Non-aggregated and water soluble non-peripherally octa substituted Co(II) and Cu(II) phthalocyanines: Synthesis and α-glucosidase inhibitory effects.

Type 2 diabetes (T2DM) is a progressive metabolic disease associated with high blood sugar levels that affects 537 million people worldwide. This study aim is to investigate the potential for use in the treatment of T2DM by examining the in vitro glucosidase inhibitory effects of novel synthesized metallophthalocyanines. For this reason, we have synthesized cobalt(II), copper(II) phthalocyanines (3PY-ON-CoQ, 3PY-ON-CuQ) that are both water-soluble and do not aggregate in water. These compounds were characterized by using various spectroscopic methods. The α-glucosidase inhibitory properties of 3PY-ON-CoQ and 3PY-ON-CuQ were carried out using the spectrophotometric method. Then, Lineweaver-Burk and Dixon plots were examined to determine the inhibitory type and constant (Ki). The IC50 values of 3PY-ON-CoQ and 3PY-ON-CuQ were 6.85 ± 1.25 µM and 55.09 ± 2.64 µM, respectively. Both compounds displayed mixed inhibitory effects on α-glucosidase according to Lineweaver-Burk plots. The Ki values of 3PY-ON-CoQ and 3PY-ON-CuQ were calculated as 6.30 ± 1.55 µM and 54.25 ± 1.20 µM, respectively. The results of this work may lead to the discovery of new compounds for the treatment of T2DM.

Synthesis and in vitro α-glucosidase and cholinesterases inhibitory actions of water-soluble metallophthalocyanines bearing ({6-[3-(diethylamino)phenoxy]hexyl}oxy groups.

In this paper, we have prepared peripherally tetra-({6-[3-(diethylamino)phenoxy]hexyl}oxy substituted cobalt(II), copper(II), manganese(III) phthalocyanines (3, 4, 5) and their water-soluble derivatives (3a, 4a, 5a). Then, in vitro α-glucosidase and cholinesterases inhibitory actions of the water-soluble 3a, 4a, 5a were examined using spectrophotometric methods. 4a had the highest inhibitory effects among the tested compounds against α-glucosidase due to IC50 values. 4a and 5a had 40 fold higher inhibitory effects than the positive control. For cholinesterases, the compounds showed significant inhibitory actions that of galantamine which was used as a positive control. According to the SI value, 3a inhibited acetylcholinesterase enzyme selectively. In kinetic studies, 4a was a mixed inhibitor for α-glucosidase, 3a was a competitive inhibitor for AChE, and 4a was a mixed inhibitor for BuChE. The therapeutic potential of these compounds has been demonstrated by in vitro studies, but these data should be supported by further studies.

Pyridine substituted BODIPYs: synthesis, characterization and cholinesterease, α-glucosidase inhibitory, DNA hydrolytic cleavage effects.

In this study, the synthesis of new monostyryl (BDPY-2) and distyryl BODIPY dyes (BDPY-4, BDPY-5) containing pyridine groups has been reported for the first time. The acetylcholinesterase from Electrophorus electricus (AChE), butyrylcholinesterase from equine serum (BuChE), α-glucosidase from Saccharomyces cerevisiae and DNA hydrolytic cleavage actions of BDPY-2, BDPY-4, BDPY-5 were investigated using various techniques. The results indicated that the compounds had varying inhibition properties against AChE, BuChE, and α-glucosidase. BDPY-4 was the most potent compound on AChE with IC50 of 54.78 ± 4.51 µM, and Lineweaver-Burk plots indicated that the compound is bound to a site other than the active site as a noncompetitive inhibitor. The compound-protein binding experiment showed that BDPY-4 changed the microenvironment around AChE. On the other hand, the compounds showed lower α-glucosidase inhibition than the positive control. The DNA hydrolytic cleavage effects were not observed on supercoiled plasmid DNA in the presence of the compounds as compared to negative controls. These findings suggested that BDPY-4 might be a promising compound to treat Alzheimer's diseases.

Synthesis of nonperipherally tetra-[5-(diethylamino)-2-formylphenoxy] substituted metallophthalocyanines and their electrochemistry.

3-[5-(diethylamino)-2-formylphenoxy]phthalonitrile ( n-TY-CN ), metallophthalocyanines n-TY-Co , n-TY-Cu , and n-TY-Mn bearing [5-(diethylamino)-2-formylphenoxy] groups at nonperipheral positions were prepared for the first time. These compounds were characterized with IR, NMR (only for n-TY-CN ), mass and UV-vis (except n-TY-CN ) spectroscopy. Voltammetric characterizations of n-TY-Co , n-TY-Cu , and n-TY-Mn revealed that while n-TY-Co , n-TY-Cu , and n-TY-Mn showed characteristic Pc ring and/or metal-based reduction reaction, n-TY-Co , n-TY-Cu , and n-TY-Mn were coated on the working electrode during the oxidation processes owing to the cationic electropolymerizations of the [5-(diethylamino)-2-formylphenoxy] substituents.

Synthesis and photodynamic activities of novel silicon(iv) phthalocyanines axially substituted with water soluble groups against HeLa cancer cell line.

In this study, compounds 1 and 2, and their silicon(iv) phthalocyanine (SiPc) derivatives 3 and 4, which bear these ligands as substituents on the axial positions were synthesized. These SiPcs (3 and 4) were also converted to their water soluble derivatives (3a and 4a). All these novel compounds were fully characterized by a combination of spectroscopic data such as FT-IR, 1H-NMR, 13C-NMR and UV-vis as well as mass spectroscopy. The photophysicochemical properties (fluorescence quantum yields and lifetimes, singlet oxygen, and photodegradation quantum yields) were investigated in DMSO for all the studied SiPcs (3 and 4) and in both DMSO and aqueous solutions for the water soluble SiPcs (3a and 4a). Effects of quaternization of these phthalocyanines on photophysicochemical properties were also determined. The photodynamic therapy activities of the water soluble SiPcs (3a and 4a) were tested against to the HeLa cancer cell lines and these phthalocyanines exhibited cytotoxicity against these cell lines.

Design, synthesis and biological evaluation of water soluble and non-aggregated silicon phthalocyanines, naphthalocyanines against A549, SNU-398, SK-MEL128, DU-145, BT-20 and HFC cell lines as potential anticancer agents.

Cancer has become an important public problem in worldwide since cancer incidence and mortality are growing rapidly. In this study, water soluble and non-aggregated silicon (IV) phthalocyanines and naphthalocyanines containing (3,5-bis{3-[3-(diethylamino)phenoxy]propoxy}phenyl)methoxy groups have been synthesized and characterized to investigate their anticancer potential. Their DNA binding/nuclease, topoisomerases inhibition were investigated using UV-Vis absorption, thermal denaturation and agarose gel electrophoresis. The in vitro cytotoxic properties of the compounds on human lung (A549), breast (BT-20), liver (SNU-398), prostate (DU-145), melanoma (SK-Mel 128) carcinoma and human fibroblast (HFC) normal cell lines were evaluated by using MTT assay. In order to determine the mechanism of cancer cell growth suppression, cell cycle analysis was carried out using flow cytometer on A549 cell line. The Kb values of SiPc1a and SiNc2a were 6.85 ± (0.35) × 106 and 1.72 ± (0.16) × 104 M-1 and Tm values of ct-DNA were calculated as 82.02 °C and 78.07 °C, respectively in the presence of both compounds. The ΔTm values of SiPc1a and SiNc2a were calculated as 6.45 and 2.50 °C, respectively. The nuclease effects of SiPc1a and SiNc2a with supercoiled plasmid pBR322 DNA demonstrated that both compounds did not trigger any DNA nuclease effects at the lowest concentrations without irradiation whereas both compounds in the presence of activating agent (H2O2) showed significant plasmid DNA nuclease actions under irradiation (22.5 J/cm2). SiPc1a and SiNc2a inhibited to topoisomerase I on increasing concentrations whilst they had lower inhibition action toward topoisomerase II that of topoisomerase I. The in vitro cytotoxicity studies displayed that SiPc1a had the highest cytotoxic effects among the tested compounds against A549, SNU-398, SK-MEL128, DU-145, BT-20 and HFC cell lines with CC50 values ranged from 0.49 to 2.99 µM. Furthermore, SiPc1a inhibited cell proliferation by cell cycle arrest in G0/G1 phase. All of these results suggested that SiPc1a is a promising candidate as an anticancer agent.

Synthesis, Characterization, and Photocatalytic Evaluation of Manganese (III) Phthalocyanine Sensitized ZnWO4 (ZnWO4MnPc) for Bisphenol A Degradation under UV Irradiation.

ZnWO4MnPc was synthesized via a hydrothermal autoclave method with 1 wt.% manganese (iii) phthalocyanine content. The material was characterized for its structural and morphological features via X-ray diffraction (XRD) spectroscopy, Fourier transform infrared (FTIR) spectroscopy, transmission emission microscopy (TEM), scanning electron microscopy-Energy dispersive X-ray spectroscopy (SEM-EDX), N2 adsorption-desorption at 77K, X-ray photoelectron spectroscopy (XPS), and UV-visible/diffuse reflectance spectroscopy(UV-vis/DRS). ZnWO4MnPc photocatalytic performance was tested on the degradation of bisphenol A (BPA). The ZnWO4MnPc material removed 60% of BPA after 4 h of 365 nm UV irradiation. Degradation process improved significantly to about 80% removal in the presence of added 5 mM H2O2 after 4 h irradiation. Almost 100% removal was achieved after 30 min under 450 nm visible light irradiation in the presence of same concentration of H2O2. The effect of ions and humic acid (HA) towards BPA removal was also investigated.

Synthesis of axially disubstituted quaternized silicon phthalocyanines as a promising photosensitizer for the photodynamic treatment of HCT-116, A549 and SH-SY5Y cancer cell lines.

In this study, novel silicon(iv) phthalocyanines axially disubstituted with bis[(4-{3-[3-(dimethylamino)phenoxy]propoxy}phenyl)methoxy] and bis[(4-{3-[3-(diethylamino)phenoxy]propoxy}phenyl)methoxy] groups and their quaternized derivatives were synthesized and characterized. Then, their supercoiled pBR322 plasmid DNA cleavage properties were investigated using agarose gel electrophoresis. The in vitro PDT effects of Si-3a and Si-4a were investigated using the MTT cell viability assay against HCT-116, A549 and SH-SY5Y cell lines. Si-3a and Si-4a did not show cleavage effects upon increasing concentrations in the dark but both compounds showed cleavage activities upon irradiation for 30 and 60 min, respectively. The MTT cell viability assay indicated that Si-4a had a cytotoxic effect in a concentration-dependent manner on the HCT-116 cell line but it did not show any statistical difference with regard to phototoxicity. Otherwise, Si-3a and Si-4a had significant phototoxic effects when compared to cytotoxic effects against A549 and SH-SY5Y. The results suggested that Si-3a and Si-4a showed better cell death against SH-SY5Y than other cell lines with irradiation.

Antifungal photodynamic activities of phthalocyanine derivatives on Candida albicans.

Antimicrobial resistance is one of the most important causes of morbidity and mortality in the treatment of infectious diseases worldwide. Candida albicans is one of the most virulent and common species of fungi to cause invasive fungal infections on humans. Alternative treatment strategies, including photodynamic therapy, are needed for controlling these infectious diseases. The aim of this study was to investigate the antifungal photodynamic activities of phthalocyanine derivatives on C. albicans. The minimum inhibitory concentration (MIC) values of compounds were determined by the broth microdilution method. Uptake of the compounds in C. albicans and dark toxicity of the compounds were also investigated. Photodynamic inhibition of growth experiments was performed by measuring the colony-forming unit/mL (CFU/mL) of the strain. Maximum uptake into the cells was observed in the presence of 64 µg/mL concentration for each compound except for ZnPc. Compounds did not show dark toxicity/inhibitory effects at sub-MIC concentrations on C. albicans when compared to the negative control groups. Zn(II)Pc, ZnPc, and ZnPc-TiO2 showed fungicidal effect after irradiation with the light dose of 90 J/cm2 in the presence of the compounds. In addition to the fungicidal effects, SubPc, SubPc-TiO2, Es-SiPc, and Es-SubPc compounds were also found to have inhibitory effects on the growth of yeast cells after irradiation.

Synthesis and effect of substituent position, metal type on the electrochemical properties of (3-morpholin-4-ylpropoxy) groups substituted cobalt, manganese phthalocyanines.

In this work, 4-(3-morpholin-4-ylpropoxy)phthalonitrile 2, 3-(3-morpholin-4-ylpropoxy)phthalonitrile 3, Co(II)Pc and Mn(III)Pcs containing (3-morpholin-4-ylpropoxy) groups at peripheral and nonperipheral positions were synthesized. Phthalonitrile derivatives (2 and 3), Co(II)Pc and Mn(III)Pcs (2a, 2b, 3a, 3b) were characterized by using FT-IR, NMR (only for 2 and 3), mass and UV-Vis (except 2 and 3) spectral data techniques. Also, electrochemistry of (3-morpholin-4-ylpropoxy) group substituted Co(II)Pc and Mn(III)Pcs were inspected by using cyclic voltammetry. Electrochemical studies show that (3-morpholin-4-ylpropoxy) group substituted Co(II)Pc and Mn(III)Pcs electropolymerized on the Pt working electrode.

Synthesis and electrochemical properties of copper(II), manganese(III) phthalocyanines bearing chalcone groups at peripheral or nonperipheral positions.

In this study, new chalcone compound 1 , new phthalonitrile derivatives 2 and 3, new copper(II), manganese(III) phthalocyanines bearing chalcone groups at peripheral or nonperipheral positions were synthesized. Electrochemistry of tetra-(4-{(2 E )-3-[2-fluoro-4-(trifluoromethyl)phenyl]prop-2-enoyl}phenoxy) substituted Co(II)Pc and Mn(III)Pcs were studied with cyclic voltammetry (CV) to determine the redox properties of the phthalocyanines. According to the results, while the CuPcs 2a and 3a showed two Pc based reduction reactions and one Pc based oxidation reaction, MnPcs 2b and 3b gave two metal-based reduction reactions. All the redox processes are shifted toward positive potentials as a result of the increased electron-withdrawing ability of the trifluoromethyl substituents.

Design, synthesis, characterization of peripherally tetra-pyridine-triazole-substituted phthalocyanines and their inhibitory effects on cholinesterases (AChE/BChE) and carbonic anhydrases (hCA I, II and IX).

In this study, phthalocyanine precursors (5 and 9) and 1,2,3-triazole-substituted metal-free and metallo phthalocyanines (9a-c) were designed and synthesized for the first time and evaluated in vitro for key molecular targets. The structures of the novel compounds were characterized via FT-IR, 1H/13C NMR, UV-Vis, and mass spectroscopy. The inhibitory activities of the compounds were tested against human carbonic anhydrase isoforms hCA I, II (cytosolic, ubiquitous isozymes), and IX (transmembrane, cancer-associated isozyme) and cholinesterases (AChE and BChE, which are associated with Alzheimer's disease). Among the three phthalocyanines and starting compounds, 9b showed the most interesting profile as a nanomolar selective inhibitor of hCA I (Ki = 37.2 nM) and 9c showed the most effective inhibitory effect on hCA II, IX, AChE and BChE (Ki = 41.9, 27.4, 5.8 and 45.8 nM, respectively). This study is also the first example of cancer-associated isozyme hCA IX inhibition by phthalocyanines.

Novel water soluble BODIPY compounds: Synthesis, photochemical, DNA interaction, topoisomerases inhibition and photodynamic activity properties.

In this study, BODIPY compounds (2, 3, 5 and 6) bearing 3,4-bis(3-pyridin-3-ylpropoxy)benzyl, 4-(3-pyridin-3-ylpropoxy)benzyl groups were synthesized for the first time and further functionalized in a Knoevenagel condensation reaction with 3,4-bis(3-pyridin-3-ylpropoxy)benzaldehyde and 4-(3-pyridin-3-ylpropoxy)benzaldehyde. The water soluble derivatives of BODIPY compounds (3a and 6a) were synthesized by treating BODIPY compounds 3 and 6 with excess iodomethane in DMF. The photochemical properties and DNA binding modes of 3a and 6a were determined using ct-DNA by UV-Vis spectrophotometer and viscometer. DNA cleavage and topoisomerases inhibition properties were studied DNA using agarose gel electrophoresis. Their topoisomerase inhibition mechanisms were investigated at molecular level and correlations with the in vitro results were searched for using molecular docking method. In addition, cytotoxicity and phototoxicity of both compounds were performed on colorectal cancer cells (HCT-116) using MTT assay for 24 h. Annexin V-FITC/PI test was performed to determine the cell death mechanism of 6a induced by irradiation. Finally, 6a-loaded liposomes (LP6a) and PLGA nanoparticles (NP6a) were prepared and their cytotoxic and phototoxic effects were evaluated by MTT assay. The results claimed that 6a had great potential as photosensitizer agent for colorectal cancer owing to its photochemical, DNA interaction and phototoxic properties.

Triazole substituted metal-free, metallo-phthalocyanines and their water soluble derivatives as potential cholinesterases inhibitors: Design, synthesis and in vitro inhibition study.

In this study, 1,2,3-triazole substituted metal-free and metallo phthalocyanines (4, 5, 6) and their water soluble derivatives (4a, 5a, 6a) were designed, synthesized for the first time and tested in vitro on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. Most phthalocyanines exhibited good inhibitory activities on these enzymes. Among the six phthalocyanines and starting compounds, 4a showed the most interesting profile as a submicromolar selective inhibitor of AChE (IC50 = 0.040 µM) and 5a showed the most effective inhibitor of BChE (IC50 = 0.1198 µM).

The synthesis of axially disubstituted silicon phthalocyanines, their quaternized derivatives and first inhibitory effect on human cytosolic carbonic anhydrase isozymes hCA I and II.

In this study a novel silicon(iv) phthalocyanine bearing [(2E)-3-[4-(dimethylamino)phenyl]-1-(4-phenoxy)prop-2-en-1-one] group and its quaternized derivative at their axial positions were synthesized for the first time. Axially disubstituted silicon(iv) phthalocyanines were also characterized by various spectroscopic techniques. The inhibition of two human cytosolic carbonic anhydrase (hCA, EC 4.2.1.1) isozymes I and II, with axially disubstituted silicon phthalocyanines and their quaternized derivatives were investigated by using the esterase assay, with 4-nitrophenyl acetate as substrate. Silicon phthalocyanines ZM-1-Si, ZM-5-Si, ZT-Si and their quaternized derivatives ZM-1-SiQ, ZM-5-SiQ, ZT-SiQ showed IC50 values in the range of 0.0178-0.1653 µM for hCA I and of 0.0172-0.1212 µM against hCA II, respectively. This study is the first example of carbonic anhydrase enzyme inhibition of phthalocyanines.

The water soluble axially disubstituted silicon phthalocyanines: photophysicochemical properties and in vitro studies.

Two novel silicon(IV) phthalocyanines bearing 1,3-bis[3(dimethylamino)phenoxy]propan-2-ol or 1,3-bis[3(diethylamino)phenoxy]propan-2-ol groups at their axial positions were synthesized. These phthalocyanines were converted into their water soluble derivatives by the quaternization reaction with methyl iodide. The quaternized phthalocyanines show excellent solubility aqueous solutions without any aggregation which makes them potential photosensitizers for use in photodynamic therapy (PDT). For this reason, the photophysical and photochemical properties such as fluorescence quantum yields, lifetimes, singlet oxygen generation and photodegradation of both non-ionic (3 and 5) and quaternized cationic silicon(IV) phthalocyanines were investigated. Furthermore, the cytotoxicity of PDT was determined by colorimetric proliferation assay against to hepatocellular carcinoma (HuH-7) cancer cells. In this study, the cells were incubated with a novel water soluble silicon(IV) phthalocyanine derivatives and thereafter the cells were illuminated using broad-band incoherent light source.

Design, Synthesis, Characterization and Electrochemical Properties of BODIPY Dyes Containing Mono, Bis-2-Naphthyloxyhexyloxy and 4-(Benzyloxy)Phenoxyhexyloxy Groups.

In this study, the synthesis of boron dipyrromethene dyes containing mono, bis-2-naphthyloxyhexyloxy and 4-(benzyloxy)phenoxyhexyloxy groups has been reported. Boron dipyrromethene dyes were synthesized from the mono, bis-benzaldehyde derivatives with 2,4-dimethylpyrrole in dichloromethane in the presence of trifluoroacetic, 2,3-dichloro-5,6-dicyano-p-benzoquinon, triethyl amine and boron trifluoride diethyl etherate, respectively. Electrochemical characterization of boron dipyrromethene dyes were carried out with voltammetric measurements. Electrochemical studies show that boron dipyrromethene dyes containing mono, bis-2-naphthyloxyhexyloxy and 4-(benzyloxy)phenoxyhexyloxy groups have reversible one reduction potentials unlike irreversible one oxidation potentials. Graphical Abstract ᅟ.

The water soluble peripherally tetra-substituted zinc(ii), manganese(iii) and copper(ii) phthalocyanines as new potential anticancer agents.

In this study, [2-(2-morpholin-4-ylethoxy)ethoxy] group substituted zinc(ii), manganese(iii) and copper(ii) phthalocyanines 2-4 and their water soluble derivatives 2a, 3a and 4a were synthesized and the interactions of compounds 2a, 3a and 4a with CT-DNA and supercoiled pBR322 plasmid DNA were investigated. The results of binding experiments showed that these compounds were able to interact with CT-DNA via intercalative mode with a strong binding affinity in the order 3a > 2a > 4a. DNA-photocleavage activities of compounds 2a, 3a and 4a were determined. These compounds cleaved supercoiled pBR322 plasmid DNA efficiently under irradiation at 650 nm for 2a and 4a, and at 750 nm for 3a. These compounds displayed remarkable inhibitory activities against topoisomerase I enzyme in a dose-dependent manner. All of these results suggest that these phthalocyanines might be suitable anticancer agents due to their strong binding affinities, significant cleavage activities and effective topoisomerase I inhibition.

Investigation of DNA binding, DNA photocleavage, topoisomerase I inhibition and antioxidant activities of water soluble titanium(IV) phthalocyanine compounds.

The binding mode of water soluble peripherally tetra-substituted titanium(IV) phthalocyanine (Pc) compounds Pc1, Pc2 and Pc3 with calf thymus (CT) DNA was investigated by using UV-Vis spectroscopy and thermal denaturation studies in this work. The results of DNA binding constants (Kb) and the changes in the thermal denaturation profile of DNA with the addition of Pc compounds indicated that Pc1, Pc2 and Pc3 are able to bind to CT-DNA with different binding affinities. DNA photocleavage studies of Pc compounds were performed in the absence and presence of oxidizing agents such as hydrogen peroxide (H2O2), ascorbic acid (AA) and 2-mercaptoethanol (ME) using the agarose gel electrophoresis method at irradiation 650 nm. According to the results of electrophoresis studies, Pc1, Pc2 and Pc3 cleaved of supercoiled pBR322 DNA via photocleavage pathway. The Pc1, Pc2 and Pc3 compounds were examined for topoisomerase I inhibition by measuring the relaxation of supercoiled pBR322 DNA. The all of Pc compounds inhibited topoisomerase I at 20 µM concentration. A series of antioxidant assays, including 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, superoxide radical scavenging (SOD) assay and metal chelating effect assay were performed for Pc1, Pc2 and Pc3 compounds. The results of antioxidant assays indicated that Pc1, Pc2 and Pc3 compounds have remarkable superoxide radical scavenging activities, moderate 2,2-diphenyl-1-picrylhydrazyl activities and metal chelating effect activities. All the experimental studies showed that Pc1, Pc2 and Pc3 compounds bind to CT-DNA via minor groove binding, cleave of supercoiled pBR322 DNA via photocleavage pathway, inhibit topoisomerase I and have remarkable superoxide radical scavenging activities. Thanks to these properties the Pc1, Pc2 and Pc3 compounds are suitable agents for photo dynamic therapy.

Axially diethylaminophenoxypropanoxy substituted new subphthalocyanines: synthesis and electropolymerization properties.

The treatment of boron(III) subphthalocyanine chloride with 1,3-bis[3-(diethylamino)phenoxy]propan-2-ol 2 and 2,3-bis[3-(diethylamino)phenoxy]propan-1-ol 4 in toluene gave the corresponding axially substituted boron(III) subphthalocyanine compounds 3 and 5. The novel axially diethylaminophenoxypropanoxy substituted subphthalocyanines were characterized by standard spectroscopy methods. The electropolymerization properties of new axially diethylaminophenoxypropanoxy substituted subphthalocyanines were also characterized by using cyclic and square wave voltammetry techniques. This study is the first example of electropolymerization of axially substituted subphthalocyanines in the literature.