Magnesium complexes of phthalocyanines (Pcs) and their aza-analogues have a great potential in medical applications or fluorescence detection. They are known to demetallate to metal-free ligands in acidic environments, however, detailed investigation of this process and its possible prevention is lacking. In this work, a conversion of lipophilic and water-soluble magnesium complexes of Pcs and tetrapyrazinoporphyrazines (TPyzPzs) to metal-free ligands was studied in relation to the acidity of the environment (organic solvent, water) including the investigation of the role of delivery systems (microemulsion or liposomes) in improvement in their acido-stability. The mechanism of the demetallation in organic solvents was based on an acidoprotolytic mechanism with the protonation of the azomethine nitrogen as the first step and a subsequent conversion to non-protonated metal-free ligands. In water, the mechanism seemed to be solvoprotolytic without any protonated intermediate. The water-soluble magnesium complexes were stable in a buffer with a physiological pH 7.4 while a time-dependent demetallation was observed in acidic pH. The demetallation was immediate at pH < 2 while the full conversion to metal-free ligand was done within 10 min and 45 min for TPyzPzs at pH 3 and pH 4, respectively. Incorporation of lipophilic magnesium complexes into microemulsion or liposomes substantially decreased the rate of the demetallation with the latter delivery system being much more efficient in the protection from the acidic environment. A comparison of two different macrocyclic cores revealed significantly higher kinetic inertness of magnesium TPyzPz complexes than their Pc analogues.

Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Faculty of Pharmacy in Hradec Kralove Charles University Akademika Heyrovskeho 1203 500 05 Hradec Kralove Czech Republic

Zobrazit více v PubMed

Linstead R.P., Lowe A.R. 214. Phthalocyanines. Part III. Preliminary experiments on the preparation of phthalocyanines from phthalonitrile. J. Chem. Soc. 1934:1022–1027. doi: 10.1039/jr9340001022. DOI

Byrne G.T., Linstead R.P., Lowe A.R. 213. Phthalocyanines. Part II. The preparation of phthalocyanine and some metallic derivatives from o-cyanobenzamide and phthalimide. J. Chem. Soc. 1934:1017–1022. doi: 10.1039/jr9340001017. DOI

Cao W., Wang K., Ledoux-Rak I., Jiang J.Z. ABAB-type phthalocyanines simultaneously bearing electron donating and electron accepting groups. Synthesis, spectroscopy, and structure. Inorg. Chem. Front. 2016;3:1146–1151. doi: 10.1039/C6QI00147E. DOI

Safonova E.A., Martynov A.G., Zolotarevskii V.I., Nefedov S.E., Gorbunova Y.G., Tsivadze A.Y. Design of UV-Vis-NIR panchromatic crown-phthalocyanines with controllable aggregation. Dalton Trans. 2015;44:1366–1378. doi: 10.1039/C4DT02759K. PubMed DOI

Kucinska M., Skupin-Mrugalska P., Szczolko W., Sobotta L., Sciepura M., Tykarska E., Wierzchowski M., Teubert A., Fedoruk-Wyszomirska A., Wyszko E., et al. Phthalocyanine Derivatives Possessing 2-(Morpholin-4-yl)ethoxy Groups As Potential Agents for Photodynamic Therapy. J. Med. Chem. 2015;58:2240–2255. doi: 10.1021/acs.jmedchem.5b00052. PubMed DOI

Kuhri S., Engelhardt V., Faust R., Guldi D.M. En route towards panchromatic light harvesting: Photophysical and electrochemical properties of Bodipy-porphyrazine conjugates. Chem. Sci. 2014;5:2580–2588. doi: 10.1039/c4sc00326h. DOI

Kharitonova N.V., Maiorova L.A., Koifman O.I. Aggregation behavior of unsubstituted magnesium porphyrazine in monolayers at air-water interface and in Langmuir-Schaefer films. J. Porphyr. Phthalocyanines. 2018;22:509–520. doi: 10.1142/S1088424618500505. DOI

Falkowski M., Rebis T., Piskorz J., Popenda L., Jurga S., Mielcarek J., Milczarek G., Goslinski T. Improved electrocatalytic response toward hydrogen peroxide reduction of sulfanyl porphyrazine/multiwalled carbon nanotube hybrids deposited on glassy carbon electrodes. Dyes Pigm. 2016;134:569–579. doi: 10.1016/j.dyepig.2016.08.014. DOI

Oter O., Aydin A.C., Zeyrek Ongun M., Celik E. Development of a nanoscale-based optical chemical sensor for the detection of NO radical. Turk. J. Chem. 2018;42:1056–1071. doi: 10.3906/kim-1712-47. DOI

Zimcik P., Novakova V., Kopecky K., Miletin M., Uslu Kobak R.Z., Svandrlikova E., Váchová L., Lang K. Magnesium Azaphthalocyanines: An Emerging Family of Excellent Red-Emitting Fluorophores. Inorg. Chem. 2012;51:4215–4223. doi: 10.1021/ic2027016. PubMed DOI

Karlikova M., Cermakova V., Demuth J., Valer V., Miletin M., Novakova V., Zimcik P. Magnesium tetrapyrazinoporphyrazines: Tuning of the pKa of red-fluorescent pH indicators. Dalton Trans. 2019;48:6162–6173. doi: 10.1039/C9DT00381A. PubMed DOI

Machacek M., Cidlina A., Novakova V., Svec J., Rudof E., Miletin M., Kucera R., Simunek T., Zimcik P. Far-Red-Absorbing Cationic Phthalocyanine Photosensitizers: Synthesis and Evaluation of the Photodynamic Anticancer Activity and the Mode of Cell Death Induction. J. Med. Chem. 2015;58:1736–1749. doi: 10.1021/jm5014852. PubMed DOI

Lapshina M.A., Norko S.I., Baulin V.E., Terentiev A.A., Tsivadze A.Y., Goldshleger N.F. Magnesium Octa[(4’-benzo-15-crown-5)oxy]phthalocyanine in Phosphate Buffer: Supramolecular Organization, Cytotoxicity and Accumulation/Localization in Tumor Cells HeLa. Macroheterocycles. 2018;11:396–403. doi: 10.6060/mhc180899l. DOI

Yabaş E., Şahin-Bölükbaşı S., Şahin-İnan Z.D. New water soluble magnesium phthalocyanine as a potential anticancer drug: Cytotoxic and apoptotic effect on different cancer cell lines. J. Porphyrins Phthalocyanines. 2022;26:65–77. doi: 10.1142/S1088424621500863. DOI

Sobotta L., Skupin-Mrugalska P., Piskorz J., Mielcarek J. Porphyrinoid photosensitizers mediated photodynamic inactivation against bacteria. Eur. J. Med. Chem. 2019;175:72–106. doi: 10.1016/j.ejmech.2019.04.057. PubMed DOI

Stolarska M., Glowacka-Sobotta A., Ziental D., Dlugaszewska J., Falkowski M., Mielcarek J., Goslinski T., Sobotta L. Photochemical properties and photocytotoxicities against wound bacteria of sulfanyl porphyrazines with bulky peripheral substituents. J. Organomet. Chem. 2021;934:121669. doi: 10.1016/j.jorganchem.2020.121669. DOI

Czarczynska-Goslinska B., Stolarska M., Ziental D., Falkowski M., Glowacka-Sobotta A., Dlugaszewska J., Goslinski T., Sobotta L. Photodynamic antimicrobial activity of magnesium(II) porphyrazine with bulky peripheral sulfanyl substituents. Phosphorus Sulfur Silicon Relat. Elem. 2022 doi: 10.1080/10426507.2021.2012780. accepted. DOI

Stolarska M., Glowacka-Sobotta A., Ziental D., Dlugaszewska J., Falkowski M., Goslinski T., Sobotta L. Photochemical properties and promising activity against staphylococci of sulfanyl porphyrazines with dendrimeric moieties. Inorg. Chim. Acta. 2021;521:120321. doi: 10.1016/j.ica.2021.120321. DOI

Lapok L., Cyza M., Gut A., Kepczynski M., Szewczyk G., Sarna T., Nowakowska M. Synthesis, spectroscopic properties and interaction with a liposomal membrane of a novel iodinated magnesium phthalocyanine. J. Photochem. Photobiol. A. 2014;286:55–63. doi: 10.1016/j.jphotochem.2014.04.006. DOI

Bartlett M.A., Sundermeyer J. Group 10 metal–thiocatecholate capped magnesium phthalocyanines—coupling chromophore and electron donor/acceptor entities and its impact on sulfur induced red-shifts. Dalton Trans. 2018;47:16255–16263. doi: 10.1039/C8DT03681K. PubMed DOI

Janczak J. Solvothermal modification of magnesium phthalocyanine. Inorg. Chim. Acta. 2018;478:88–103. doi: 10.1016/j.ica.2018.03.018. DOI

Kossanyi J., Chahraoui D. Electron transfer reaction and demetalation of phthalocyanines. Int. J. Photoenergy. 2000;2:9–15. doi: 10.1155/S1110662X00000027. DOI

Jang C.K., Byun S.H., Kim S.H., Lee D.K., Jaung J.Y. Synthesis and optical properties of tetrapyrazinoporphyrazines containing camphorquinone group. J. Porphyr. Phthalocyanines. 2009;13:794–797. doi: 10.1142/S1088424609000991. DOI

Chen Y., Fang W., Wang K., Liu W., Jiang J. Nonperipheral Tetrakis(dibutylamino)phthalocyanines. New Types of 1,8,15,22-Tetrakis(substituted)phthalocyanine Isomers. Inorg. Chem. 2016;55:9289–9296. doi: 10.1021/acs.inorgchem.6b01371. PubMed DOI

Stuzhin P.A., Bauer E.M., Ercolani C. Tetrakis(thiadiazole)porphyrazines. 1. Syntheses and Properties of Tetrakis(thiadiazole)porphyrazine and Its Magnesium and Copper Derivatives. Inorg. Chem. 1998;37:1533–1539. doi: 10.1021/ic9609259. DOI

Barker C.A., Zeng X.S., Bettington S., Batsanov A.S., Bryce M.R., Beeby A. Porphyrin, phthalocyanine and porphyrazine derivatives with multifluorenyl substituents as efficient deep-red emitters. Chem. Eur. J. 2007;13:6710–6717. doi: 10.1002/chem.200700054. PubMed DOI

Sobotta L., Dlugaszewska J., Ziental D., Szczolko W., Koczorowski T., Goslinski T., Mielcarek J. Optical properties of a series of pyrrolyl-substituted porphyrazines and their photoinactivation potential against Enterococcus faecalis after incorporation into liposomes. J. Photochem. Photobiol. A. 2019;368:104–109. doi: 10.1016/j.jphotochem.2018.09.015. DOI

Piskorz J., Konopka K., Düzgüneş N., Gdaniec Z., Mielcarek J., Goslinski T. Diazepinoporphyrazines Containing Peripheral Styryl Substituents and Their Promising Nanomolar Photodynamic Activity against Oral Cancer Cells in Liposomal Formulations. ChemMedChem. 2014;9:1775–1782. doi: 10.1002/cmdc.201402085. PubMed DOI

Berezin B.D., Shukhto O.V., Berezin D.B. A new type of metal porphyrin dissociation reaction. Russ. J. Inorg. Chem. 2002;47:1763–1768.

Berezin B.D., Shukhto O.V., Berezin D.B. Unusual spectral and kinetic properties of magnesium phthalocyanine. Izv. Vyssh. Uchebn. Zaved. Khim. Khim. Tekhnol. 2002;45:5–11.

Petrik P., Zimcik P., Kopecky K., Musil Z., Miletin M., Loukotova V. Protonation and deprotonation of nitrogens in tetrapyrazinoporphyrazine macrocycles. J. Porphyr. Phthalocyanines. 2007;11:487–495. doi: 10.1142/S1088424607000564. DOI

Stuzhin P.A. Azaporphyrins and phthalocyanines as multicentre conjugated ampholites. J. Porphyr. Phthalocyanines. 1999;3:500–513. doi: 10.1002/(SICI)1099-1409(199908/10)3:6/7<500::AID-JPP168>3.0.CO;2-9. DOI

Ivanova S.S., Stuzhin P.A. Indium(III) complexes of octaphenylporphyrazine: Effect of halide coordination on the basic properties and stability in acid media. J. Porphyr. Phthalocyanines. 2011;15:1299–1309. doi: 10.1142/S108842461100421X. DOI

Fukuzumi S., Honda T., Kojima T. Structures and photoinduced electron transfer of protonated complexes of porphyrins and metallophthalocyanines. Coord. Chem. Rev. 2012;256:2488–2502. doi: 10.1016/j.ccr.2012.01.011. DOI

Kasuga K., Yashiki K., Sugimori T., Handa M. Bathochromic shift of the Q-bands of octakis(p-t-butylbenzyloxy) phthalocyanines with magnesium(II), nickel(II) and copper(II) in a solvent mixture of chloroform and acetic acid. J. Porphyr. Phthalocyanines. 2005;9:646–650. doi: 10.1142/S1088424605000757. DOI

Kristensen K., Henriksen J.R., Andresen T.L. Adsorption of Cationic Peptides to Solid Surfaces of Glass and Plastic. PLoS ONE. 2015;10:e0122419. doi: 10.1371/journal.pone.0122419. PubMed DOI PMC

Malinin A.S., Kalashnikova I.V., Rakhnyanskaya A.A., Yaroslavov A.A. Adsorption of cationic polymers on the surfaces of anionic glass microspheres. Polym. Sci. Ser. A. 2012;54:81–86. doi: 10.1134/S0965545X1201004X. DOI

Liu X., Cheng J., Lu X., Wang R. Surface acidity of quartz: Understanding the crystallographic control. Phys. Chem. Chem. Phys. 2014;16:26909–26916. doi: 10.1039/C4CP02955K. PubMed DOI

Behrens S.H., Grier D.G. The charge of glass and silica surfaces. J. Chem. Phys. 2001;115:6716–6721. doi: 10.1063/1.1404988. DOI

Matos C., Moutinho C., Lobao P. Liposomes as a model for the biological membrane: Studies on daunorubicin bilayer interaction. J. Membr. Biol. 2012;245:69–75. doi: 10.1007/s00232-011-9414-2. PubMed DOI

Peetla C., Stine A., Labhasetwar V. Biophysical Interactions with Model Lipid Membranes: Applications in Drug Discovery and Drug Delivery. Mol. Pharm. 2009;6:1264–1276. doi: 10.1021/mp9000662. PubMed DOI PMC

Zimcik P., Miletin M., Radilova H., Novakova V., Kopecky K., Svec J., Rudolf E. Synthesis, Properties and In Vitro Photodynamic Activity of Water-soluble Azaphthalocyanines and Azanaphthalocyanines. Photochem. Photobiol. 2010;86:168–175. doi: 10.1111/j.1751-1097.2009.00647.x. PubMed DOI

Novakova V., Laskova M., Vavrickova H., Zimcik P. Phenol-Substituted Tetrapyrazinoporphyrazines: pH-Dependent Fluorescence in Basic Media. Chem. Eur. J. 2015;21:14382–14392. doi: 10.1002/chem.201502533. PubMed DOI

Zimcik P., Miletin M., Kopecky K., Musil Z., Berka P., Horakova V., Kucerova H., Zbytovska J., Brault D. Influence of aggregation on interaction of lipophilic, water-insoluble azaphthalocyanines with DOPC vesicles. Photochem. Photobiol. 2007;83:1497–1504. doi: 10.1111/j.1751-1097.2007.00193.x. PubMed DOI

Mellman I., Fuchs R., Helenius A. Acidification of the endocytic and exocytic pathways. Annu. Rev. Biochem. 1986;55:663–700. doi: 10.1146/annurev.bi.55.070186.003311. PubMed DOI

Kostka M., Zimcik P., Miletin M., Klemera P., Kopecky K., Musil Z. Comparison of aggregation properties and photodynamic activity of phthalocyanines and azaphthalocyanines. J. Photochem. Photobiol. A. 2006;178:16–25. doi: 10.1016/j.jphotochem.2005.06.014. DOI