a strong N+-H···O- hydrogen bond in the studied co-crystal.

Specific Interactions between Rifamycin Antibiotics and Water Influencing Ability To Overcome Natural Cell Barriers and the Range of Antibacterial Potency.

Rifamycins are a group of macrocyclic antibiotics mainly used for the treatment of various bacterial infections including tuberculosis. Spectroscopic studies of rifamycins evidence the formation of temperature- and solvent-dependent equilibria between A-, B-, and C-type conformers in solutions. The B- and C-type conformers of rifamycin antibiotics are exclusively formed in the presence of water molecules. A- and B-type conformers exhibit a hydrophilic and "open" ansa-bridge nature whereas the C-type conformer is more lipophilic due to the presence of a "closed" ansa-bridge structure. The involvement of the lactam moiety of the ansa-bridge in intramolecular H-bonds within rifapentine and rifampicin implicates the formation of a more hydrophilic A-type conformer. In contrast to rifampicin and rifapentine, for rifabutin and rifaximin, the "free" lactam group enhances conformational flexibility of the ansa-bridge, thereby enabling interconversion between A- and C-type conformers. In turn, an equilibrium between A- and C-type conformers for rifamycins improves their adaptation to the changing nature of bacteria cell membranes, especially those of Gram-negative strains and/or to efflux pump systems.

Covalently Linked Bis(Amido-Corroles): Inter- and Intramolecular Hydrogen-Bond-Driven Supramolecular Assembly.

Four bis-corroles linked by diamide bridges were synthesized through peptide-type coupling of a trans-A2 B-corrole acid with aliphatic and aromatic diamines. In the solid state, the hydrogen-bond pattern in these bis-corroles is strongly affected by the type of solvent used in the crystallization process. Although intramolecular hydrogen bonds play a decisive role, they are supported by intermolecular hydrogen bonds and weak N-H⋅⋅⋅π interactions between molecules of toluene and the corrole cores. In an analogy to mono(amido-corroles), both in crystalline state and in solutions, the aliphatic or aromatic bridge is located directly above the corrole ring. When either ethylenediamine or 2,3-diaminonaphthalene are used as linkers, incorporation of polar solvents into the crystalline lattice causes a roughly parallel orientation of the corrole rings. At the same time, both NHCO⋅⋅⋅NH corrole hydrogen bonds are intramolecular. In contrast, solvation in toluene causes a distortion with one of the hydrogen bonds being intermolecular. Interestingly, intramolecular hydrogen bonds are always formed between the -NHCO- functionality located further from the benzene ring present at the position 10-meso. In solution, the hydrogen-bonds pattern of the bis(amido-corroles) is strongly affected by the type of the solvent. Compared with toluene (strongly high-field shifted signals), DMSO and pyridine disrupt self-assembly, whereas hexafluoroisopropanol strengthens intramolecular hydrogen bonds.

Spectroscopic studies of the intramolecular hydrogen bonding in o-hydroxy Schiff bases, derived from diaminomaleonitrile, and their deprotonation reaction products.

The structural study of five Schiff bases derived from diaminomaleonitrile (DAMN) and 2-hydroxy carbonyl compounds was performed using 1H, 13C and 15N NMR methods in solution and in the solid state as well. ATR-FTIR and X-Ray spectroscopies were used for confirmation of the results obtained by NMR method. The imine obtained from DAMN and benzaldehyde was synthesized as a model compound which lacks intramolecular hydrogen bond. Deprotonation of all synthesized compounds was done by treating with tetramethylguanidine (TMG). NMR data revealed that salicylidene Schiff bases in DMSO solution exist as OH forms without intramolecular hydrogen bonds and independent on the substituents in aromatic ring. In the case of 2-hydroxy naphthyl derivative, the OH proton is engaged into weak intramolecular hydrogen bond. Two of imines (salDAMN and 5-BrsalDAMN) exist in DMSO solution as equilibrium mixtures of two isomers (A and B). The structures of equilibrium mixture in the solid state have been studied by NMR, ATR-FTIR and X-Ray methods. The deprotonation of three studied compounds (salDAMN, 5-BrsalDAMN, and 5-CH3salDAMN) proceeded in two different ways: deprotonation of oxygen atom (X form) or of nitrogen atom of free primary amine group of DAMN moiety (Y form). For 5-NO2salDAMN and naphDAMN only one form (X) was observed.

Hydrogen Bonds Involving Cavity NH Protons Drives Supramolecular Oligomerization of Amido-Corroles.

trans-A2 B-Corroles with amide substituents at different positions versus the macrocyclic core have been synthesized. Their self-organizing properties have been comprehensively evaluated both in solid-state and in solution. The rigid arrangement of the amide functionality with the corrole ring led to the formation of strong intramolecular interactions and precluded intermolecular interactions. Replacement of sterically hindered C6 F5 substituents at positions 5 and 15 with smaller electron-withdrawing CO2 Me groups resulted in significant changes in the self-assembly pattern. With these substituents, tetramers formed in a crystalline state, in which one of the H-pyrrole subunits is out of the corrole plane. This allows the N-H group to form a hydrogen bond with a neighboring carbonyl group of the n-butyl amide fragment. DOSY NMR studies showed that amido-corroles bearing the OCH2 CONHnBu motif formed dimers in millimolar solutions in nonpolar solvents and the dimers existed in equilibrium with monomers. However, the corroles possessing meso-ester groups did not form dimers in polar tetrahydrofuran. Comprehensive optical studies allowed the absorption and emission features of the monomer corroles to be characterized in dilute solutions.

13C and 15N CP/MAS, 1H-15N SCT CP/MAS and FTIR spectroscopy as tools for qualitative detection of the presence of zwitterionic and non-ionic forms of ansa-macrolide 3-formylrifamycin SV and its derivatives in solid state.

(13)C, (15)N CP/MAS, including (1)H-(13)C and (1)H-(15)N short contact time CP/MAS experiments, and FTIR methods were applied for detailed structural characterization of ansa-macrolides as 3-formylrifamycin SV (1) and its derivatives (2-6) in crystal and in powder forms. Although HPLC chromatograms for 2/CH3 OH and 2/CH3 CCl3 were the same for rifampicin crystals dissolved in respective solvents, the UV-vis data recorded for them were different in 300-375 nm region. Detailed solid state (13)C and (15)N CP/MAS NMR and FTIR studies revealed that rifampicin (2), in contrast to 3-formylrifamycin SV (1) and its amino derivatives (3-6), can occur in pure non-ionic or zwitterionic forms in crystal and in pure these forms or a mixture of them in a powder. Multinuclear CP/MAS and FTIR studies demonstrated also that 3-6 derivatives were present exclusively in pure zwitterionic forms, both in powder and in crystal. On the basis of the solid state NMR and FTIR studies, two conformers of 3-formylrifamycin SV were detected in powder form due to the different orientations of carbonyl group of amide moiety. The PM6 molecular modeling at the semi-empirical level of theory, allowed visualization the most energetically favorable non-ionic and zwitterionic forms of 1-6 antibiotics, strongly stabilized via intramolecular H-bonds. FTIR studies indicated that the originally adopted forms of these type antibiotics in crystal or in powder are stable in standard laboratory conditions in time. The results presented point to the fact that because of a possible presence of two forms of rifampicin (compound 2), quantification of the content of this antibiotic in relevant pharmaceuticals needs caution.

Structure investigation of intramolecular hydrogen bond in some substituted salicylaldehydes and 4-aminoantipyrine derivatives in solution and in the solid state.

Seven imine derivatives obtained by condensation of appropriate aldehydes and salicylaldehydes with 4-aminoantipyrine were investigated in terms of intramolecular hydrogen bond structure. On the base of (1)H, (13)C and (15)N NMR measurements in solution and in the solid state we found out that all compounds which can form such structure exist as OH forms with strong H-bonds to nitrogen atom. The structure conclusions taken from NMR study were confirmed by pKa measurements. Surpassingly, the positions of protons in H-bridges only very slightly depend on the substituents in aldehyde used for condensation and on the phase (solution vs. solid state). The influence of antipyrine moiety seems to be the major factor defining H-bond structure.

Hydrogen bonding in Schiff bases--NMR, structural and experimental charge density studies.

A series of sixteen Schiff bases (derivatives of salicylaldehydes and aryl amines) was studied to reveal the influence of substituents and the length of the linker on the properties of the H-bonding formed. In theory, two groups of compounds, derivatives of 2-(2-hydroxybenzylidenoamine)phenol) and 2-hydroxy-N-(2-hydroxybenzylideno)benzylamine, can form different types of H-bonds using one or two hydroxyl groups present in the molecules. Two other groups of compounds, derivatives of 4-(2-hydroxybenzylidenoamine)phenol and N-(2-hydroxybenzyideno)benzylamine, can form only one type of H-bond. It was confirmed by (15)N and (13)C NMR experiments, that in all cases only traditional, H-bonded six-membered chelate rings were formed. The positions of the hydrogen atom in the rings depend on the substituent and phase. Generally, the OH H-bond form dominates in solution, with exception of the nitro derivatives, where the NH tautomer is present. In the solid state the tautomeric equilibrium is strongly shifted to the NH form. Only for the 5-Br derivative of one compound was the reverse relationship found. According to the results of experimental charge density investigations, two intramolecular H-bonds in the 5-methoxy derivative of 2-hydroxy-N-(2'-hydroxybenzylideno)benzylamine) differ significantly in terms of charge density properties. The intra- and intermolecular H-bonds formed by the deprotonated oxygen atom from 2-OH group are strong, with significant charge density concentration at the bond critical point and a straight, well-defined bond path, whereas the second intramolecular H-bond formed by the oxygen atom from the 2'-OH group is quite weak, with ca. five times smaller charge density concentration than in the previous case and a bent bond path. In terms of energy densities, the latter H-bond appears to be a non-bonding interaction, with total energy density being slightly positive. In terms of source contributions to the density at the H-bond critical point from the atoms involved, the intermolecular, linear H-bond is very strong and charge-assisted in the source function classification, the N(1)-H(1N)···O(1) H-bond is medium-strength, while the third H-bond is extremely weak.

CP/MAS spectroscopy in the determination of the tautomeric forms of gossypol, its Schiff bases and hydrazones in the solid state.

New Schiff bases and new hydrazones were synthesized and studied by (13)C and (15)N CP/MAS spectroscopy and by (1)H--(1)H COSY, (1)H--(13)C HMBC, (1)H--(13)C HSQC, (1)H--(15)N HMQC and (1)H--(15)N HSQC correlations. The CP/MAS investigation of gossypol has demonstrated that in the solid state it exists exclusively in the aldehyde-aldehyde tautomeric form. In contrast, CP/MAS studies of hydrazones and Schiff bases reveal that these compounds occur in the solid state in the N-imine-N-imine and enamine-enamine tautomeric forms, respectively. It is shown that the (13)C resonances of C-6, C-7 and C-11 carbon atoms are suitable for distinguishing between the tautomeric forms of aza-derivatives of gossypol in the solid state. Furthermore, we have proved that the (15)N CP/MAS spectra can be used to identify these tautomeric forms.

Multinuclear magnetic resonance, electrospray ionization-mass spectroscopy, and parametric method 5 studies of a new derivative of gossypol with 2-thiophenecarbohydrazide as well as its complexes with LI+, Na+, K+, RB+, and Cs+ cations.

A new derivative of racemic gossypol with 2-thiophenecarbohydrazide (GHHT) and its complexes with monovalent cations have been synthesized and studied by electrospray ionization-mass spectroscopy (ESI-MS), multinuclear nuclear magnetic resonance (NMR), as well as by the Parametric Method 5 (PM5) methods. It is demonstrated that GHHT forms stable complexes of 1:1 stoichiometry with monovalent metal cations. The structures of the complexes are stabilized by three types of intramolecular hydrogen bonds. The spectroscopic methods have provided clear evidence that GHHT and its complexes exist in the DMSO-d6 solution in the N-imine-N-imine tautomeric forms. The structures of the GHHT and its complexes with Li+, Na+, K+, Rb+, and Cs+ cations are visualized and discussed in detail.

1H and 13C NMR chemical shifts and spin-spin coupling constants in trans- and cis-decalins.

The NMR parameters characterizing the spectra of trans- and cis-decalins were determined from theoretical calculations and experimental spectra. The calculated values of the shielding constants are in good agreement with the measured chemical shifts, with a small but noticeable difference in accuracy for the bridgehead atoms. Of all the spin-spin coupling constants, only most of (1)J(C,C) and (1)J(C,H) values could be extracted from the spectra, and the corresponding computed values are in good agreement with experiment. It appears that the applied density functional theory (DFT) approach overestimates slightly the J(C,C) coupling and underestimates the differences between one-bond (1)J(C,H) coupling constants. For all these constants [J(C,C), J(C,H) and J(H,H)] through one to three bonds, which could not be obtained experimentally, the predicted values are in good agreement with the general rules relating spin-spin coupling to the number and spatial arrangement of the intervening bonds.

The spectroscopic study of hydrogen bonding in some 3,3'-derivatives of 2,2'-bipyridyl.

Four 3,3'-derivatives of 2,2'-bipyridyl have been investigated by multinuclear NMR, IR and X-ray methods. In all cases the weak intramolecular hydrogen bonds between exocyclic nitrogen-containing substituent and pyridine-type ring nitrogen atom were found. In contrast to the previous results the nitrogen chemical shifts of pyridine ring atom do not provide valuable information about hydrogen bond strength. The presence of intramolecular hydrogen bonds were confirmed by nitrogen chemical shifts of exocyclic amino and acetamide groups, deuterium isotope effects in the solid state and IR measurements in both chloroform solution and the solid state. The X-ray structures obtained for asymmetric 3-amino-3'-methylamino and 3,3'-diacetamide derivatives confirmed conclusions made on the base of spectral results.

Investigations of intramolecular hydrogen bonding in three types of Schiff bases by 2H and 3H NMR isotope effects.

Hydrogen bonding within the structures of three Schiff bases (1-3), obtained by condensation of 4-methoxy-, 5-methoxy- and 4,6-dimethoxysalicylaldehyde with methylamine, was investigated by measuring deuterium and tritium NMR isotope effects. The primary deuterium and tritium isotope effects (delta(XH)-delta(XD/T)) and secondary one-bond nitrogen deuterium effect appear to be very useful parameters for defining the character of intramolecular hydrogen bonds. The tritium isotope effects were also determined for nitrogen-hydrogen one-bond coupling constants for both 4-methoxy and 4,6-dimethoxy derivatives. These parameters are seen to be highly sensitive to hydrogen bond characteristics and can be used to distinguish localized and tautomeric hydrogen bonds.