Synthesis, antiproliferative and antibacterial activity of new amides of salinomycin.

A series of 11 novel amides of salinomycin were synthesized for the first time. All the obtained compounds were found to show potent antiproliferative activity against human cancer cell lines including the drug-resistant cancer cells. Four new salinomycin derivatives revealed good antibacterial activity against clinical isolates of methicillin-resistant Staphylococcus epidermidis (MRSE).

Synthesis, anticancer and antibacterial activity of salinomycin N-benzyl amides.

A series of 12 novel monosubstituted N-benzyl amides of salinomycin (SAL) was synthesized for the first time and characterized by NMR and FT-IR spectroscopic methods. Molecular structures of three salinomycin derivatives in the solid state were determined using single crystal X-ray method. All compounds obtained were screened for their antiproliferative activity against various human cancer cell lines as well as against the most problematic bacteria strains such as methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE), and Mycobacterium tuberculosis. Novel salinomycin derivatives exhibited potent anticancer activity against drug-resistant cell lines. Additionally, two N-benzyl amides of salinomycin revealed interesting antibacterial activity. The most active were N-benzyl amides of SAL substituted at -ortho position and the least anticancer active derivatives were those substituted at the -para position.

Monensin A acid complexes as a model of electrogenic transport of sodium cation.

New Monensin A acid complexes with water molecule, sodium chloride and sodium perchlorate were obtained and studied by X-ray and (1)H, (13)C NMR and FT-IR methods as well as ab initio calculations. The crystal structure of the complexes indicates the complexation of the water molecule and Na(+) cation in the pseudo-cycle conformation of the Monensin acid molecule stabilised by intramolecular hydrogen bonds. Important for stabilisation of this structure is also the intermolecular hydrogen bonds with water molecule or the coordination bonds with Na(+) cation. It is demonstrated that the counterions forming intermolecular hydrogen bonds with OH groups influence the strength of the intramolecular hydrogen bonds, but they have no influence on the formation of pseudo-cyclic structure. Spectroscopic studies of the complexes in dichloromethane solution have shown that the pseudo-cyclic structure of the compounds is conserved. As follows from the ab initio calculations, the interactions between the Na(+) cation and the electronegative oxygen atoms of Monensin acid totally change the molecular electrostatic potential around the supramolecular Monensin acid-Na(+) cationic complex relative to that of the neutral Monensin acid molecule.

One-pot synthesis and cytotoxicity studies of new Mannich base derivatives of polyether antibiotic--lasalocid acid.

Seven Mannich base derivatives of polyether antibiotic Lasalocid acid (2a-2g) were synthesized and screened for their antiproliferative activity against various human cancer cell lines. A novel chemoselective one-pot synthesis of these Mannich bases was developed. Compounds 2a-2c and 2g with sterically smaller dialkylamine substituent, displayed potent antiproliferative activity (IC50: 3.2-7.3 µM), and demonstrated higher than twofold selectivity for specific type of cancer. The nature of Mannich base substituent on C-2 atom at the aromatic ring may be critical in the search for selectivity towards a particular cancer cell.

Synthesis and antimicrobial activity of amide derivatives of polyether antibiotic-salinomycin.

For the first time a direct and practical approach to the synthesis of eight amide derivatives of polyether antibiotic-salinomycin is described. The structure of allyl amide (3a) has been determined using X-ray diffraction. Salinomycin and its amide derivatives have been screened for their in vitro antimicrobial activity against the typical gram-positive cocci, gram-negative rods and yeast-like organisms, as well as against a series of clinical isolates of methicillin-resistant Staphylococcus aureus and methicillin-sensitive S. aureus. Amides of salinomycin have been found to show a wide range of activities, from inactive at 256 µg/mL to active with MIC of 2 µg/mL, comparable with salinomycin. As a result, phenyl amide (3b) was found to be the most active salinomycin derivative against gram-positive bacteria, MRSA and MSSA.

Antiproliferative activity of salinomycin and its derivatives.

Antiproliferative activity of seven amides and one benzotriazole ester derivative of salinomycin, a polyether ionophore antibiotic, with recently reported antibacterial activity, are herein described. Salinomycin and the majority of derivatives exhibit potent antiproliferative activity against the drug-resistant cancer cell lines. Moreover almost all derivatives show stronger activity against LoVo/DX cell line than that of unmodified salinomycin.

X-ray crystallographic, FT-IR, and density functional theory studies of the salt formed between dipicrylamine and 1,5,7-triazabicyclo[4.4.0]dec-1-ene.

The DPA-TBD (dipicrylamine-1,5,7-triazabicyclo[4.4.0]dec-1-ene) salt has been synthesized and characterized by FT-IR spectroscopy, X-ray single-crystal diffraction, and theoretical study. In the FT-IR spectrum of the crystalline DPA-TBD salt, an unexpected intense band at 1742 cm(-1) is present. The optimized geometry and the FT-IR spectra of the DPA salt were calculated at the B3LYP/6-31G+(d) level and give an explanation of the nature of this band as the ν(C═N═C) vibration. For comparison, the calculated IR spectra of the DPA anion, hydrogen-bonded DPA anion, and neutral DPA and TBD molecules as well as for the TBD cation are also shown. The presence of the free DPA anion in the gas phase was directly detected in the negative ion mode electrospray ionization MS spectra. The fragmentation of the DPA anion is also discussed.

The influence of protonation on molecular structure and physico-chemical properties of gossypol Schiff bases.

Protonation of gossypol Schiff bases (S1 and S2), possessing different numbers of basic N-atoms, was studied using potentiometric, spectroscopic, ESI MS and PM5 methods. Titration of S1 and S2 with HClO(4), monitored by the FT-IR and (1)H NMR, indicated that the change from the enamine-enamine into the protonated imine-imine tautomeric form occurs at different Schiff base-H(+) ratio. The FT-IR and PM5 results show that for S1 the first protonation step occurs at Schiff base moiety whereas for S2 it is realised at N-atom of the morpholine. The formation of N(+)-HO hydrogen bond between morpholine moieties within S2 contributes to high pK(a(ACN)) = 22.65.

Structure elucidation, complete NMR assignment and PM5 theoretical studies of new hydroxy-aminoalkyl-alpha,beta-unsaturated derivatives of the macrolide antibiotic josamycin.

Four new hydroxy-aminoalkyl derivatives of alpha,beta-unsaturated macrolide-josamycin (2-5) have been synthesised and their structures have been studied by means of (1)H and (13)C NMR and FT-IR methods. Complete assignment of resonances in the (1)H and (13)C NMR spectra has been made on the basis of (1)H-(13)C HSQC, (1)H-(13)C HMBC, (1)H-(1)H COSY, (1)H-(1)H NOESY 2D experiments. Spectroscopic data indicated that for the derivatives 3 and 4 some equilibrium between two different structures exists in contrast to derivatives 2 and 5. The lowest-energy structures of the new derivatives of josamycin have been calculated and visualised by PM5 method at semi-empirical level of theory, taking into account the NMR and FT-IR data. The most significant differences between the structures of josamycin and its newly synthesised derivatives' were found in the conformation of the macrolide aglycone part and in the mutual orientation of the 4-O-isovalerylmycarosylmycaminose moiety relative to the aglycone part. PM5 semi-empirical calculations indicated that the structures of the new macrolide derivatives are stabilised by rather weak intramolecular hydrogen bonds in agreement with spectroscopic data. Antimicrobial properties of the new derivatives 2-5 as well as those having an acetate group at C-3 (6 and 7) were determined and compared to that of the parent macrolide antibiotic josamycin (1).

Antifungal activity of alkyl and heterocyclic aza-derivatives of gossypol as well as their complexes with NaClO4 against Fusarium oxysporum f. sp. lupini.

Eight alkyl and six heterocyclic aza-derivatives of gossypol (2-15) have been synthesized using gossypol (1) extracted from Gossypium Herbaceum cottonseeds. The ability of gossypol aza-derivatives to form complexes with NaClO(4) has been investigated by electrospray ionisation (ESI) mass spectra recorded in the positive and negative ion detection modes. The gossypol aza-derivatives have been characterized by FT-IR, (1)H and (13)C NMR spectroscopic methods and subsequently tested for their antifungal properties against Fusarium oxysporum. Four alkyl aza-derivatives (2-5), present in the enamine-enamine tautomeric form, have shown activity comparable or higher than that of gossypol against this fungus. To improve the antifungal activity the complexes of the most active compounds 2-5 with NaClO(4) were prepared. Complexes of 2 and 5 with NaClO(4) have shown antifungal activity higher than that of the uncomplexed compounds.

Synthesis and antimicrobial properties of monensin A esters.

The esters (2-10) of the ionophore antibiotic Monensin (1) were synthesized by four different methods, which are discussed in detail. These new esters were characterized by various spectroscopic techniques and subsequently tested in the face of their antimicrobial properties. Three derivatives (3, 8 and 10) showed activity against Gram-positive bacteria. Additionally derivative (10) exhibited a relatively low antifungal activity against Candida in contrast to Monensin A.

Molecular structures and stability constants of gossypol and its aza-derivative complexes with silver(I) cations studied by potentiometric, ESI MS, NMR, and AM1d semiempirical methods.

Stability constants of complexes formed by gossypol and by ten of its Schiff bases with Ag (+) cations were determined by the potentiometric method. The potentiometric and ESI MS experiments indicate the formation of AgL (+) and Ag 2L (2+) complexes between the Schiff bases G1-G7 and Ag (+) cations as well as the formation of AgL (+), Ag 2L (2+), AgL 2 (+) and Ag 3L 2 (3+) complexes between the Schiff bases G8-G10 and Ag (+) cations. The highest stability constant was found for the AgL (+) complex of G8 Schiff base and the lowest one for the AgL (+) complex of G molecule. The (13)C NMR spectra of mixtures between G and AgClO 4 as well as G1-G10 and AgClO 4 indicate that the complexation of the Ag (+) cations is exclusively realized by the aldehyde-aldehyde tautomer of gossypol and by the enamine-enamine form of gossypol Schiff bases, respectively. We show that the main coordination sites for the Ag (+) metal cations are either the oxygen or the nitrogen atoms of the amine parts of the Schiff bases of gossypol. The energetically most favorable structures of the Ag (+) complexes with gossypol (G) or with the gossypol Schiff bases (G1-G10) were calculated and visualized by the AM1d method at an semiempirical level of theory.

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.

Spectroscopic and semiempirical studies of a proton channel formed by the methyl ester of monensin A.

Monensin A is an ionophore able to carry protons and cations through the cell membrane. Its methyl ester (MON1) and its hydrates have been studied in acetonitrile, and its deuterated analogue by Fourier transform infrared (FTIR) and (1)H and (13)C NMR spectroscopies as well as by vapor pressure osmotic and PM5 semiempirical methods. Interestingly, these hydrates show new and unexpected biophysical and biochemical properties. The formation of the hydrates starts with a transfer of a proton from the O(IV)-H hydroxyl group of MON1 to an oxygen atom of a water molecule, which is subsequently hydrated by other water molecules forming the (MON1 + 3H(2)O) species. This hydrate exhibits a ringlike structure in which the water molecules form an almost linear hydrogen-bonded chain. Within this chain, the excess proton fluctuates very fast inside the water cluster as indicated by a continuous absorption in the FTIR spectra. The formation of the (MON1 + 3H(2)O) species is accompanied by a self-assembly process, leading to the formation of a proton channel made up of eight (MON1 + 3H(2)O) units with a length of 60 A, in which the proton can fluctuate over the whole distance. Semiempirical calculations suggest that due to the hydrophobic surface the channel can be incorporated readily in a lipid bilayer. This hypothetical new channel is thought to be able to transport protons through the cell membrane. Thus it is a suitable model for studying proton-transfer processes, and in addition, it may open interesting new fields of application.

Spectroscopic studies of the equilibrium between complexes of lasalocid acid with propargylamine and metal cations.

The molecular structure of 1:1 complex formed between the naturally occurring polyether ionophore, called lasalocid acid (LAS) and propargylamine (PROP) is studied by X-ray, FT-IR, (1)H NMR, (13)C NMR and ESI-MS methods. The complex formed between deprotonated LAS acid and protonated PROP molecule is stabilized by intra- and inter-molecular hydrogen bonds. The protons of the protonated amine group are hydrogen bonded to etheric and hydroxyl oxygen atoms of the LAS anion. The similarity of the FT-IR spectra of the LAS-PROP complex in solid state and in solution demonstrated that the molecular structures of the complex in both states are comparable. It is shown that LAS in solution can form concurrent complexes with metal cations (M=Li(+), Na(+), K(+)) and amine existing in equilibrium. Analysis of the structures of lasalocid complexes is important for a better understanding of the antibacterial and anticancer properties of lasalocid acid.

Spectroscopic, crystallographic and theoretical studies of lasalocid complex with ammonia and benzylamine.

A natural antibiotic--Lasalocid is able to form stable complexes with ammonia and organic amines. New complexes of lasalocid with benzylamine and ammonia were obtained in the crystal forms and studied using X-ray, FT-IR, (1)H NMR, (13)C NMR and DFT methods. These studies have shown that in both complexes the proton is transferred from the carboxylic group to the amine group with the formation of a pseudo-cyclic structure of lasalocid anion complexing the protonated amine or NH4(+) cation. The spectroscopic and DFT studies demonstrated that the structure of the complex formed between Lasalocid and benzylamine in the solid is also conserved in the solution and gas phase. In contrast, the structure of the complex formed between lasalocid and ammonium cation found in the solid state undergoes dissociation in chloroform solution accompanied with a change in the coordination form of the NH4(+) cation.

Synthesis, cytotoxicity and antibacterial activity of new esters of polyether antibiotic - salinomycin.

A series of 12 novel ester derivatives of naturally occurring polyether antibiotic - salinomycin were synthesized, characterised by spectroscopic method and evaluated for their in vitro antibacterial activity and cytotoxicity. The new esters were demonstrated to form complexes with monovalent and divalent metal cation of 1:1 stoichiometry in contrast to the salinomycin which forms only complexes with monovalent cations. All the obtained compounds show potent antiproliferative activity against human cancer cell lines and a good selectivity index for cancer versus mammalian cells. Additionally, 3 compounds showed higher antiproliferative activity against the drug-resistant cancer cells and lower toxicity towards normal cells than those of unmodified salinomycin and standard anticancer drugs such as cisplatin and doxorubicin. Some of the synthesized compounds showed good inhibitory activity against Staphylococcus strains and clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE). These studies show that salinomycin esters are interesting scaffolds for the development of novel anticancer and Gram-positive antibacterial agents.

Structures and properties of naturally occurring polyether antibiotics.

Polyether ionophores represent a large group of natural, biologically active substances produced by Streptomyces spp. They are lipid soluble and able to transport metal cations across cell membranes. Several of polyether ionophores are widely used as growth promoters in veterinary. Polyether antibiotics show a broad spectrum of bioactivity ranging from antibacterial, antifungal, antiparasitic, antiviral, and tumour cell cytotoxicity. Recently, it has been shown that some of these compounds are able to selectively kill cancer stem cells and multidrug-resistant cancer cells. Thus, they are recognized as new potential anticancer drugs. The biological activity of polyether ionophores is strictly connected with their molecular structure; therefore, the purpose of this paper is to present an overview of their formula, molecular structure, and properties.

Synthesis, FT-IR, ¹H, ¹³CNMR, ESI MS and PM5 studies of a new Mannich base of polyether antibiotic - Lasalocid acid and its complexes with Li⁺, Na⁺ and K⁺ cations.

The polyether antibiotic Lasalocid acid has been converted to its Mannich base derivative by a chemoselective one-pot reaction with formaldehyde and morpholine through the decarboxylation process. Spectroscopic studies of the structure of this new derivative have shown that in this ortho-phenol Mannich base the O-H⋯N intarmolecular hydrogen bond is present. The compound forms complexes with Li(+), Na(+) and K(+) cations of exclusively 1:1 stoichiometry. The structures of these complexes have been studied and visualized by semi-empirical calculation based on results of spectrometric and spectroscopic investigation. It is demonstrated that in contrast to Lasalocid acid the novel Mannich type derivative forms preferential complexes with Li(+) cation.