Ewa Tykarska

Phthalocyanine Derivatives Possessing 2-(Morpholin-4-yl)ethoxy Groups As Potential Agents for Photodynamic Therapy

Three 2-(morpholin-4-yl)ethoxy substituted phthalocyanines were synthesized and characterized. Phthalocyanine derivatives revealed moderate to high quantum yields of singlet oxygen production depending on the solvent applied (e.g., in DMF ranging from 0.25 to 0.53). Their photosensitizing potential for photodynamic therapy was investigated in an in vitro model using cancer cell lines. Biological test results were found particularly encouraging for the zinc(II) phthalocyanine derivative possessing two 2-(morpholin-4-yl)ethoxy substituents in nonperipheral positions. Cells irradiated for 20 min at 2 mW/cm(2) revealed the lowest IC50 value at 0.25 μM for prostate cell line (PC3), whereas 1.47 μM was observed for human malignant melanoma (A375) cells. The cytotoxic activity in nonirradiated cells of novel phthalocyanine was found to be very low. Moreover, the cellular uptake, localization, cell cycle, apoptosis through an ELISA assay, and immunochemistry method were investigated in LNCaP cells. Our results showed that the tested photosensitizer possesses very interesting biological activity, depending on experimental conditions.

Phthalocyanines functionalized with 2-methyl-5-nitro-1H-imidazolylethoxy and 1,4,7-trioxanonyl moieties and the effect of metronidazole substitution on photocytotoxicity

Four novel magnesium(II) and zinc(II) phthalocyanines bearing 1,4,7-trioxanonyl, polyether and/or (2-methyl-5-nitro-1H-imidazol-1-yl)ethoxy, heterocyclic substituents at their non-peripheral positions were synthesized and assessed in terms of physicochemical and biological properties. Magnesium phthalocyanine derivatives bearing polyether substituents (Pc-1), a mixed system of polyether and heterocyclic substituents (Pc-3), and four heterocyclic substituents (Pc-4), respectively, were synthesized following the Linstead macrocyclization reaction procedure. Zinc phthalocyanine (Pc-2) bearing polyether substituents at non-peripheral positions was synthesized following the procedure in n-pentanol with the zinc acetate, and DBU. Novel phthalocyanines were purified by flash column chromatography and characterized using NMR, MS, UV-Vis and HPLC. Moreover, two precursors in macrocyclization reaction phthalonitriles were characterized using X-ray. Photophysical properties of the novel macrocycles were evaluated, including UV-Vis spectra analysis and aggregation study. All macrocycles subjected to singlet oxygen generation and the oxidation rate constant measurements exhibited lower quantum yields of singlet oxygen generation in DMSO than in DMF. In addition, the Pc-2 molecule was found to be the most efficient singlet oxygen generator from the group of macrocycles studied. The photocytotoxicity evaluated on the human oral squamous cell carcinoma cell line, HSC-3, for Pc-3 was significantly higher than that for Pc-1, Pc-2, and Pc-4. Interestingly, Pc-3 was found to be the most active macrocycle in vitro although its ability to generate singlet oxygen was significantly lower than those of Pc-1 and Pc-2. However, attempts to encapsulate phthalocyanines Pc-1-Pc-3 in liposomal membranes were unsuccessful. The phthalocyanine-nitroimidazole conjugate, Pc-4 was encapsulated in phosphatidylglycerol:phosphatidylcholine unilamellar liposomes and subjected to photocytotoxicity study.

Differences between the N·H·O and O·H·O hydrogen bonds in complexes of 2,6-dichloro-4-nitrophenol with pyridines and pyridine N-oxides

Abstract Complexes of five pyridines and nine pyridine N-oxides with 2,6-dichloro-4-nitrophenol (DCNP) in solution and the solid state were studied by Fourier transform IR and UV spectroscopy, by quantum-mechanical calculations with the semiempirical parametric method 3 (PM3) and by X-ray analysis. The crystals of the 1 : 1 complex of 4-methoxy-2,6-dimethylpyridine N-oxide with DCNP are monoclinic, space group P 2 1 n , a = 4.5936(5) A , b = 21.953(3) A , c = 15.664(2) A , β = 92.87(1)°, V = 1577.6(8) A 3 , Z = 4. The molecules of the complex are joined together by an N+OH⋯O− hydrogen bond with an O⋯O distance of 2.425(3) A, a CO− distance of 1.286(3) A and a (N+O)H⋯O− angle of 152.9°. The PM3 method predicts for all the investigated complexes two minima, the deeper one for B⋯HA complexes and the shallower one for the B+H⋯A− forms. For the 4-methylpyridine complex the N+H⋯O− distance is reproduced correctly but for the 4-methoxy-2,6-dimethylpyridine N-oxide complex the N+H⋯O− distance is too long. The predicted hydrogen-bond angles differ from the experimental values by more than 10°. In solid state complexes of pyridines the N⋯O distances and the broad absorption due to a protic vibration are not directly related to ΔpKa. This is due to the crystal packing forces. In solution the broad absorption varies with ΔpKa. A band in the 3500 cm−1 region due to the solvated phenol is present in all investigated complexes in solution. Absorption in the 3000−2000 cm−1 region of pyridine complexes is more intense than that of the pyridine N-oxides, in agreement with the difference in N⋯O and NO⋯O distances. The broad absorption in the spectra of pyridine complexes is more influenced by solvent effects than in the pyridine N-oxide complexes. The UV spectra of the pyridine complexes show two bands due to B⋯HA (305–315 nm) and B+H⋯A− (382–395 nm) forms. The UV spectra of complexes of pyridine N-oxides of intermediate strengths in CH2Cl2 are not combinations of the spectra of phenol and phenolate. The band in the intermediate position denotes that neither species close to phenol nor to phenoxide ion is present. In these complexes the proton is probably localized in a single minimum and the minimum moves from the donor to the acceptor or, what is more probable, reorganization of the solvent molecules around the complex is faster than the time range of UV spectroscopy. In acetonitrile the situation is quite different as two bands are present, in agreement with a prototropic equilibrium. Effects of solvent, concentration and stoichiometry on interactions of DCNP with pyridines and pyridine N-oxides are compared and discussed. An extended mechanism of the proton-transfer reaction is proposed.

Synthesis and characterization of periphery-functionalized porphyrazines containing mixed pyrrolyl and pyridylmethylamino groups

The condensation reaction of 2-amino-3-[(3-pyridylmethyl)amino]-2(Z)-butene-1,4-dinitrile with a series of diketones led to novel dinitriles, of which 2-(2,5-dimethyl-1H-pyrrol-1-yl)-3-[methyl(3-pyridylmethylene)amino]-2(Z)-butene-1,4-dinitrile, the product of the Paal-Knorr reaction, was successfully utilized in the Linstead macrocyclization towards symmetrical and unsymmetrical porphyrazines. NMR and X-ray study revealed an almost perpendicular orientation of the pyrrolyl groups in relation to the porphyrazine platform. The newly synthesized macrocycles with different peripheral groups show interesting spectroscopic and electrochemical properties. Due to selective sensor/coordination properties they are expected to find applications as chemical sensors and electronic materials.

Hydrogen bonds in 1:2 complexes of substituted pyridine N-oxides with pentachlorophenol

Abstract Pyridine N-oxides form two types of crystalline complexes with phentachlorophenol, with 1:1 and 1:2 base-to-acid ratios. The 1:2 complex of 2,6-dimethylpyridine N-oxide with pentachlorophenol crystallizes in space group P1 with a = 7.335(1) A , b = 11.324(2) A , c = 15.824(2) A , α = 100.38(1)°, β = 94.63(1)°, γ = 106.60(1)°, V = 1226.7(6) A 3 and Z = 2. The structure has been refined to R = 0.046 for 3408 observed Mo Kα reflections. The oxygen atom of the N-oxide group accepts hydrogen bonds from two molecules of pentachlorophenol, with Otctdot;O distances of 2.639(5) and 2.642(5) A and OHO angles of 141.2° and 157.6°, respectively. Both NOtctdot;HO bridges are formed in, or near, the directions of the electron lone-pairs of the N-oxygen atom. The two pentachlorophenol rings (A and B) are nearly parallel to each other and they are almost perpendicular to the pyridine ring. FTIR spectra of eleven 1:2 complexes in the solid state are similar and independent of the proton acceptor properties of the N-oxides. Five lines in the 35 Cl NQR spectra of the 1:2 complexes provide evidence that both molecules of pentachlorophenol are equivalent. In CHCl 3 solution, all the 1:2 complexes exist as a mixture of the 1:1 complex and pentachlorophenol.

FT-IR, UV—visible and X-ray studies of complexes of pyridine N-oxides with pentachlorophenol

Abstract The crystal structure of the 4-methoxy-2,6-dimethylpyridine N -oxide·pentachlorophenol complex has been determined by X-ray analysis. The O ··· O distance is 2.439(6) A, the OHO angle is 152.3° and the hydrogen-bonded proton is close to the phenol molecule. The FT-IR spectra of pentachlorophenol complexes with some substituted pyridine N -oxides in the solid state and seven aprotic solvents of different polarity (ϵ from 2.27 to 37.5) show a broad absorption. The broad absorption shows weak dependence upon solvent polarity and is classified as type (ii). UV spectra show that in the investigated complexes protons are not transferred from the phenol to the N -oxides. Formamide ( ϵ = 111) is a much stronger proton acceptor than the pyridine N -oxides. Pentachlorophenol in formamide is converted to the phenolate ion.

X-Ray, FTIR and quantum chemical studies of short and asymmetric hydrogen bonds in bis(2,6-dimethylpyridine-N-oxide) sulphate [2,6-(CH3)2C5H3N+OH]2[SO2−4]

Abstract Crystals of bis(2,6-dimethylpyridine-N-oxide) sulphate are monoclinic, space group P2 1 c , a = 14.098(2) A , b = 7.855(1) A , c = 15.203(3) A , β = 104.84(1)°. The crystal structure has been refined to R = 0.0373 (2052 reflections). The disordered SO2−4 anion accepts hydrogen bonds from two protonated 2,6-dimethylpyridine-N-oxides and two alternative conformations of the SO2−4 group are distinguished. The occupancy factor of the predominant orientation is 0.63 and the O...O distances are 2.445(2) and 2.453(4) A; in the second form (fraction, 0.37), these distances are 2.445(2) and 2.544(9) A. The PM3 and AM1 methods predict three minima for the title complex, whereas the SAM1 and BLYP/6-31G methods predict only one. All methods predict that molecular complex 3 is the most stable. The SAM1 geometry is very close to that of BLYP/6-31G. The Fourier transform IR (FTIR) spectrum shows a very intense and broad (continuum) absorption within the 1600-400 cm−1 region, typical of short hydrogen bonds. There is no absorption in the 3000-2000 cm−1 region expected for the longer hydrogen bond (2.544(9) A) in the less populated orientation. Isotope and solvent effects are discussed.

Redetermination of rifampicin pentahydrate revealing a zwitterionic form of the antibiotic.

Rifampicin belongs to the family of naphthalenic ansamycin antibiotics. The first crystal structure of rifampicin in the form of the pentahydrate was reported in 1975 [Gadret, Goursolle, Leger & Colleter (1975). Acta Cryst. B 31, 1454-1462] with the rifampicin molecule assumed to be neutral. Redetermination of this crystal structure now shows that one of the phenol -OH groups is deprotonated, with the proton transferred to a piperazine N atom, confirming earlier spectroscopic results that indicated a zwitterionic form for the molecule, namely (2S,12Z,14E,16S,17S,18R,19R,20R,21S,22R,23S,24E)-21-acetyloxy-6,9,17,19-tetrahydroxy-23-methoxy-2,4,12,16,18,20,22-heptamethyl-8-[(E)-N-(4-methylpiperazin-4-ium-1-yl)formimidoyl]-1,11-dioxo-1,2-dihydro-2,7-(epoxypentadeca[1,11,13]trienimino)naphtho[2,1-b]furan-5-olate pentahydrate, C(43)H(58)N(4)O(12)·5H(2)O. The molecular structure of this antibiotic is stabilized by a system of four intramolecular O-H···O and N-H···N hydrogen bonds. Four of the symmetry-independent water molecules are arranged via hydrogen bonds into helical chains extending along [100], whereas the fifth water molecule forms only one hydrogen bond, to the amide group O atom. The rifampicin molecules interact via O-H···O hydrogen bonds, generating chains along [001]. Rifampicin pentahydrate is isostructural with recently reported rifampicin trihydrate methanol disolvate.

Synthesis and singlet oxygen generation of pyrazinoporphyrazines containing dendrimeric aryl substituents

Pyrazinoporphyrazines and tribenzopyrazinoporphyrazines were synthesized and studied towards their potential applications in photodynamic therapy. The macrocycles were obtained via Linstead macrocyclization with good yields. The expansion of the porphyrazine periphery with hyperbranched aryl substituents was beneficial in terms of purification and isolation of compounds, effectively hampering their aggregation tendency in different concentrations. The obtained macrocycles were assessed for their singlet oxygen generation quantum yields and revealed far better efficacies for tribenzopyrazinoporphyrazines than pyrazinoporphyrazines. A comparison of the crystal packing of two 2,3-dicyanopyrazine derivatives revealed that the recurring motif of the supramolecular architecture is a dimer formed by π–π stacking interactions between aromatic pyrazine and phenyl rings of the inversion center related molecules.

Experimental and computational study on the reactivity of 2,3-bis[(3-pyridylmethyl)amino]-2(Z)-butene-1,4-dinitrile, a key intermediate for the synthesis of tribenzoporphyrazine bearing peripheral methyl(3-pyridylmethyl)amino substituents.

An earlier developed alkylating path leading to tetraalkylated diaminomaleonitrile derivatives was explored. Attempts to explain the reactivity of the representative dialkylated diaminomaleonitrile 2,3-bis[(3-pyridylmethyl)amino]-2(Z)-butene-1,4-dinitrile during the alkylation reaction were performed using X-ray and density functional theory (DFT) studies. The condensed Fukui functions accompanied by softness indices were found to be useful in explaining its reactivity observed during the reaction. The values of the Fukui functions and condensed softness for electrophilic attack calculated from Mulliken, Löwdin, and natural population analyses closely corresponded to the experimental observations. When 2,3-bis[(3-pyridylmethyl)amino]-2(Z)-butene-1,4-dinitrile disodium salt was treated with dimethyl sulfate at lower temperatures the alkylation reaction prevailed, whereas at higher temperatures the alkylating agent acted as a hydride anion acceptor, which favored the elimination reaction. The tetraalkylated dinitrile 2,3-bis[methyl(3-pyridylmethyl)amino]-2(Z)-butene-1,4-dinitrile was used in the synthesis of tribenzoporphyrazine bearing methyl(3-pyridylmethyl)amino groups, which was subsequently subjected to solvatochromic and metallation studies. The changes observed during metallation seem to result from the coordination of the 3-pyridyl group by a palladium ion. This could influence the configuration of the methyl(3-pyridylmethyl)amino moiety, causing more effective donation of a lone pair of electrons from peripheral nitrogen to the macrocyclic ring.Graphical abstract.