WO2017046813A1 - FLUORESCENT CYCLOMETALATED Ir (III) COMPLEXES AND FORMULATIONS/ COMPOSITIONS COMPRISING THE SAME - Google Patents

FLUORESCENT CYCLOMETALATED Ir (III) COMPLEXES AND FORMULATIONS/ COMPOSITIONS COMPRISING THE SAME Download PDF

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WO2017046813A1
WO2017046813A1 PCT/IN2016/000228 IN2016000228W WO2017046813A1 WO 2017046813 A1 WO2017046813 A1 WO 2017046813A1 IN 2016000228 W IN2016000228 W IN 2016000228W WO 2017046813 A1 WO2017046813 A1 WO 2017046813A1
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complexes
fluorescent
formula
cyclometalated
iii
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PCT/IN2016/000228
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Parna GUPTA
Partho Sarothi Ray
Soumalya SINHA
Soumik MANDAL
Smitha SAHADEVAN
Dipak Kumar PORIA
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Gupta Parna
Partho Sarothi Ray
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
    • C07F15/0033—Iridium compounds
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
    • B01J23/38—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals
    • B01J23/40—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals of the platinum group metals
    • B01J23/46—Ruthenium, rhodium, osmium or iridium
    • B01J23/468—Iridium

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  • the present invention provides for fluorescent cyclometalated Ir (III) complexes and/or salts thereof, and more particularly, provides for formulations/ compositions comprising the same together with its process of preparation that is found to be highly efficient in causing photo-induced death of cancer cells on exposure to laser illumination and also specifically localize and exhibit fluorescence in the endoplasmic reticulum, when employed in effective amounts.
  • the generic molecular structure of said complex is provided hereunder as Formula 1 wherein salts include salts of anion Z " of chloride, bromide.
  • the cyclometalated heteroleptic iridium (III) complexes [F. Neve, A. Crispini, S. Campagna, S. Serroni, inorg. Chem. 1999, 38, 2250] of polypyridyl ligands are highly efficient in imaging of cells and cellular organelles, and are important tools for studying cellular function.
  • the efficacy of the cyclometalated iridium (III) complexes in this field has been demonstrated with a range of substituted phenyl pyridine and polypyridyl units [Q. Zhao, C. Huanga, F. Li, Chem. Soc. Rev. , 2011, 40, 2508]
  • small-molecular dyes, fluorophore-conjugated antibodies or fluorescent proteins are used commercially as imaging agents for cellular organelles such as nuclei, mitochondria, endoplasmic reticulum (ER), Golgi complex and lysosomes [S. A. Hilderbrand, Methods Mol Biol. , 2010, 591, 17] .
  • the cyclometalated iridium (III) complexes provide a number of important advantages over these currently available imaging agents.
  • the factors that influence the cellular uptake and distribution within the microenvironment include permeability through the cell membrane, diffusion in the cellular cytoplasm, the charge-interaction associated with the organellar membranes during the uptake and interaction with organellar components through non-covalent forces, e.g. hydrogen bonds, ionic bonds, van der Waals forces and hydrophobic interactions, which results in specific localization.
  • specific localization is mostly regulated by pH [J. Han, K. Burgess, Chem. Rev. , 2010, 110, 2709.], dielectric constant, hydrophobic and hydrophilic interactions and redox potential [Z. Liu, P. J. Sadler Acc. Chem. Res. 2014, 47, 1174] .
  • Cyclometalated iridium complexes have been reported as cellular imaging probes for visualization of different organelles like nucleoli, [C. Li, M . Yu, Y. Sun, Y. Wu, C. Huang, F. A. Li, J. Am. Chem. Soc , 2011, 133, 11231] Golgi complex, [K. Y. Zhang, . H.-W. Liu, T. T.-H. Fong, X.-G. Chen, K. K.-W. Lo, Inorg. Chem. , 2010, 49, 5432] lysosomes and endosomes [P. Steunenberg, A. uggi, N. S. van den Berg, T. Buckle, J. Kuil, F. W.
  • PDT uses photosensitizing agents in less invasive and more targeted form of cancer treatment. It is also used for the therapy of various inflammatory diseases of the skin such as psoriasis.
  • the photosensitizing agents such as porphyrins, phthalocyanines or methylene blue [H. Ali, J. E. van Lier, Chem. Rev., 1999, 99, 2379.] have been shown to generate reactive singlet oxygen or other reactive oxygen species (ROS) which causes cell death by damaging cellular organelles, cell membrane, DNA etc.
  • ROS reactive oxygen species
  • said fluorescent cyclometalated complexes is selectively photosensitizing to favour imaging of Endoplasmic Reticulum (ER) of cells and/or in having photodynamic therapeutic (PDT) characteristics is suitable for cellular imaging and/or photoinduced cell death.
  • ER Endoplasmic Reticulum
  • PDT photodynamic therapeutic
  • said fluorescent cyclometalated complexes comprises P2 of Formula 2 as hereunder.
  • said fluorescent cyclometalated complexes possesses selectivity to localize in the endoplasmic reticulum (ER) and/or cause photo- induced cell death only upon photo-irradiation wherein the ER localization in upto 100% cells achievable on incubation with 10 ⁇ of complexes for 15 min and/or cell death in upto 100% cells achievable upon 15 min incubation with 10 ⁇ of complexes fol lowed by laser irradiation for about 35 mi n at 8% laser power.
  • ER endoplasmic reticulum
  • said fluorescent cyclometalated Ir(III) complexes and/ or salts thereof comprises com plexes of cyclometalating ligands selected from 2- phenylpyrid ine, 2-p-tolylpyridine, benzo[ 7]quinoline, 5-methyl-2-phenylpyridine, 5-Benzyl-4-phenyl-lH-l,2,3-triazole, l-Benzyl-4-phenyl- lW" l,2,3-triazole, 1- methyl-4-phenyl-lH- l, 2,3-triazole, l-Benzyl-4-p-tolyl- lW- l,2,3-triazole and wherei n said salts include salts of anions of chloride and bromide.
  • fluorescent cyclometalated Ir(III) complexes in amou nts of atleast 10 ⁇ is effective to selectively localize in the endoplasmic reticulum (ER) and cause photo-induced " cell death only upon photo-irradiation.
  • a process for manufacture of said fluorescent cyclometalated Ir(III) complexes comprising the steps of providing [Ir(CnN) 2 CI] 2 [Tetrakis(CnN)(u-dichloro)iridium(III)] and cyclometalating ligands selected from 2-phenylpyridine, 2-p-tolylpyridine, benzo[/7]quinoline, 5- methyl-2-phenylpyridine, 5-Benzyl-4-phenyl-lW-l ,2,3- triazole, l -Benzyl-4-phenyl- lH- l, 2,3-triazole, l-methyl-4-phenyl- lW- l ,2,3- triazole, l-Benzyl-4-p-tolyl- l f- l ,2,3-triazole for reaction in solvent mix to obta i n Ir(III) complexes of Formula 1 therefrom
  • said solvent mix involves solvent mix of dichloromethane, methanol and acetonitrile with the rate of synthesis of the fluorescent cyclometalated complexes getting significantly enhanced on addition of acetonitrile as a solvent.
  • composition/formulation for cellular imaging and/or photodynamic therapy comprising at least one fluorescent cyclometalated Ir(III) complexes of Formula 1 and/ or salts thereof represented by the following structure
  • PDT photodynamic therapeutic
  • Red (2nd panel) represents the complex
  • Green (3rd panel) represents Cell Light ER-GFP
  • the 4th panel represent merged images of both
  • Figure 3 Illustrates photoinduced cell death caused by 10 ⁇ of the complex P2 on laser irradiation at 405 nm for 40 minutes, Arrows indicate the cells which have undergone death after the treatment;
  • FIG. 4 Illustrates reactive oxygen species (ROS) generation in cells treated with P2 followed by photoirradiation.
  • the central circle shows cells which have been photoirradiated with 405 nm laser following treatment with P2;
  • Figure 5 Illustrates in AnnexinV-FITC and Propidium iodide staining of cells treated with P2 followed by laser irradiation (upper panel) and treated with P2 but without laser irradiation (lower panel). AnnexinV-FITC and PI staining shows that apoptosis is only happening in cells treated with P2 followed by photoirradiation;
  • Figure 6 Illustrates Cytotoxicity measurement of P2 by MTT assay after treatment with 10-75 ⁇ of P2 for 10 and 22 hours.
  • the present invention provides for fluorescent cyclometalated Ir(IIl) complexes and/ or salts thereof, composition/formulations for cellular imaging and/or for photodynamic therapy (PDT) comprising the same together with its process of preparation that specifically localize and exhibit fluorescence in the endoplasmic reticulum and is also highly efficient in causing photo-induced death of " cancer cells on exposure to laser illumination when employed in effective amounts.
  • PDT photodynamic therapy
  • the generic molecular structure of said cyclometalated Ir(III) complex is provided hereunder as Formula 1
  • the preferred Formula 1 compound is P2 of Formula 2 hereunder
  • Formula 2 having selectivity to localize in the endoplasmic reticulum (ER.) and cause photo-induced cell death only upon photo-irradiation.
  • various ligands were initially synthesized and treated with a cyclometalated iridiumCHI) precursor to form phosphorescent iridium(III) complexes.
  • the complexes exhibit significant fluorescence intensity between pH 3 and 8 in a pH-dependent manner in vitro.
  • Cellular imaging with these complexes showed differential fluorescence intensity in cells, and remarkable selectivity for the ER by the complexes.
  • Alteration of the ancillary ligand in a systematic manner and synthesis of complexes of Formula 1 enabled locating functional moieties and their interactions responsible for the ER localization and fluorescence emission.
  • EXAMPLE 1 Process of preparation of Styryl bipyridyl ligand with -N0 2 group at 2-position
  • 2,2'-bipyridyl-4,4'-carboxylic acid 4,4'-Dimethyl-2,2'-bipyridyl (4g, 0.02 mol) taken in a 250ml round-bottomed flask is placed in a ice-bath. Sodium dichromate (16g, 0.06 mol) is added. The mixture was mixed well by stirring . 80 mL Concentrated sulphuric acid was added dropwise to the mixture while stirring for a period of 2 h and the stirring is continued for another period of 30 minutes. The solution was diluted with water (200 mL) and the white solid is filtered .
  • 4,4'-bis(hydroxyrnethyl)-2,2'-bipyridine Sodium borohydride ( 14g, 0.37 mol) is mixed with 5g (0.016mol) of 4,4'-Dicarboxyethyl Ester 2,2'-Bipyridine and 300 mL absolute ethanol is added. The mixture is refluxed at 80°C for 3 h. The resultant mixture was quenched with ammonium chloride to obtain the desired product as white solid.
  • 4,4'-Bis(bromomethyl)-2,2'-bipyridine A solution of 4,4'-dihydroxymethyl-2,2'- bipyridine (2.0 g, 0.01 mol) in 48% HBr (40 mL) and concentrated sulfuric acid (20 mL) was heated at reflux overnight and then allowed to cool to room temperature. The addition of water (80 mL), followed by neutralization (pH 7) with a concentrated aqueous sodium hydroxide solution, led to the precipitation of a white solid. The solid was collected by filtration and washed with water.
  • 4,4'-Bis(diethylphosphonomethyl)-2,2'-bipyridine A solution of 4,4'- bis(bromomethyl)-2,2'-bipyridine (3 g, 0.01 mol) in triethylphosphite (6.6 mL, 0.17 mol) was purged with argon for 15 min and then heated at 80 °C for 3 h. The reaction mixture was allowed to cool and hexane (30 mL) was added, causing the precipitation of an off-white solid. The product was collected by vacuum filtration.
  • a process for the preparation of Styryl bipyridyl, N02 group at 2-position of the iridium(III) complexes and its analogs are provided as outlined in Scheme 1 below comprising the steps of providing [Ir(ppy) 2 CI] 2 and 4,4'-(2-nitro styryl- 2,2'- bipyridyl) for reaction in solvent mix of dichlorpmethane and methanol, refluxing for 4 hours to obtain Formula 1 compounds including Formula 2 compound P2 therefrom.
  • ⁇ , I, A, ⁇ are qua ntum yield, integ ral emission intensity, a bsorbance and refractive index of the solvents respectively, in which the sample or reference was dissolved .
  • Example 5 Representative Lipophilicity (indicating cellular permeability) : The lipophilicity of the complex was determined bv the "shake flask" method using a pH 7.4 phosphate buffer (0.129 M NaCI) and n-octanol as solvents. Each compound was dissolved in the phase in which it is most soluble, resulting in concentration of ⁇ . Duplicate determinations using three different solvent ratios were performed for the complex. Following mixing and phase separation, each phase was analyzed for solute content, and the concentration was determined using spectrophotometry methods. Al l the n-octanol/water partition coefficients were determined by UV/vis spectroscopy. Octanol and buffer solutions were presaturated . Fifty rotations were performed by hand, followed by 1 h of settling time. Equilibration and absorption measurements were made at 2Q° C.
  • Formula 1 complexes and/or salts thereof including Formula 2 compound P2 and its analogs are highly effective in causing death of cancer cells on photoirradiation and hence is an effective photosensitizing agent.
  • Photo-induced cell death is the basis of photodynamic therapy (PDT) of various cancers and other diseases such as psoriasis, rheumatoid arthritis etc. and the synthesis of Formula 1 compounds including Formula 2 compound P2 and its analogs surprisingly provided highly efficient agents for causing photo-induced cell death .
  • PDT uses photosensitizing agents in a less invasive and more targeted form of cancer treatment.
  • ER endoplasmic reticulum
  • cells were also transduced with a commercially avialble baculovirus-mammalian expression vector encoding Green Fluorescent Protein (GFP) fused with the calreticulin ER insertion sequence and the KDEL tetrapeptide retention sequence (CellLight ER-GFP from Life Technologies Inc.) .
  • GFP Green Fluorescent Protein
  • P2 and its analogs of Formula 1 compounds showed efficient co-localization with ER-GFP demonstrating their specific localization in the ER as exemplified in Figure 2. This biological property allows the compounds to be used as imaging agents for imaging the ER.
  • Example 7 Photo-induced cell death caused by Formula 2 compound of P2 and its analogs of Formula 1
  • the cell death was found to be due to generation of reactive oxygen species (ROS), which was detected by treatment with 2', 7'-dichlorofluorescin diacetate • (DCFDA), a fluorogenic dye that fluoresces in presence of ROS with excitation and emission maxima at 495 nm and 529 nm respectively ( Figure 4). It was further found that the cell death is due to the triggering of an apoptotic response, as demonstrated by staining the cells with AnnexinV-FITC (Fluorescein isothiocyanate) and Propidium iodide (Figure 5). Together, the data demonstrate P2 and its analogs caused very efficient photoinduced apoptotic cell death mediated by ROS generation.
  • ROS reactive oxygen species
  • a photosensitizing and cellular imaging agent comprising cyclometalated Ir(III) complexes with the cyclometalating ligands selected from 2-phenylpyridine, 2-p-tolylpyridine, benzo[/?]quinoline, 5-methyl-2-phenylpyridine, 5-Benzyl-4-phenyl-l/7-l,2,3- triazole, l-Benzyl-4-phenyl-lW-l,2,3-triazole, l-methyl-4-phenyl-l/V-l,2,3- triazole, l-Benzyl-4-p-tolyl-lH-l,2,3-triazole which specifically localizes in the endoplasmic reticulum (ER) having cellular imaging characteristics and also advantageously causes photo-induced cell death only upon photo-irradiation, making them excellent candidates for specific and targeted photodynamic therapy, which advantageously also selectively stains the endoplasmic reticulum of cells

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Abstract

Fluorescent cyclometalated Ir(III) complexes and/or salts thereof are provided including formulations/ compositions comprising the same together with its process of preparation that is found to be highly efficient in causing photo- induced death of cancer cells on exposure to laser illumination and also specifically localize and exhibit fluorescence in the endoplasmic reticulum, when employed in effective amounts.

Description

TITLE: FLUORESCENT CYCLOMETALATED Ir (III) COMPLEXES AND FORMULATIONS/ COMPOSITIONS COMPRISING THE SAME
FIELD OF THE INVENTION
The present invention provides for fluorescent cyclometalated Ir (III) complexes and/or salts thereof, and more particularly, provides for formulations/ compositions comprising the same together with its process of preparation that is found to be highly efficient in causing photo-induced death of cancer cells on exposure to laser illumination and also specifically localize and exhibit fluorescence in the endoplasmic reticulum, when employed in effective amounts. The generic molecular structure of said complex is provided hereunder as Formula 1 wherein salts include salts of anion Z" of chloride, bromide.
Figure imgf000003_0001
BACKGROUND ART
The cyclometalated heteroleptic iridium (III) complexes [F. Neve, A. Crispini, S. Campagna, S. Serroni, inorg. Chem. 1999, 38, 2250] of polypyridyl ligands are highly efficient in imaging of cells and cellular organelles, and are important tools for studying cellular function. The efficacy of the cyclometalated iridium (III) complexes in this field has been demonstrated with a range of substituted phenyl pyridine and polypyridyl units [Q. Zhao, C. Huanga, F. Li, Chem. Soc. Rev. , 2011, 40, 2508]
Presently, small-molecular dyes, fluorophore-conjugated antibodies or fluorescent proteins are used commercially as imaging agents for cellular organelles such as nuclei, mitochondria, endoplasmic reticulum (ER), Golgi complex and lysosomes [S. A. Hilderbrand, Methods Mol Biol. , 2010, 591, 17] . The cyclometalated iridium (III) complexes provide a number of important advantages over these currently available imaging agents. These include enhanced chemical and photochemical stability within the cellular environment, permeability, minimization of self-quenching due to the significant Stokes' shift, long-lived triplet excited state (t ~ ps) compared to organic dyes (t ~ ns) that helps to eliminate the short-lived autofluorescence of biological samples, and microenvironment-sensitive emission characteristics which are less damaging to cellular components [C. L Ho, K.-L. Wong, H.-K. Kong, Y.-M. Ho, C. T.-L. Chan, W.-M. Kwok, K. S.-Y. Leung, H.-L. Tarn, M. H.-W. Lam, X.-F. Ren, A.-M. Ren,. J.- K. Feng, W.-Y. Wong, Chem. Commun. , 2012, 48, 2525] .
Kinetic inertness of the low-spin octahedral d6 complexes contributes to both reducing the cytotoxicity of the heavy metal ions and enhancing the stability of the complexes. The high photostability of these complexes allows the continuous monitoring of biological events by fluorescence spectroscopy and microscopy. High fluorescence lifetimes and tunable emission properties have resulted in their exploitation in sensors [V. W.-W. Yam, K. M .-C. Wo, Chem. Commun. , 2011, 47,11579], OLEDs [C.-H. Chang, Z.-J. Wu, C.-H. Chiu, Y.-H. Liang, Y.-S. Tsai, J.-L. Liao, Y. Chi, H.-Y. Hsieh, T.-Y. Kuo, G.-H. Lee, H.-A. Pan, P.-T. Chou, J.-S. Lin, M.-R. Tseng, ACS Appl. Mater. Interfaces, 2013, 5, 7341. ], catalysts for water splitting [P. N. Curtin, L. L. Tinker, C. M. Burgess, E. D. Cline, S. Bernhard, Inorg. Chem. , 2009, 48, 10498] and dye-sensitized solar cells (DSSCs) [E. Baranoff, J.-H. Yum, I. Jung,. R. Vulcano, M. Grtzel and M.. K. Nazeeruddin, Chem. Asian J. , 2010, JL. 496], OLECs [A. C. Brooks, K. Basore, S. Bernhard, Inorg. Chem. , 2013, 52, 5794] together' with successful usage as cellular imaging [Y. You . W. Nam. Chem Snc RPV. . 2012 41 . 7Γ)6 Π A major challenge in . the field of cellular imaging is the selective staining of specific cell organelles or sub-cellular compartments. The factors that influence the cellular uptake and distribution within the microenvironment include permeability through the cell membrane, diffusion in the cellular cytoplasm, the charge-interaction associated with the organellar membranes during the uptake and interaction with organellar components through non-covalent forces, e.g. hydrogen bonds, ionic bonds, van der Waals forces and hydrophobic interactions, which results in specific localization. Within the micro- or nano-environment of the cell, specific localization is mostly regulated by pH [J. Han, K. Burgess, Chem. Rev. , 2010, 110, 2709.], dielectric constant, hydrophobic and hydrophilic interactions and redox potential [Z. Liu, P. J. Sadler Acc. Chem. Res. 2014, 47, 1174] .
Cyclometalated iridium complexes have been reported as cellular imaging probes for visualization of different organelles like nucleoli, [C. Li, M . Yu, Y. Sun, Y. Wu, C. Huang, F. A. Li, J. Am. Chem. Soc , 2011, 133, 11231] Golgi complex, [K. Y. Zhang, . H.-W. Liu, T. T.-H. Fong, X.-G. Chen, K. K.-W. Lo, Inorg. Chem. , 2010, 49, 5432] lysosomes and endosomes [P. Steunenberg, A. uggi, N. S. van den Berg, T. Buckle, J. Kuil, F. W. B. van Leeuwen, A. H . Velders, Inorg. Chem ., 2012, 51, 2105] cytoplasm, [H. Wu, T. Yang, Q. Zhao, J. Zhou, C. Li, F. A. .Li, Dalton Trans. , 2011, 40, 1969] mitochondria [S. P.-Y. Li, C. T.-S. Lau, M.-W. Louie, Y.-W. Lam, S. H. Cheng, K. K.-W. Lo Biomaterials, 2013, 34, 7519], and endoplasmic reticulum [R. Cao, J. Jia, X. Ma, M . Zhou, H. Fei, J. Med. Chem. , 2013, 56, 3636] as well as intracellular metal- containing molecules [Y. You, S. Cho, W. Nam, Inorg. Chem. , 2013, 53, 1804] , They have also been reported to act as efficient photosensitizing agents in cells, i.e. upon cellular uptake they can cause cell death upon irradiation with specific wavelengths of light [S. Moromizato, Y. Hisamatsu, T. Suzuki, Y. Matsuo, R. Abe, S. Aoki, Inorg. Chem., 2012, 51, 12697.] Therefore they have the potential of being used for photodynamic therapy (PDT) which involves the targeted destruction of tumor cells by photoirradiation. [J. P. Celli, B. Q. Spring, I. Rizvi, C. L. Evans, K. S. Samkoe, S. Verma, B. W. Pogue, T. Hasan, Chem. Rev., 2010, 110, 2795]
PDT uses photosensitizing agents in less invasive and more targeted form of cancer treatment. It is also used for the therapy of various inflammatory diseases of the skin such as psoriasis. In many cases, the photosensitizing agents such as porphyrins, phthalocyanines or methylene blue [H. Ali, J. E. van Lier, Chem. Rev., 1999, 99, 2379.] have been shown to generate reactive singlet oxygen or other reactive oxygen species (ROS) which causes cell death by damaging cellular organelles, cell membrane, DNA etc. [T. Yogo, Y. Urano, A. Mizushima, H . Sunahara, T. Inoue, K. Hirose, M. lino, K. Kikuchi, T. Nagano, Proc. Natl. Acad. Sci.V.S.A. , .2008, 105, 28] . PDT utilizes this property of photosensitizing agents to be used for specific destruction of cancer cells by exposure to illumination.
It is apparent from the above prevailing state of the art that in order to be a potential photodynamic therapeutic agent the compound/ material should be an efficient photosensitizing agent for cells and stable chemically and photochemically that would also be kinetically inert in moderating the toxicity of heavy metal ions. It is thus the need of the day to explore iridium(III) complexes as suitable candidates far photodynamic therapy (PDT) which in being stable and kinetically inert in being low spin octahedral d6 complexes and would also have great potential in the field of PDT due to their high phosphorescence lifetime and cell permeability.
OBJECTS OF THE INVENTION
It is thus a primary object of the present invention to provide for a easy to handle, stable fluorescent cyclometalated Ir(III) complexes that would find end use and application in cell imaging and photodynamic therapy (PDT).
It is another object of the present invention to provide for said stable cyclometalated Ir(III) complexes that would be stable both chemically and photochemically and would cause photoinduced cell death of cancer cells only upon illuminatio It is yet another object of the present invention to provide for said stable cyclometalated Ir('III) complexes that would be soluble in aqueous buffer and growth media would have cellular permeability and localize in specific cell organelle. It is another object of the present invention to provide for said stable cyclometalated Ir(III) complexes that would have significant Stokes shift to minimize the self-quenching process that would aid in distinguishing the emission of the fluorophore from autofluorescence.
It is yet another object of the present invention to provide for said stable cyclometalated Ir(III) complexes that would possess high-luminescehce quantum yields to offer high sensitivity and would also have long lifetimes compared to organic dyes that would eliminate the short lived autofluorescence (t ~ ns) from biological samples efficiently.
It is still another object of the present invention to provide for said cyclometalated Ir(III) complexes and a facile process of preparing the same that would be kinetically inert to have very low rates of ligand exchange crucial towards moderating the toxicity of heavy metal ions.
SUMMARY OF THE INVENTION
It is thus the basic aspect of the present invention to provide for fluorescent cyclometalated complexes and/ or salts thereof comprising fluorescent cyclometalated Ir(III) complexes of Formula 1 represented by the following structure:
Figure imgf000008_0001
Formula 1
Advantageously, said fluorescent cyclometalated complexes is selectively photosensitizing to favour imaging of Endoplasmic Reticulum (ER) of cells and/or in having photodynamic therapeutic (PDT) characteristics is suitable for cellular imaging and/or photoinduced cell death.
Preferably said fluorescent cyclometalated complexes comprises P2 of Formula 2 as hereunder.
Figure imgf000008_0002
Formula 2
More advantageously said fluorescent cyclometalated complexes possesses selectivity to localize in the endoplasmic reticulum (ER) and/or cause photo- induced cell death only upon photo-irradiation wherein the ER localization in upto 100% cells achievable on incubation with 10 μΜ of complexes for 15 min and/or cell death in upto 100% cells achievable upon 15 min incubation with 10 μΜ of complexes fol lowed by laser irradiation for about 35 mi n at 8% laser power. More preferably said fluorescent cyclometalated Ir(III) complexes and/ or salts thereof comprises com plexes of cyclometalating ligands selected from 2- phenylpyrid ine, 2-p-tolylpyridine, benzo[ 7]quinoline, 5-methyl-2-phenylpyridine, 5-Benzyl-4-phenyl-lH-l,2,3-triazole, l-Benzyl-4-phenyl- lW" l,2,3-triazole, 1- methyl-4-phenyl-lH- l, 2,3-triazole, l-Benzyl-4-p-tolyl- lW- l,2,3-triazole and wherei n said salts include salts of anions of chloride and bromide.
Advantageously said fluorescent cyclometalated Ir(III) complexes in amou nts of atleast 10 Μ is effective to selectively localize in the endoplasmic reticulum (ER) and cause photo-induced" cell death only upon photo-irradiation.
Preferably said fluorescent cyclometalated Ir(III) complexes is chemically and photochemically stable, soluble in aqueous buffer and has cellular permeability, has significant stokes shift of 10 x 104 to 13 χ 104 cm" 1 has high luminescence quantum yields in the range of 1.21 to 15% thereby offering high sensitivity, has long lifetimes in the range of (τ = 15 - 20 ps) and is kinetically inert thus moderating the toxicity of heavy metal ions.
According to another aspect of the present invention a process for manufacture of said fluorescent cyclometalated Ir(III) complexes is provided comprising the steps of providing [Ir(CnN)2CI]2 [Tetrakis(CnN)(u-dichloro)iridium(III)] and cyclometalating ligands selected from 2-phenylpyridine, 2-p-tolylpyridine, benzo[/7]quinoline, 5- methyl-2-phenylpyridine, 5-Benzyl-4-phenyl-lW-l ,2,3- triazole, l -Benzyl-4-phenyl- lH- l, 2,3-triazole, l-methyl-4-phenyl- lW- l ,2,3- triazole, l-Benzyl-4-p-tolyl- l f- l ,2,3-triazole for reaction in solvent mix to obta i n Ir(III) complexes of Formula 1 therefrom. Preferably in said process for the manufacture of fluorescent cyclometalated complexes said solvent mix involves solvent mix of dichloromethane, methanol and acetonitrile with the rate of synthesis of the fluorescent cyclometalated complexes getting significantly enhanced on addition of acetonitrile as a solvent.
According to another aspect of the present invention a composition/formulation for cellular imaging and/or photodynamic therapy (PDT) comprising at least one fluorescent cyclometalated Ir(III) complexes of Formula 1 and/ or salts thereof represented by the following structure
Figure imgf000010_0001
Formula 1
with or without carriers and excipients is provided having selectively photosensitizing, imaging and/or photodynamic therapeutic (PDT) characteristics for delivery in mammalian cells and/ or in culture and/or live animals.
BRIEF DESCRIPTION OF FIGURES
Figure 1: Generic structure of the complex of Formula 1;
Figure 2: Representative Confocal fluorescence images of MCF7 cells treated with formula 2 compound P2 showing ER localization; The same cells were transduced with Cell Light ER-GFP. The cells were imaged at Aex = 405 nm and Aem = 550-610 nm for the complexes and at Aex = 488 nm and Aem = 510 nm for Cell Light ER-GFP. Red (2nd panel) represents the complex, Green (3rd panel) represents Cell Light ER-GFP, and the 4th panel represent merged images of both; Figure 3: Illustrates photoinduced cell death caused by 10 μΜ of the complex P2 on laser irradiation at 405 nm for 40 minutes, Arrows indicate the cells which have undergone death after the treatment;
Figure 4: Illustrates reactive oxygen species (ROS) generation in cells treated with P2 followed by photoirradiation. The central circle shows cells which have been photoirradiated with 405 nm laser following treatment with P2;
Figure 5: Illustrates in AnnexinV-FITC and Propidium iodide staining of cells treated with P2 followed by laser irradiation (upper panel) and treated with P2 but without laser irradiation (lower panel). AnnexinV-FITC and PI staining shows that apoptosis is only happening in cells treated with P2 followed by photoirradiation;
Figure 6: Illustrates Cytotoxicity measurement of P2 by MTT assay after treatment with 10-75 μΜ of P2 for 10 and 22 hours. DETAILED DESCRIPTION OF THE INVENTION
As discussed hereinbefore the present invention provides for fluorescent cyclometalated Ir(IIl) complexes and/ or salts thereof, composition/formulations for cellular imaging and/or for photodynamic therapy (PDT) comprising the same together with its process of preparation that specifically localize and exhibit fluorescence in the endoplasmic reticulum and is also highly efficient in causing photo-induced death of " cancer cells on exposure to laser illumination when employed in effective amounts. The generic molecular structure of said cyclometalated Ir(III) complex is provided hereunder as Formula 1
Figure imgf000012_0001
Formula 1
According to a preferred embodiment of the present invention the preferred Formula 1 compound is P2 of Formula 2 hereunder
Figure imgf000012_0002
Formula 2 having selectivity to localize in the endoplasmic reticulum (ER.) and cause photo- induced cell death only upon photo-irradiation.
According to an embodiment of the present invention various ligands were initially synthesized and treated with a cyclometalated iridiumCHI) precursor to form phosphorescent iridium(III) complexes. The complexes exhibit significant fluorescence intensity between pH 3 and 8 in a pH-dependent manner in vitro. Cellular imaging with these complexes showed differential fluorescence intensity in cells, and remarkable selectivity for the ER by the complexes. Alteration of the ancillary ligand in a systematic manner and synthesis of complexes of Formula 1 enabled locating functional moieties and their interactions responsible for the ER localization and fluorescence emission. The ER localized complex was also found to have significant photosensitizing property, efficiently causing cell death induced by photoirradiation at 405 nm. EXAMPLE 1 : Process of preparation of Styryl bipyridyl ligand with -N02 group at 2-position
Figure imgf000013_0001
2,2'-bipyridyl-4,4'-carboxylic acid : 4,4'-Dimethyl-2,2'-bipyridyl (4g, 0.02 mol) taken in a 250ml round-bottomed flask is placed in a ice-bath. Sodium dichromate (16g, 0.06 mol) is added. The mixture was mixed well by stirring . 80 mL Concentrated sulphuric acid was added dropwise to the mixture while stirring for a period of 2 h and the stirring is continued for another period of 30 minutes. The solution was diluted with water (200 mL) and the white solid is filtered .
Figure imgf000013_0002
4,4'-Dicarboxyethyl Ester 2,2'-Bipyridine: Concentrated sulfuric acid (10 mL) was added to a solutio of 4,4'-dicarboxy-2,2'-bipyridine ( 10.0 g, 0.04 mol) in absolute ethanol (150 mL). The reaction mixture was refluxed for 3 h (80°C). After cooling, the same was added to ice water (200 mL) and the pH was adjusted to 7 to obtain a white solid. The solid was filtered, washed with water, and dried.
Figure imgf000014_0001
4,4'-bis(hydroxyrnethyl)-2,2'-bipyridine: Sodium borohydride ( 14g, 0.37 mol) is mixed with 5g (0.016mol) of 4,4'-Dicarboxyethyl Ester 2,2'-Bipyridine and 300 mL absolute ethanol is added. The mixture is refluxed at 80°C for 3 h. The resultant mixture was quenched with ammonium chloride to obtain the desired product as white solid.
Figure imgf000014_0002
4,4'-Bis(bromomethyl)-2,2'-bipyridine: A solution of 4,4'-dihydroxymethyl-2,2'- bipyridine (2.0 g, 0.01 mol) in 48% HBr (40 mL) and concentrated sulfuric acid (20 mL) was heated at reflux overnight and then allowed to cool to room temperature. The addition of water (80 mL), followed by neutralization (pH 7) with a concentrated aqueous sodium hydroxide solution, led to the precipitation of a white solid. The solid was collected by filtration and washed with water.
Figure imgf000015_0001
If itrDgca atauKflMie
4,4'-Bis(diethylphosphonomethyl)-2,2'-bipyridine: A solution of 4,4'- bis(bromomethyl)-2,2'-bipyridine (3 g, 0.01 mol) in triethylphosphite (6.6 mL, 0.17 mol) was purged with argon for 15 min and then heated at 80 °C for 3 h. The reaction mixture was allowed to cool and hexane (30 mL) was added, causing the precipitation of an off-white solid. The product was collected by vacuum filtration.
Figure imgf000015_0002
Overall yield= 40.5% 4,4'-(2-hitro styryl- 2,2'-bipyridyl) : The synthesis has been done by Horner- Wadsworth-Emmons coupling reactions: 4,4'-Bis(diethylmethylphosphonate)- 2,2'-bipyridine (500mg, 1.01 mmol) in 30mL of dry THF solution with 2- nitrobenzaldehyde (75.5mg, 0.5mmol) in presence of ^uOK were stirred under dark condition for overnight. The reaction was quenched by the addition of 50mL H20 and stirred again for 10 mins. The precipitate was filtered, off and washed thoroughly with H20 and air-dried. Example 2: Process for the preparation of Formula 1 complexes
According to an embodiment of the present invention a process for the preparation of Styryl bipyridyl, N02 group at 2-position of the iridium(III) complexes and its analogs are provided as outlined in Scheme 1 below comprising the steps of providing [Ir(ppy)2CI]2 and 4,4'-(2-nitro styryl- 2,2'- bipyridyl) for reaction in solvent mix of dichlorpmethane and methanol, refluxing for 4 hours to obtain Formula 1 compounds including Formula 2 compound P2 therefrom.
Figure imgf000016_0001
Scheme 1
Example 3: Representative Analytical data
ESI-MS: Mass spectra were recorded on a Q-Tof-Micromass spectrometer by positive-ion mode eiectrospray ionization with methanol solution of the sample.
Table 1: ESI-MS P2
Figure imgf000017_0002
Example 4: Representative Photophysical properties
Fluorescence spectra were taken on a HORIBA JOBINYVON spectrofluorimeter. Mass spectra were recorded on a Q-Tof-Micromass spectrometer by positive-ion mode eiectrospray ionization . Quantum yields were determined in CH2CI2 with Quinine Sulfate in 0.1M H2SQ4 solution as a reference (Φ=0.577), and calculated with the following equation :
Figure imgf000017_0001
Φ, I, A, η are qua ntum yield, integ ral emission intensity, a bsorbance and refractive index of the solvents respectively, in which the sample or reference was dissolved .
Table 2
Figure imgf000017_0003
Example 5: Representative Lipophilicity (indicating cellular permeability) : The lipophilicity of the complex was determined bv the "shake flask" method using a pH 7.4 phosphate buffer (0.129 M NaCI) and n-octanol as solvents. Each compound was dissolved in the phase in which it is most soluble, resulting in concentration of ΙΟΟμΜ . Duplicate determinations using three different solvent ratios were performed for the complex. Following mixing and phase separation, each phase was analyzed for solute content, and the concentration was determined using spectrophotometry methods. Al l the n-octanol/water partition coefficients were determined by UV/vis spectroscopy. Octanol and buffer solutions were presaturated . Fifty rotations were performed by hand, followed by 1 h of settling time. Equilibration and absorption measurements were made at 2Q° C.
Table 3
Figure imgf000018_0001
It was thus a significant and surprising finding of the present invention that Formula 1 and Formula 2 compound of P2 and its analogs show the following properties selected from anyone or more of
1. Being stable chemically and photochemically, soluble in aqueous buffer and cell growth media ;
2. Significant Stokes shift that minimize the self-quenching process and help to distinguish the emission of the fluorophore from autofluorescence; (excited at
405 nm emission at 560 - 580 nm);
3. High-luminescence quantum yields offer high sensitivity;
4. Long lifetimes ( r = 15 - 20 ps) compared to organic dyes; eliminates the short lived autofluorescence ( r ~ ns) from biological samples efficiently;
5. Kinetic inertness: Low-spin octahedral d6 complexes have very low rates of ligand exchange, crucial in moderating the toxicity of heavy metal ions.
It was significantly found by way of the present invention that Formula 1 complexes and/or salts thereof including Formula 2 compound P2 and its analogs are highly effective in causing death of cancer cells on photoirradiation and hence is an effective photosensitizing agent. Photo-induced cell death is the basis of photodynamic therapy (PDT) of various cancers and other diseases such as psoriasis, rheumatoid arthritis etc. and the synthesis of Formula 1 compounds including Formula 2 compound P2 and its analogs surprisingly provided highly efficient agents for causing photo-induced cell death . PDT uses photosensitizing agents in a less invasive and more targeted form of cancer treatment. Developing efficient photosensitizers is one of the main challenges in developing PDT as a method of treating cancer which the present invention circumvents by providing for such highly efficient photosensitizing agents. Secondly, and most advantageously Formula 1 compounds including Formula 2 compound P2 and its analogs selectively stains , the endoplasmic reticulum of cells to make them excellent agents for cellular imaging for exploring the functions of the cells.
Example 6: Cellular localization of Formula 2 compound of P2 and its analogs of Formula 1
Experiments for cellular localization of P2 of Formula 2 and its analogs of Formula. 1 were conducted employing MCF7 breast carcinoma cells (the MCF7 cell line is sourced from American Type Culture Collection (ATCC), 10801 University Boulevard, Manassas, VA 20110 USA. The ATCC number for this cell line is HTB- 22.), which were treated with 10 μΜ of P2 and its analogs for 15 minutes, following which the cells were fixed with 4% paraformaldehyde and imaged in confocal laser scanning microscope at 405 nm excitation wavelength and 550 nm - 610 nm emission wavelengths. For identifying the ER (endoplasmic reticulum), cells were also transduced with a commercially avialble baculovirus-mammalian expression vector encoding Green Fluorescent Protein (GFP) fused with the calreticulin ER insertion sequence and the KDEL tetrapeptide retention sequence (CellLight ER-GFP from Life Technologies Inc.) . P2 and its analogs of Formula 1 compounds showed efficient co-localization with ER-GFP demonstrating their specific localization in the ER as exemplified in Figure 2. This biological property allows the compounds to be used as imaging agents for imaging the ER. Example 7: Photo-induced cell death caused by Formula 2 compound of P2 and its analogs of Formula 1
Experiments on photoinduced cell death of P2 and its analogs were conducted to investigate the role of P2 and its analogs in causing photo-induced cell death, for which CF7 breast carcinoma cells were treated with 10 μΜ of P2 or its analogs and live cells in a humidified atmosphere with 5% C02 and were exposed to laser illumination at 405 nm. After photoirradiation for around 40 minutes, the cells which had taken up said P2 and its analogs showed extensive membrane blebbing and contraction finally leading to cell death as exemplified in Figure 3. The cell death was found to be due to generation of reactive oxygen species (ROS), which was detected by treatment with 2', 7'-dichlorofluorescin diacetate • (DCFDA), a fluorogenic dye that fluoresces in presence of ROS with excitation and emission maxima at 495 nm and 529 nm respectively (Figure 4). It was further found that the cell death is due to the triggering of an apoptotic response, as demonstrated by staining the cells with AnnexinV-FITC (Fluorescein isothiocyanate) and Propidium iodide (Figure 5). Together, the data demonstrate P2 and its analogs caused very efficient photoinduced apoptotic cell death mediated by ROS generation. It was also found that P2 and its analogs do not have significant autonomous cytotoxic effect. Treatment with increasing concentrations (upto 75 μΜ) of P2 for 10 hours did not cause any cell death whereas treatment for 22 hours caused 50% cell death only in presence of the highest concentration of P2 with minimal cell death at the 10 μΜ concentration, at which the photoinduced cell death is caused (Figure 6) . These data show that P2 have little autonomous cytotoxicity and causes cell death only on photo- irradiation, making them excellent candidates for specific and targeted photodynamic therapy.
The activity of Formula 1 complexes of the present invention is summarized under Table 4 below.
Table 4
Figure imgf000021_0001
Figure imgf000022_0001
20 It is thus' possible for the present advancement to provide for a photosensitizing and cellular imaging agent comprising cyclometalated Ir(III) complexes with the cyclometalating ligands selected from 2-phenylpyridine, 2-p-tolylpyridine, benzo[/?]quinoline, 5-methyl-2-phenylpyridine, 5-Benzyl-4-phenyl-l/7-l,2,3- triazole, l-Benzyl-4-phenyl-lW-l,2,3-triazole, l-methyl-4-phenyl-l/V-l,2,3- triazole, l-Benzyl-4-p-tolyl-lH-l,2,3-triazole which specifically localizes in the endoplasmic reticulum (ER) having cellular imaging characteristics and also advantageously causes photo-induced cell death only upon photo-irradiation, making them excellent candidates for specific and targeted photodynamic therapy, which advantageously also selectively stains the endoplasmic reticulum of cells thus making- them excellent agents for cellular imaging for exploring the functions of the cells. .

Claims

We Claim:
1. Fluorescent cyclometalated complexes comprising fluorescent cyclometalated Ir(III) complexes of Formula 1 and/ or salts thereof represented by the following structure:
Figure imgf000024_0001
Formula 1
2. Fluorescent cyclometalated complexes as claimed in preceding claim 1 that is selectively photosensitizing to favour imaging of Endoplasmic Reticulum (ER) of cells and/or in having photodynamic therapeutic (PDT) characteristics is suitable for cellular imaging and/or photoinduced cell death. 3. Fluorescent cyclometalated complexes as claimed in anyone of preceding claims 1 or 2 comprising P2 of Formula 2 as hereunder.
Figure imgf000025_0001
Formula 2
Fluorescent cyciometalated complexes as claimed in anyone of preced claims 1-3 having selectivity to localize in the endoplasmic reticulum (ER) and/or cause photo-induced cell death only upon photo-irradiation wherein the ER localization in upto 100% cells achievable on incubation with 10 μΜ of complexes for 15 min and/or cell death in upto 100% cells achievable upon 15 min incubation with 10 μΜ of complexes followed by laser irradiation for about 35 min at 8% laser power.
5. Fluorescent cyciometalated complexes as claimed in anyone of preceding claims 1-4 wherein said cyciometalated Ir(III) complexes Formula 1 and/ or salts thereof comprises complexes of cyclometalating ligands selected from 2- phenylpyridine, 2-p-tolylpyridine, benzo[r)]quinoline, 5-methyl-2-phenylpyridine, 5-Benzyl-4-phenyl-lW- l,2,3-triazole, l-Benzyl-4-phenyl-lH- l,2,3-triazole, 1- methyl-4-phenyl-lA7-l,2,3-triazole, l-Benzyl-4-p-tolyl-lW- l,2,3-triazole and wherein said salts include salts of anions of chloride, bromide.
6. Fluorescent cyciometalated complexes as claimed in anyone of preceding claims 1-5 wherein the cyciometalated Ir(III) complexes of Formula 1 in amounts of atleast 10 μ is effective to selectively localize in the endoplasmic reticulum (ER) and cause photo-induced cell death only upon photo-irradiation.
7. Fluorescent cyciometalated complexes as ' claimed in anyone of preceding claims 1-6 which is chemically and photochemically stable, soluble in aqueous buffer and has cellular permeability, has significant stokes shift of 10 χ 104 to 13 x 104 cm" 1 has high luminescence quantum yields in the range of 1.21 to 15% thereby offering high sensitivity, has long lifetimes in the range of (τ = 15-20 μ≤) and is kinetically inert thus moderating the toxicity of heavy metal ions.
8. A process for manufacture of fluorescent cyclometalated complexes as claimed in anyone of claims 1-7 comprising the steps of providing [Ir(CnN)2CI]2 [Tetrakis(CnN)(p-dichloro)iridium(III)] and cyclometalating ligands selected from 2-phenylpyridine, 2-p-tolylpyridine, benzo[/7]quinoline, 5-methyl-2- phenylpyridine, 5-Benzyl-4-phenyl- lW- l,2,3-triazole, l-Benzyl-4-phenyl- lW- 1,2,3-triazole, l-methyl-4-phenyl- lW- l,2,3-triazole, l-Benzyl-4-p-tolyl-lAy-l,2,3- triazole for reaction in solvent mix to obtain Ir(III) complexes of Formula 1 therefrom.
9. A process for the manufacture of fluorescent cyclometalated complexes as claimed in claim 8 wherein the solvent mix involves solvent mix of dichloromethane, methanol and acetonitrile with the rate of synthesis of the fluorescent cyclometalated complexes getting significantly enhanced on addition of acetonitrile as a solvent.
10. A composition/formulation for cellular imaging and/or photodynamic therapy (PDT) comprising at least one fluorescent cyclometalated Ir(III) complexes of Formula 1 and/ or salts thereof represented by the following structure
Figure imgf000027_0001
Formula 1
with or without carriers and excipients, having selectively photosensitizing, imaging and/or photodynamic therapeutic (PDT) characteristics for delivery in mammalian cells and/ or in culture and/or live animals .
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Title
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Publication number Priority date Publication date Assignee Title
WO2021089644A1 (en) * 2019-11-04 2021-05-14 Paris Sciences Et Lettres - Quartier Latin Metal complexes bearing bisstyryl-bipyridine ligand and their use as photosensitizer agent in one and two-photon photodynamic therapy
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