Exploring the Antitumor Efficacy of N-Heterocyclic Nitrilotriacetate Oxidovanadium(IV) Salts on Prostate and Breast Cancer Cells.

The crystal structures of two newly synthesized nitrilotriacetate oxidovanadium(IV) salts, namely [QH][VO(nta)(H2O)](H2O)2 (I) and [(acr)H][VO(nta)(H2O)](H2O)2 (II), were determined. Additionally, the cytotoxic effects of four N-heterocyclic nitrilotriacetate oxidovanadium(IV) salts-1,10-phenanthrolinium, [(phen)H][VO(nta)(H2O)](H2O)0.5 (III), 2,2'-bipyridinium [(bpy)H][VO(nta)(H2O)](H2O) (IV), and two newly synthesized compounds (I) and (II)-were evaluated against prostate cancer (PC3) and breast cancer (MCF-7) cells. All the compounds exhibited strong cytotoxic effects on cancer cells and normal cells (HaCaT human keratinocytes). The structure-activity relationship analysis revealed that the number and arrangement of conjugated aromatic rings in the counterion had an impact on the antitumor effect. The compound (III), the 1,10-phenanthrolinium analogue, exhibited the greatest activity, whereas the acridinium salt (II), with a different arrangement of three conjugated aromatic rings, showed the lowest toxicity. The increased concentrations of the compounds resulted in alterations to the cell cycle distribution with different effects in MCF-7 and PC3 cells. In MCF-7 cells, compounds I and II were observed to block the G2/M phase, while compounds III and IV were found to arrest the cell cycle in the G0/G1 phase. In PC3 cells, all compounds increased the rates of cells in the G0/G1 phase.

Phosphinoborenium cations stabilized by N-heterocyclic carbenes: synthesis, structure, and reactivity.

Phosphinoborenium cations stabilized by N-heterocyclic carbenes (NHCs) were synthesized via the reaction of bromo(phosphino)boranes with NHCs. Their structures were investigated by heteronuclear magnetic resonance spectroscopy, X-ray diffraction, and density functional theory calculations. They possess a planar trigonal boron center directly bonded with the pyramidal phosphanyl group (PR2) and can be treated as cationic phosphinoboranes. The reactivity of the selected NHC-phosphinoborenium cation was tested toward AuCl·SMe2 and Ph2PCl. In both reactions, the titled compound acted as a phosphido group donor under heterolytic cleavage of the P-B bond. Control experiments with parent phosphinoborane emphasized differences between the reactivity of low-coordinate neutral and cationic species with P-B functionality.

Novel 2-alkythio-4-chloro-N-[imino(heteroaryl)methyl]benzenesulfonamide Derivatives: Synthesis, Molecular Structure, Anticancer Activity and Metabolic Stability.

A series of novel 2-alkythio-4-chloro-N-[imino-(heteroaryl)methyl]benzenesulfonamide derivatives, 8-24, were synthesized in the reaction of the N-(benzenesulfonyl)cyanamide potassium salts 1-7 with the appropriate mercaptoheterocycles. All the synthesized compounds were evaluated for their anticancer activity in HeLa, HCT-116 and MCF-7 cell lines. The most promising compounds, 11-13, molecular hybrids containing benzenesulfonamide and imidazole moieties, selectively showed a high cytotoxic effect in HeLa cancer cells (IC50: 6-7 µM) and exhibited about three times less cytotoxicity against the non-tumor cell line HaCaT cells (IC50: 18-20 µM). It was found that the anti-proliferative effects of 11, 12 and 13 were associated with their ability to induce apoptosis in HeLa cells. The compounds increased the early apoptotic population of cells, elevated the percentage of cells in the sub-G1 phase of the cell cycle and induced apoptosis through caspase activation in HeLa cells. For the most active compounds, susceptibility to undergo first-phase oxidation reactions in human liver microsomes was assessed. The results of the in vitro metabolic stability experiments indicated values of the factor t½ for 11-13 in the range of 9.1-20.3 min and suggested the hypothetical oxidation of these compounds to sulfenic and subsequently sulfinic acids as metabolites.

Do Phenyl Substituents Affect the Properties of Azobenzocrown Derivatives?

New products of photo- and thermal rearrangements of 19-membered azoxybenzocrown with phenyl substituents in benzene rings in the para positions to oligooxyethylene fragments are characterized in this work. The yields of photochemical transformations depend on the solvent. Para-hydroxyazocrown is formed with yields over 50 % in propan-2-ol. Ortho-hydroxyazobenzocrown is obtained with yields up to 70 % in toluene/acetic acid mixture. Macrocyclic Ph-20-ester is obtained in yield 90 % under thermochemical rearrangement conditions. Structure of new hydroxyazobenzocrowns and also atypical product of rearrangements, 20-membered ester, was confirmed by X-ray diffraction analysis. Azophenol ← → ${ \mathbin{{\stackrel{\textstyle\rightarrow} { {\smash{\leftarrow}\vphantom{_{\vbox to.5ex{\vss}}}} } }} }$ quinone-hydrazone tautomeric equilibrium of new hydroxyazobenzocrowns and the influence of metal cations on tautomeric equilibrium was investigated using 1 H NMR and UV-Vis spectroscopy in acetonitrile. The highest value of stability constant (logK 7.25) was obtained for strontium complex of p-hydroxyazobenzocrown. For the first time p-hydroxyazobenzocrown was used as a chromoionophore in the receptor layer of an optical sensor. Comparative analysis with data obtained previously for series 19-membered analogs have shown the influence of the presence of substituents in benzene rings for the course and products distribution of photo and thermal rearrangement. The effect of substituents was also discussed against the tautomeric equilibrium and metal cation complexation properties.

Application of nonmetallic frustrated cations in the activation of small molecules.

The concept of nonmetallic frustrated cations has been used in small molecule activation. The in situ generated ambiphilic phosphinoborinium cation activated phenyl isocyanate, diisopropylcarbodiimide, and acetonitrile under very mild conditions without any catalyst, yielding single-, double-, or mixed-activation products. Furthermore, the mechanisms of the reactions of the phosphinoborinium cation with small molecules were elucidated using density functional theory calculations.

Synthesis of 3-(2-Alkylthio-4-chloro-5-methylbenzenesulfonyl)-2-(1-phenyl-3-arylprop-2-enylideneamino)guanidine Derivatives with Pro-Apoptotic Activity against Cancer Cells.

The untypical course of reaction between chalcones and benzenesulfonylaminoguanidines led to the new 3-(2-alkylthio-4-chloro-5-methylbenzenesulfonyl)-2-(1-phenyl-3-arylprop-2-enylideneamino)guanidine derivatives 8-33. The new compounds were tested in vitro for their impact on the growth of breast cancer cells MCF-7, cervical cancer cells HeLa and colon cancer cells HCT-116 by MTT assay. The results revealed that the activity of derivatives is strongly related to the presence of hydroxy group in the benzene ring at the 3-arylpropylidene fragment. The most cytotoxic compounds 20 and 24 displayed mean IC50 values of 12.8 and 12.7 µM, respectively, against three tested cell lines and were almost 3- and 4-fold more active toward MCF-7 and HCT-116 when compared with non-malignant HaCaT cells. Furthermore, compound 24 induced apoptosis in cancer cells and caused a decrease of mitochondrial membrane potential as well as an increase of cells in sub-G1 phase in contrast to its inactive analog 31. The strongest activity against the most sensitive HCT-116 cell line was found for compound 30 (IC50 = 8 µM), which was 11-fold more effective in the growth inhibition of HCT-116 cells than those of HaCaT cells. Based on this fact, the new derivatives may be promising leading structures for the search for agents for the treatment of colon cancer.

Reactivity of triphosphinoboranes towards H3B·SMe2: access to derivatives of boraphosphacycloalkanes with diverse substituents.

Triphosphinoboranes activated the B-H bond in the BH3 molecule without any catalysts at room temperature. Hydroboration reactions led to boraphosphacyloalkanes with diverse structures. The outcomes of reactions depend on the size of the phosphanyl substituent on the boron atom of the parent triphosphinoborane, where derivatives of boraphosphacyclobutane and boraphosphacyclohexane were obtained. Furthermore, the precursor of triphosphinoboranes, namely bromodiphosphinoborane, also exhibited high reactivity towards H3B·SMe2, yielding bromo-substituted boraphosphacyclobutane. The obtained products were characterized by heteronuclear NMR spectroscopy, single crystal X-ray diffraction, and elemental analysis.

Simple colorimetric copper(II) sensor - Spectral characterization and possible applications.

New o-hydroxyazocompound L bearing pyrrole residue was obtained in the simple synthetic protocol. The structure of L was confirmed and analyzed by X-ray diffraction. It was found that new chemosensor can be successfully used as copper(II) selective spectrophotometric regent in solution and can be also applied for the preparation of sensing materials generating selective color signal upon interaction with copper(II). Selective colorimetric response towards copper(II) is manifested by a distinct color change from yellow to pink. Proposed systems were effectively used for copper(II) determination at concentration level 10-8 M in model and real samples of water.

Phosphinophosphoranes: Mixed-Valent Phosphorus Compounds with Ambiphilic Properties.

Herein, we present a simple synthesis of mixed-valent phosphinophosphoranes bearing three- and five-coordinate phosphorus centers. Compounds with phosphorus-phosphorus bonds were synthesized via a reaction of lithium phosphides RR'PLi with cat2PCl (cat = catecholate), whereas derivatives with methylene-linked phosphorus centers were obtained via a reaction of phosphanylmethanides RR'CH2Li with cat2PCl. The presence of accessible lone-pair electrons on the P-phosphanyl atom of phosphinophosphoranes during the reaction of the title compounds with H3B·SMe2, where phosphinophosphorane-borane adducts were formed quantitatively, was confirmed. Furthermore, the Lewis basic and Lewis acidic properties of the phosphinophosphoranes in reactions with phenyl isothiocyanate were tested. Depending on the structure of the starting phosphinophosphorane, phosphinophosphorylation of PhNCS or formation of a five-membered zwitterionic adduct was observed. The structures of the isolated compounds were unambiguously determined by heteronuclear nuclear magnetic resonance spectroscopy and single-crystal X-ray diffraction. Moreover, by applying density functional theory calculations, we compared the Lewis basicity and nucleophilicity of diversified trivalent P-centers.

Phosphinoborinium cation: a synthon for cationic B-P bond systems.

Herein, we report access to phosphinoborinium cations via heterolytic cleavage of the boron-bromide bond in bromophosphinoborane. The product of the reaction was isolated as a dimeric dication possessing a planar B2P2 core. Activation of the C-H and C-P bonds in the dication led to the formation of the borinium-phosphaborene adduct. Reactivity studies revealed that the title cation exhibits ambiphilic properties and intramolecular frustrated Lewis pair features.

New 2-[(4-Amino-6-N-substituted-1,3,5-triazin-2-yl)methylthio]-N-(imidazolidin-2-ylidene)-4-chloro-5-methylbenzenesulfonamide Derivatives, Design, Synthesis and Anticancer Evaluation.

In the search for new compounds with antitumor activity, new potential anticancer agents were designed as molecular hybrids containing the structures of a triazine ring and a sulfonamide fragment. Applying the synthesis in solution, a base of new sulfonamide derivatives 20-162 was obtained by the reaction of the corresponding esters 11-19 with appropriate biguanide hydrochlorides. The structures of the compounds were confirmed by spectroscopy (IR, NMR), mass spectrometry (HRMS or MALDI-TOF/TOF), elemental analysis (C,H,N) and X-ray crystallography. The cytotoxic activity of the obtained compounds toward three tumor cell lines, HCT-116, MCF-7 and HeLa, was examined. The results showed that some of the most active compounds belonged to the R1 = 4-trifluoromethylbenzyl and R1 = 3,5-bis(trifluoromethyl)benzyl series and exhibited IC50 values ranging from 3.6 µM to 11.0 µM. The SAR relationships were described, indicating the key role of the R2 = 4-phenylpiperazin-1-yl substituent for the cytotoxic activity against the HCT-116 and MCF-7 lines. The studies regarding the mechanism of action of the active compounds included the assessment of the inhibition of MDM2-p53 interactions, cell cycle analysis and apoptosis induction examination. The results indicated that the studied compounds did not inhibit MDM2-p53 interactions but induced G0/G1 and G2/M cell cycle arrest in a p53-independent manner. Furthermore, the active compounds induced apoptosis in cells harboring wild-type and mutant p53. The compound design was conducted step by step and assisted by QSAR models that correlated the activity of the compounds against the HCT-116 cell line with molecular descriptors.

Exploring the Reactivity of Unsymmetrical Diphosphanes toward Heterocumulenes: Access to Phosphanyl and Phosphoryl Derivatives of Amides, Imines, and Iminoamides.

We present a comprehensive study on the diphosphanation of iso(thio)cyanates by unsymmetrical diphosphanes. The reactions involving unsymmetrical diphosphanes and phenyl isocyanate or phenyl thioisocyanate gave rise to phosphanyl, phosphoryl, and thiophosphoryl derivatives of amides, imines, and iminoamides. The structures of the diphosphanation products were confirmed through NMR spectroscopy, IR spectroscopy, and single-crystal X-ray diffraction. We showed that unsymmetrical diphosphanes could be used as building blocks to synthesize phosphorus analogues of important classes of organic molecules. The described transformations provided a new methodology for the synthesis of organophosphorus compounds bearing phosphanyl, phosphoryl, or thiophosphoryl functional groups. Moreover, theoretical studies on diphosphanation reactions explained the influence of the steric and electronic properties of the parent diphosphanes on the structures of the diphosphanation products.

Products of Photo- and Thermochemical Rearrangement of 19-Membered di-tert-Butyl-Azoxybenzocrown.

The preparation and characterization of products of the photochemical and thermochemical rearrangements of 19-membered azoxybenzocrowns with two, bulky, tert-butyl substituents in benzene rings in the para positions to oligooxyethylene fragments (meta positions to azoxy group, i.e., t-Bu-19-Azo-O have been presented. In photochemical rearrangement, two colored typical products were expected, i.e., 19-membered o-hydroxy-m,m'-di-tert-butyl-azobenzocrown (t-Bu-19-o-OH) and 19-membered p-hydroxy-m,m'-di-tert-butyl-azobenzocrown (t-Bu-19-p-OH). In experiments, two colored atypical macrocyclic derivatives, one 6-membered and one 5-membered ring, bearing an aldehyde group (t-Bu-19-al) or intramolecular ester group (t-Bu-20-ester), were obtained. Photochemical rearrangement led to one more macrocyclic product being isolated and identified: a 17-membered colorless compound, without an azo moiety, t-Bu-17-p-OH. The yield of the individual compounds was significantly influenced by the reaction conditions. Thermochemical rearrangement led to t-Bu-20-ester as the main product. The structures of the four crystalline products of the rearrangement-t-Bu-19-o-OH, t-Bu-19-p-OH, t-Bu-20-ester and t-Bu-17-p-OH-were determined by the X-ray method. Structures in solution of atypical derivatives (t-Bu-19-al and t-Bu-20-ester) and t-Bu-19-p-OH were defined using NMR spectroscopy. For the newly obtained hydroxyazobenzocrowns, the azo-phenol⇄quinone-hydrazone tautomeric equilibrium was investigated using spectroscopic methods. Complexation studies of alkali and alkaline earth metal cations were studied using UV-Vis absorption spectroscopy. 1H NMR spectroscopy was additionally used to study the cation recognition of metal cations. Cation binding studies in acetonitrile have shown high selectivity towards calcium over magnesium for t-Bu-19-o-OH.

Monomeric Triphosphinoboranes: Intramolecular Lewis Acid-Base Interactions between Boron and Phosphorus Atoms.

Herein, we present the synthesis of the first fully characterized monomeric triphosphinoboranes. The simple reaction of boron tribromide with 3 equiv of bulky lithium phosphide tBu2PLi yielded triphosphinoborane (tBu2P)3B. Triphosphinoboranes with diversified phosphanyl substituents were obtained via a two-step reaction, in which isolable bromodiphosphinoborane (tBu2P)2BBr is first formed and then reacts with 1 equiv of less bulky phosphide R2PLi (R2P = Cy2P, iPr2P, tBuPhP, or Ph2P). By utilizing this method, we obtained a series of triphosphinoboranes with the general formula (tBu2P)2BPR2. On the basis of structural and theoretical studies, two main types of triphosphinoborane structures can be distinguished. In the first type, all three electron lone pairs interact with the formally empty p orbital of the central boron atom, resulting in delocalized π bonding, whereas in the second type, one localized P═B bond and two P-B bonds are observed. The Lewis acidic-basic properties of triphosphinoboranes during the reaction of (tBu2P)2BPiPr2 with H3B·SMe2 were analyzed. The P-B bond-containing compound mentioned above not only formed an adduct with BH3 but also activated the B-H bond of the borane molecule, resulting in the incorporation of the BH2 unit into two phosphorus atoms and migration of a hydride to the boron atom of the parent triphosphinoborane. The structures of the triphosphinoboranes were confirmed by single-crystal X-ray analysis, multinuclear nuclear magnetic resonance spectroscopy, and elemental analysis.

Novel Diazocrowns with Pyrrole Residue as Lead(II)Colorimetric Probes.

Novel 18- and 23-membered diazomacrocycles were obtained with satisfactory yields by diazocoupling of aromatic diamines with pyrrole in reactions carried under high dilution conditions. X-ray structure of macrocycle bearing five carbon atoms linkage was determined and described. Compounds were characterized as chromogenic heavy metal ions receptors. Selective color and spectral response for lead(II) was found in acetonitrile and its mixture with water. Complexation properties of newly obtained macrocycles with a hydrocarbon chain were compared with the properties of their oligoether analogs. The influence of the introduction of hydrocarbon residue as a part of macrocycle on the lead(II) binding was discussed. Selective and sensitive colorimetric probe for lead(II) in aqueous acetonitrile with detection limit 56.1 µg/L was proposed.

Diphosphinoboranes as Intramolecular Frustrated Lewis Pairs: P-B-P Bond Systems for the Activation of Dihydrogen, Carbon Dioxide, and Phenyl Isocyanate.

Herein, we present the first example of the activation of small molecules by P-B-P bond systems. The reactivity study involves reactions of two selected diphosphinoboranes, (t-Bu2P)2BPh (1') and (Cy2P)2BNiPr2 (2), that differ in terms of their structural and electronic properties for the activation of dihydrogen, carbon dioxide, and phenyl isocyanate. Diphosphinoborane 1' activates H2 under very mild conditions in the absence of a catalyst with the formation of the dimer (t-Bu2PB(Ph)H)2 and t-Bu2PH. Conversely, diphosphinoborane 2 did not react with H2 under the same conditions. The reaction of 1' with CO2 led to the formation of a compound with an unusual structure, where two phosphinoformate units were coordinated to the PhBOBPh moiety. In addition, 2 reacted with CO2 to insert two CO2 molecules into the P-B bonds of the parent diphosphinoborane. Both diphosphinoboranes activated PhNCO, yielding products resulting from the addition of two and/or three PhNCO molecules and the formation of new P-C, B-O, B-N, and C-N bonds. The products of the activation of small molecules by diphosphinoboranes were characterized with nuclear magnetic resonance (NMR) and infrared (IR) spectroscopy, single-crystal X-ray diffraction, and elemental analysis. Additionally, the reaction mechanisms of the activation of small molecules by diphosphinoboranes were elucidated by theoretical methods.

The influence of the type of halogen substituent and its position on the molecular conformation, intermolecular interactions and crystal packing for a series of 1-benzoyl-3-(halogenophenyl)thioureas.

By the reaction of benzoyl chloride, potassium isothiocyanate and the appropriate halogenoaniline, i.e. 2/3/4-(bromo/iodo)aniline, we have obtained five new 1-benzoyl-3-(halogenophenyl)thioureas, namely, 1-benzoyl-3-(2-bromophenyl)thiourea and 1-benzoyl-3-(3-bromophenyl)thiourea, C14H11BrN2OS, and 1-benzoyl-3-(2-iodophenyl)thiourea, 1-benzoyl-3-(3-iodophenyl)thiourea and 1-benzoyl-3-(4-iodophenyl)thiourea, C14H11IN2OS. Structural and conformational features of the compounds have been analyzed using X-ray diffraction and theoretical calculations. The novel compounds were characterized by solid-state IR and 1H/13C NMR spectroscopy. The conformations and intermolecular interactions, such as hydrogen bonds, π-π and S(6)...π stacking, and X...O (X = I or Br), I...S and I...π, have been examined and rationalized, together with four analogous compounds described previously in the literature. The set of nine compounds was chosen to examine how a change of the halogen atom and its position on the phenyl ring affects the molecular and crystal structures.

Effect of chemical structure on complexation efficiency of aromatic drugs with cyclodextrins: The example of dibenzazepine derivatives.

It is widely believed that the hydrophobic effect governs the binding of guest molecules to cyclodextrins (CDs). However, it is also known that high hydrophobicity of guest molecules does not always translate to the formation of stable inclusion complexes with CDs. Indeed, a plethora of other factors can play a role in the efficiency of guest-CD interactions, rendering structure-based prediction of the complexation efficiency with CDs a non trivial task. In this combined experimental and computational study, we examine the major structural factors governing complexation efficiency of polycyclic aromatic drug-like compounds with natural CDs, using as an example iminostilbene and its N-substituted derivatives. We find that purely hydrophobic IS derivatives show negligible complexation efficiency with CDs and only IS with hydrophilic substituents form stable inclusion complexes in water. We show that the balance between the guest solubility and its affinity to CDs is critical for the effective formation of inclusion complexes. Finally, our results demonstrate that guest-host hydrogen bonds facilitate the formation of crystalline inclusion complexes with CDs.

Photochemical Rearrangement of a 19-Membered Azoxybenzocrown: Products and their Properties.

The preparation and characterization of products of the chemical and photochemical rearrangements of a 19-membered o,o'-azoxybenzocrown are presented. In photochemical rearrangement, besides the expected product i. e. 19-membered o-hydroxy-o,o'-azobenzocrown (19-o-OH) obtained under defined conditions with 75 % yield, also other macrocyclic products were isolated and identified, namely: 19-membered p-hydroxy-o,o'-azobenzocrown (19-p-OH), 21-membered o'-hydroxy-o,p'-azobenzocrown (21-o'-OH) and 19-membered macrocycle containing a 5-membered ring bearing an aldehyde group (19-al). The structures of two atypical products of the photochemical rearrangement - 21-o'-OH and 19-al - were determined in the solid state by X-ray analysis and in solution using NMR spectroscopy. Tautomeric equilibrium of the formed hydroxyazobenzocrowns and its change depending on acidity/basicity of the environment and alkali and alkaline earth metal cations complexation were studied using UV-Vis spectrophotometry, spectrofluorimetry and 1 H NMR spectroscopy.

The Quaternization Reaction of 5-O-Sulfonates of Methyl 2,3-o-Isopropylidene-ß-D-Ribofuranoside With Selected Heterocyclic and Aliphatic Amines.

The synthesis of N-((methyl 5-deoxy-2,3-O-isopropylidene-ß-D-ribofuranoside)-5-yl)ammonium salts are presented. To determine the effect of the nucleophile type and outgoing group on the quaternization reaction, selected aliphatic and heterocyclic aromatic amines reacted with: methyl 2,3-O-isopropylidene-5-O-tosyl-ß-D-ribofuranoside or methyl 2,3-O-isopropylidene-5-O-mesyl-ß-D-ribofuranoside or methyl 2,3-O-isopropylidene-5-O-triflyl-ß-D-ribofuranoside were performed on a micro scale. High-resolution 1H- and 13C-NMR spectral data for all new compounds were recorded. Additionally, the single-crystal X-ray diffraction analysis for methyl 2,3-O-isopropylidene-5-O-mesyl-ß-D-ribofuranoside and selected in silico interaction models are reported.