US20210252152A1 - Near-infrared (nir) absorbing photosensitizers - Google Patents

Near-infrared (nir) absorbing photosensitizers Download PDF

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US20210252152A1
US20210252152A1 US16/973,435 US201816973435A US2021252152A1 US 20210252152 A1 US20210252152 A1 US 20210252152A1 US 201816973435 A US201816973435 A US 201816973435A US 2021252152 A1 US2021252152 A1 US 2021252152A1
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aryl derivatives
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Gorkem GUNBAS
Safacan KOLEMEN
Osman KARAMAN
Gizem ATAKAN
Toghrul ALMAMMADOV
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Koc Universitesi
Orta Dogu Teknik Universitesi
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Orta Dogu Teknik Universitesi
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07F17/00—Metallocenes
    • C07F17/02—Metallocenes of metals of Groups 8, 9 or 10 of the Periodic System
    • 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
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/022—Boron compounds without C-boron linkages
    • 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
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
    • C07F7/0814—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring said ring is substituted at a C ring atom by Si
    • 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
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
    • C07F7/0816—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring said ring comprising Si as a ring atom
    • 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
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
    • C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom

Definitions

  • the present invention relates to photosensitizers to be used for imaging and treatment of cancer by using photodynamic therapy (PDT).
  • PDT photodynamic therapy
  • Photodynamic therapy is a treatment that uses special drugs, called photosensitizing agents, along with light to kill cancer cells.
  • the drugs only work after they have been activated or turned on by certain kinds of light.
  • PDT therapeutic action is satisfied by the generation of singlet oxygen (1O2) upon irradiation of well-designed PDT agents (photosensitizers or drugs) by light.
  • Singlet oxygen is the excited form of molecular oxygen (3O2) and it is cytotoxic due to its high reactivity towards vital biomolecules.
  • PDT also restricts the flow of nutrients and oxygen to cancer cells by disturbing the vasculatures around tumor regions and at the same time activates the immune system against cancer cells.
  • the advantages and importance of PDT are more pronounced when it is compared with widely used conventional chemotherapy and radiotherapy.
  • PDT When considered from this aspect; PDT is highly promising, however its broader applicability in clinical treatments is restricted due to some problems. The most important one is the limited penetration of the irradiation light through tissues, which leaves the deeper tumors out from the scope of PDT. Studies have shown that red or near-IR (NIR) absorbing PDT agents should be employed to get the best penetration depth and to avoid the absorption of incoming light by biomolecules. Although, a very wide range of well-known fluorescent probe cores have been converted to PDT agents, red and near-IR absorbing PDT agents are still rare.
  • NIR near-IR
  • the second major problem of the PDT is the oxygen deficiency (hypoxia) in cancer cells.
  • hypoxia oxygen deficiency
  • singlet oxygen generation is highly dependent on oxygen, which decreases the efficacy of the treatment on hypoxic cancer cells.
  • further oxygen consumption of PDT agents aggravates tumor hypoxia.
  • some of the signaling pathways (ex: HIF-1) are turned-on under severe hypoxia and cause angiogenesis, proliferation and metastasis of hypoxic cancer cells.
  • the third problem that PDT should overcome is the selective generation of singlet oxygen only in cancer cells without giving harm to healthy cells by employing water soluble and activatable drugs.
  • BODIPY dipyrrometheneboron difluoride
  • resorufin cores have been extensively used as fluorescent agents for bio-imaging during the last decades, but have not been employed in PDT studies.
  • Resorufin skeleton is quite suitable for PDT applications as it is intrinsically red-absorbing without any modification, photostable and water-soluble.
  • enzyme activated resorufin based PDT agents and BODIPY based PDT agents are synthesized to use in treatment of cancer.
  • the invention is about new photosensitizers for wide variety of cancer cells treatment by using photodynamic therapy. These photosensitizers can be activated with wavelengths of light that can penetrate through the body not just skin. Hence the present invention aims to transform PDT from being a specialized treatment to a generally applicable one. PDT is almost completely non-invasive compared to current treatment methods. Additionally due to its non-invasive nature treatment, it can be performed with much shorter intervals compared to chemotherapy. From the perspective of financials, it is known that chemotherapy reagents are expensive.
  • the photosensitizers developed in this invention designed in a way that target compounds can be attained with very small number of steps with cost effective reagents/reactants.
  • FIG. 1 Absorption of selenophene-substituted BODIPY derivative.
  • BODIPY based and resorufin based photosensitizers are synthesized for use in photodynamic therapy of cancer.
  • sensitizers are modified with selenophene (Se-BOD) or iodo-selenophene (SeI-BOD) units at 2 and 6 positions of the BODIPY core in order to facilitate intersystem crossing (ISC) upon external light irradiation as a result of heavy atom (selenium or selenium (Se) and iodine (I)) mediated spin-orbit coupling.
  • ISC intersystem crossing
  • Te selenium
  • I iodine
  • BODIPY derivatives absorb red-light around 650 nm and highly water soluble with the help of methyl pyridinium moeties such that only 0.1% DMSO as a co-solvent is needed to get clear solutions.
  • Methyl pyridinium groups contribute to three important issues.
  • the system described here in this invention is a patient ready cancer treatment PDT drug.
  • Fluorescence quantum yield of the sensitizers (8.5% for Se-BOD) are low as ISC pathway is active.
  • Singlet oxygen quantum yield for Se-BOD was calculated as 18% in phosphate buffered saline (PBS) (pH 7.4, 10 mM) with 0.1% dimethyl sulfoxide (DMSO).
  • PBS phosphate buffered saline
  • DMSO dimethyl sulfoxide
  • N-bromosuccinimide N-bromosuccinimide
  • N-iodosuccinimide N-iodosuccinimide
  • CH 2 Cl 2 a solution of N-iodosuccinimide (NIS) in CH 2 Cl 2 is added. Reaction mixture is stirred for 12-24 h at 0-40° C. and washed with water and sodium bicarbonate (NaHCO 3 ). Purification is performed by column chromatography to yield Compound 5.
  • heavy atoms are used in the synthesis of photosensitizer derivatives. Presence of heavy atoms is a requirement for a PDT drug. Once the sensitizers are excited with light to a singlet excited state presence of heavy atoms results in inter system crossing and a triplet excited state is generated. This triplet excited states is responsible for the generation of triplet oxygen from the oxygen present in the cells. Iodine as a heavy atom favors inter-system crossing by itself. In this invention, the aim is to increase the number of heavy atoms on the BODIPY core in order to increase the singlet oxygen generation yield of the drug synthesized in this invention through synergistic effect of selenium and iodine.
  • PDT Upon generation of singlet oxygen, it reacts with vital bio-molecules causing oxidative damage, which results in cell death. In addition to direct killing of cancer cells, PDT also restricts the follow of nutrients and oxygen to cancer cells by damaging the vasculatures around tumor regions and at the same time activates immune system against cancer cells.
  • Resorufin derivatives are introduced as photosensitizers for photodynamic therapy of cancer for the first time in this invention.
  • Iodine is incorporated to the core structure as a heavy atom in order to favor ISC.
  • These resorufin-based sensitizers are enzyme activated in such a way that cytotoxicity can only be observed in cancer cells.
  • PDT agent a sugar cage group ⁇ -D-galactopyranoside is attached to the iodinated-resorufin core and this modification shifted the absorption maximum of the drug to 500 nm.
  • PDT drug functions are similar, but the cage group is replaced by a propanamine, which can be selectively cleaved by monoamine oxidase (MAO) enzyme.
  • the PDT drug does not show any cytotoxicity in health cells, but it is highly cytotoxic in cancer cells upon 600 nm irradiation.
  • a new fluorophore core, silicon-substituted resorufin (Turkey Red) is designed and synthesized in this invention. It has red shifted absorption and emission signals compared to conventional resorufin (oxygen-substituted resorufin).
  • This new core is also converted to a cytotoxic photosensitizer for PDT applications simply by decorating the core structure with heavy atoms such as bromine or iodine.
  • 4,4′-azanediyldiphenol is brominated with NBS (2-4 equivalents) in acetonitrile at ( ⁇ 10) ⁇ 25° C. The mixture is stirred for 2-8 hours. Solvent is removed and the residue is dissolved in THF. The mixture is filtered through Celite and purified by column chromatography to give the dibrominated product 4,4′-azanediylbis(3-bromophenol).
  • 4,4′-azanediylbis(3-bromophenol) is treated with sodium hydride (NaH, 4-6 equivalents) in DMF at ( ⁇ 10) ⁇ 25° C. Mixture is stirred for 1-2 hours and then benzyl bromide (4-6 equivalents) is added and the mixture is heated to 70-100° C. for 4-18 hours. Water is added and the mixture was extracted with diethyl ether (Et 2 O). The solvent is evaporated and the product shown in below is attained by column chromatography.
  • N-benzyl-4-(benzyloxy)-N-(4-(benzyloxy)-2-bromophenyl)-2-bromoaniline N-benzyl-4-(benzyloxy)-N-(4-(benzyloxy)-2-bromophenyl)-2-bromoaniline is dissolved in Et 2 O and the mixture is cooled to ⁇ 80° C. to ⁇ 20° C. n-butyllithium (n-BuLi) is added and the mixture is stirred for 1 hour. Then dichloro(dimethyl)silane (SiMe 2 Cl 2 ) is added and the mixture is gradually warmed to room temperature. Et 2 O and water are added into the mixture and the organic phase is separated.
  • 10,10-dimethyl-5,10-dihydrodibenzo[b,e][1,4]azasiline-2,8-diol is dissolved in DCM. Pyridine is added and the mixture is cooled to ( ⁇ 20) ⁇ 10° C. Trifilic anhydride is then added and the mixture is stirred for 1-4 hours. The mixture is diluted with DCM and washed with water. The organic solvent is evaporated and the product shown in below is attained.
  • N-benzyl-4-(benzyloxy)-N-(4-(benzyloxy)-2-bromophenyl)-2-bromoaniline was dissolved in Et20 and the mixture was cooled to ⁇ 80 to ⁇ 20° C.
  • n-BuLi was added and the mixture was stirred for 1 hour.
  • PPhCl2 was added and the mixture was gradually warmed to room temperature.
  • H 2 O 2 was added and the mixture was stirred for 1-3 hours.
  • EtOAc was added and water was added the organic phase was separated. Solvent was evaporated and the residue purified by column chromatography to give the title compound.

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Abstract

Near-infrared (NIR) absorbing photosensitizers for imaging and treatment of cancer in a photodynamic therapy (PDT) are provided. Specifically, the NIR photosensitizers are mitochondria targeted and water-soluble, and used as a cytotoxic drug in a photodynamic therapy of the cancer. The NIR photosensitizers are activated with wavelengths of light, wherein the light penetrates through a body not just a skin. Hence the NIR photosensitizers aim to transform PDT from being a specialized treatment to a generally applicable one. PDT is almost completely non-invasive compared to current treatment methods.

Description

    TECHNICAL FIELD OF THE INVENTION
  • The present invention relates to photosensitizers to be used for imaging and treatment of cancer by using photodynamic therapy (PDT).
    • PRIOR ART OF THE INVENTION
  • Photodynamic therapy (PDT) is a treatment that uses special drugs, called photosensitizing agents, along with light to kill cancer cells. The drugs only work after they have been activated or turned on by certain kinds of light.
  • In PDT, therapeutic action is satisfied by the generation of singlet oxygen (1O2) upon irradiation of well-designed PDT agents (photosensitizers or drugs) by light. Singlet oxygen is the excited form of molecular oxygen (3O2) and it is cytotoxic due to its high reactivity towards vital biomolecules. In addition to this oxidative damage triggered direct killing mode (apoptosis or necrosis) arises from 1O2 reactivity, PDT also restricts the flow of nutrients and oxygen to cancer cells by disturbing the vasculatures around tumor regions and at the same time activates the immune system against cancer cells. The advantages and importance of PDT are more pronounced when it is compared with widely used conventional chemotherapy and radiotherapy. Although these therapies are the primary choices in clinic practices with a huge market in pharmaceutical industry, they have numerous side effects and give serious damage to the immune system which make them patient unfriendly.
  • When considered from this aspect; PDT is highly promising, however its broader applicability in clinical treatments is restricted due to some problems. The most important one is the limited penetration of the irradiation light through tissues, which leaves the deeper tumors out from the scope of PDT. Studies have shown that red or near-IR (NIR) absorbing PDT agents should be employed to get the best penetration depth and to avoid the absorption of incoming light by biomolecules. Although, a very wide range of well-known fluorescent probe cores have been converted to PDT agents, red and near-IR absorbing PDT agents are still rare.
  • The second major problem of the PDT is the oxygen deficiency (hypoxia) in cancer cells. During PDT; singlet oxygen generation is highly dependent on oxygen, which decreases the efficacy of the treatment on hypoxic cancer cells. In addition to this, further oxygen consumption of PDT agents aggravates tumor hypoxia. Accordingly, some of the signaling pathways (ex: HIF-1) are turned-on under severe hypoxia and cause angiogenesis, proliferation and metastasis of hypoxic cancer cells.
  • The third problem that PDT should overcome is the selective generation of singlet oxygen only in cancer cells without giving harm to healthy cells by employing water soluble and activatable drugs.
  • Most of the initial photosensitizers (first-generation) and FDA approved drugs are based on a porphyrin skeleton. Although they are really satisfying in terms of singlet oxygen generation and cytotoxicity, almost all of them have water solubility and photostability problems. Later phthalocyanine derivatives were introduced as promising photosensitizers for PDT applications, however synthetic problems and lack of control on photophysical properties restricted their use.
  • At this point, dipyrrometheneboron difluoride (BODIPY) core appeared to be good candidate due to its tunable photophysical properties, ease of synthesis and modification. Parent BODIPY core is highly hydrophobic and absorbs around 500 nm. Thus; for PDT applications, the core should be modified with water-soluble groups and p-conjugation should be extended in order to have a red-absorbing photosensitizer.
  • In literature, it is possible to find different version of BODIPYs serving as PDT drugs, however a water-soluble, red-absorbing and at the same time mitochondria targeted BODIPY based PDT agent has not been introduced before. Mitochondria is an important target in order to address hypoxia problem of PDT. It is known that oxygen mechanism is highly evaluated in mitochondria, and this high level of oxygen can be used by PDT agents to generate singlet oxygen efficiently even in aggressive solid tumors, in which severe hypoxia can be observed.
  • Also; resorufin cores have been extensively used as fluorescent agents for bio-imaging during the last decades, but have not been employed in PDT studies. Resorufin skeleton is quite suitable for PDT applications as it is intrinsically red-absorbing without any modification, photostable and water-soluble.
  • There is no doubt that revealing new PDT agent cores holding aforementioned properties is highly critical but the most promising and breakthrough outcomes will come from the studies aimed at gaining precise control over the location and rate of the cytotoxic singlet oxygen generation. To that end, most of the new generation PDT drugs are so called “activatable”. They remain in a passive state (no cytotoxicity) even under light irradiation and are activated at the site where therapy is desired by cancer cell associated stimuli. In literature, the most widely used approach is to take advantage of the acidic microenvironment of tumors by designing acidic pH activatable PDT drugs. Another common design principle is to employ bio-thiols that are elevated in cancer cells such as glutathione (GSH) as an activating biological input.
  • As studies on cancer biology and signalling pathways increase, role of many different enzymes in cancer have been uncovered during last decades. Consequently enzymes that are overexpressed in cancer cells appeared to be good candidates for activatable PDT drug designs. Accordingly, caspase-3, cathepsin B, nitroreductase and b-galactosidase activated PDT drugs were introduced with conventional PDT agent cores, however enzyme-activated agents are still rare and their potential can be further evaluated with the help of new generation PDT drug cores.
  • In this invention, enzyme activated resorufin based PDT agents and BODIPY based PDT agents are synthesized to use in treatment of cancer.
    • BRIEF DESCRIPTION AND OBJECTIVES OF THE INVENTION
  • The invention is about new photosensitizers for wide variety of cancer cells treatment by using photodynamic therapy. These photosensitizers can be activated with wavelengths of light that can penetrate through the body not just skin. Hence the present invention aims to transform PDT from being a specialized treatment to a generally applicable one. PDT is almost completely non-invasive compared to current treatment methods. Additionally due to its non-invasive nature treatment, it can be performed with much shorter intervals compared to chemotherapy. From the perspective of financials, it is known that chemotherapy reagents are expensive. The photosensitizers developed in this invention designed in a way that target compounds can be attained with very small number of steps with cost effective reagents/reactants. Most of the known literature compounds require long synthetic approaches towards achieving some of properties (water solubility, targeting, Near-IR absorption, etc.). The synthetic approaches described in this invention require a small number of steps from commercially available starting materials. Core structures can be attained in 5-6 steps. This creates a significant opportunity for commercialization of these drugs as PDT agents. In addition to this, the BODIPY derivatives synthesized in this invention are addressing the critical light penetration depth and hypoxia problems of PDT and theses BODIPY based photosensitizers are water-soluble, red-absorbing and at the same time mitochondria targeted.
    • DEFINITION OF THE FIGURES DESCRIBING THE INVENTION
  • FIG. 1. Absorption of selenophene-substituted BODIPY derivative.
    •  DETAILED DESCRIPTION OF THE INVENTION
  • In the present invention, BODIPY based and resorufin based photosensitizers are synthesized for use in photodynamic therapy of cancer.
    • BODIPY-Based Photosensitizers
  • These sensitizers are modified with selenophene (Se-BOD) or iodo-selenophene (SeI-BOD) units at 2 and 6 positions of the BODIPY core in order to facilitate intersystem crossing (ISC) upon external light irradiation as a result of heavy atom (selenium or selenium (Se) and iodine (I)) mediated spin-orbit coupling. These BODIPY derivatives absorb red-light around 650 nm and highly water soluble with the help of methyl pyridinium moeties such that only 0.1% DMSO as a co-solvent is needed to get clear solutions. Methyl pyridinium groups contribute to three important issues. First, these groups improve the water solubility of the PDT drug as mentioned. Second, they cause a red-shift in the absorption signal and finally they direct the drug to mitochondria (mitochondria targeting). It is known in the literature that most of the solid tumors are oxygen deficient (hypoxic). This hypoxic condition within the tumor cells is a real challenge for PDT drugs since the therapy itself consumes oxygen to generate cytotoxic singlet oxygen, which makes PDT a self-restricting method. One way to address this drawback is to direct PDT drugs to mitochondria, where the oxygen metabolism is high. Common strategy for mitochondria targeting is to use cationic species such as triphenylphosphine and methyl/hexyl pyridinium moieties. In this invention it is decided to use preferably methyl pyridinium, since it has several aforementioned advantages and it is easy to synthesize.
  • Figure US20210252152A1-20210819-C00001
  • All these features mentioned above combined with selenophene incorporation into the BODIPY results in a PDT drug with high water solubility, absorption in the near IR region (>650 nm) increased singlet oxygen generation efficiency (compared to bromine substitution) and mitochondria targeting abilities. Hence, the system described here in this invention is a patient ready cancer treatment PDT drug. Fluorescence quantum yield of the sensitizers (8.5% for Se-BOD) are low as ISC pathway is active. Singlet oxygen quantum yield for Se-BOD was calculated as 18% in phosphate buffered saline (PBS) (pH 7.4, 10 mM) with 0.1% dimethyl sulfoxide (DMSO).
  • Figure US20210252152A1-20210819-C00002
  • Commercially available benzoyl chloride (C6H5COCl) and 2,4-dimethylpyrrole are dissolved in methylene chloride (CH2Cl2) and stirred at 0° C. to 40° C. until starting material finished. Then proper amine base and boron trifluoride diethyl etherate (BF3.OEt2) is added and stirred 6-12 h. Then washed with water and purified by column chromatography and Compound 1 is synthesized successfully.
  • Figure US20210252152A1-20210819-C00003
  • To a solution of Compound 1 in CH2Cl2, a solution of N-bromosuccinimide (NBS) in CH2Cl2 is added and stirred 2-4 h at 0-40° C. then washed with water and brine and purified by column chromatography and Compound 2 is synthesized successfully.
  • Figure US20210252152A1-20210819-C00004
  • Compound 2 dissolved in dry N,N-dimethylformamide (DMF) and 4-pyridinecarboxyaldehyde, piperidine and acetic acid (AcOH) are added. Reaction mixture is stirred for 1-2 h at 0°−40° C., then solvent is evaporated and purified by column chromatography to yield Compound 3 successfully.
  • Figure US20210252152A1-20210819-C00005
  • Compound 3 is dissolved in toluene, then stannylated selenophene and palladium (Pd) catalyst (Pd(PPh3)Cl2, Pd(OAc)2 etc.) are added and stirred for 4-6 days at 100-140° C. Then it is washed with potassium fluoride (KF) solution and purified by column chromatography to yield Compound 4.
  • Figure US20210252152A1-20210819-C00006
  • To a solution of Compound 4 in CH2Cl2, a solution of N-iodosuccinimide (NIS) in CH2Cl2 is added. Reaction mixture is stirred for 12-24 h at 0-40° C. and washed with water and sodium bicarbonate (NaHCO3). Purification is performed by column chromatography to yield Compound 5.
  • Figure US20210252152A1-20210819-C00007
  • To a solution of Compound 5 in dry DMF, methyliodide is added and stirred 1-3 days at 0-40° C. The reaction mixture is precipitated with diethylether with the presence of DMF and Compound 6 is synthesized successfully.
  • In this invention heavy atoms are used in the synthesis of photosensitizer derivatives. Presence of heavy atoms is a requirement for a PDT drug. Once the sensitizers are excited with light to a singlet excited state presence of heavy atoms results in inter system crossing and a triplet excited state is generated. This triplet excited states is responsible for the generation of triplet oxygen from the oxygen present in the cells. Iodine as a heavy atom favors inter-system crossing by itself. In this invention, the aim is to increase the number of heavy atoms on the BODIPY core in order to increase the singlet oxygen generation yield of the drug synthesized in this invention through synergistic effect of selenium and iodine. Upon generation of singlet oxygen, it reacts with vital bio-molecules causing oxidative damage, which results in cell death. In addition to direct killing of cancer cells, PDT also restricts the follow of nutrients and oxygen to cancer cells by damaging the vasculatures around tumor regions and at the same time activates immune system against cancer cells.
    • General Structure of Synthesized BODIPY-based Photosensitizers
  • Figure US20210252152A1-20210819-C00008
    Figure US20210252152A1-20210819-C00009
    Figure US20210252152A1-20210819-C00010
    • Resorufin-Based Photosensitizers
  • Resorufin derivatives are introduced as photosensitizers for photodynamic therapy of cancer for the first time in this invention. Iodine is incorporated to the core structure as a heavy atom in order to favor ISC. These resorufin-based sensitizers are enzyme activated in such a way that cytotoxicity can only be observed in cancer cells. In the case of PDT agent, a sugar cage group β-D-galactopyranoside is attached to the iodinated-resorufin core and this modification shifted the absorption maximum of the drug to 500 nm. In literature it is known that β-D-galactopyranoside sugar cage can be removed selectively with b-galactosidase enzyme, which is overexpressed in several cancer types including ovarian and liver cancers. As a result of reaction between b-galactosidase and the PDT agent sugar cage removed and the absorption maximum of the resorufin core is red-shifted to 600 nm. Consequently, by adjusting the excitation wavelength during the PDT action to 600 nm, the PDT agent becomes cytotoxic only in cancer cells in which the b-galactosidase concentration is high, and on the contrary no cytotoxicity is observed in healthy cells as the PDT agent does not absorb the irradiation light at 600 nm. PDT drug functions are similar, but the cage group is replaced by a propanamine, which can be selectively cleaved by monoamine oxidase (MAO) enzyme. The PDT drug does not show any cytotoxicity in health cells, but it is highly cytotoxic in cancer cells upon 600 nm irradiation.
  • A new fluorophore core, silicon-substituted resorufin (Turkey Red) is designed and synthesized in this invention. It has red shifted absorption and emission signals compared to conventional resorufin (oxygen-substituted resorufin). This new core is also converted to a cytotoxic photosensitizer for PDT applications simply by decorating the core structure with heavy atoms such as bromine or iodine.
  • Figure US20210252152A1-20210819-C00011
  • Replacing oxygen with silicon and phosphine oxide is causing approximately 100 nm red shift in the absorption spectra of the cores which is quite unusual. Just replacing one atom of the core results in a very strong shift which in turn makes these cores quite valuable for PDT applications. The change of sp2 carbon atom with nitrogen in the fluorescein core results in resorufin. Here almost a 100 nm shift is also observed. One of the main ideas in this invention is combining both sp2 carbon to nitrogen change and oxygen to silicon/phosphine oxide change in the same core and has a combined effect of almost 200 nm red shift. This results in a record red shift with simply modifying the core structures which is very valuable since other approaches to attain NIR absorption requires many synthetic steps and transformations which make the drug candidates extremely expensive.
    • The Synthesis of Resorufin-Based Photosensitizer of Formula Below:
  • Figure US20210252152A1-20210819-C00012
  • Commercially available bis(4-methoxyphenyl)amine is treated with %30-50 hydrogen bromide (HBr) and Aliquat 336 at 70-120° C. for 12-48 hours. Mixture is diluted with water and extracted with ethyl acetate (EtOAc). The solvent is evaporated and residue is washed with hexane to get the demethylated product 4,4′-azanediyldiphenol.
  • Figure US20210252152A1-20210819-C00013
  • 4,4′-azanediyldiphenol is brominated with NBS (2-4 equivalents) in acetonitrile at (−10)−25° C. The mixture is stirred for 2-8 hours. Solvent is removed and the residue is dissolved in THF. The mixture is filtered through Celite and purified by column chromatography to give the dibrominated product 4,4′-azanediylbis(3-bromophenol).
  • Figure US20210252152A1-20210819-C00014
  • 4,4′-azanediylbis(3-bromophenol) is treated with sodium hydride (NaH, 4-6 equivalents) in DMF at (−10)−25° C. Mixture is stirred for 1-2 hours and then benzyl bromide (4-6 equivalents) is added and the mixture is heated to 70-100° C. for 4-18 hours. Water is added and the mixture was extracted with diethyl ether (Et2O). The solvent is evaporated and the product shown in below is attained by column chromatography.
  • Figure US20210252152A1-20210819-C00015
  • N-benzyl-4-(benzyloxy)-N-(4-(benzyloxy)-2-bromophenyl)-2-bromoaniline N-benzyl-4-(benzyloxy)-N-(4-(benzyloxy)-2-bromophenyl)-2-bromoaniline is dissolved in Et2O and the mixture is cooled to −80° C. to −20° C. n-butyllithium (n-BuLi) is added and the mixture is stirred for 1 hour. Then dichloro(dimethyl)silane (SiMe2Cl2) is added and the mixture is gradually warmed to room temperature. Et2O and water are added into the mixture and the organic phase is separated. Solvent is evaporated and the residue is purified by column chromatography to give 5-benzyl-2,8-bis(benzyloxy)-10,10-dimethyl-5,10-dihydrodibenzo[b,e][1,4]azasiline.
  • Figure US20210252152A1-20210819-C00016
    • 5-benzyl-2,8-bis(benzyloxy)-10,10-dimethyl-5,10-dihydrodibenzo[b,e][1,4]azasiline
  • 5-benzyl-2,8-bis(benzyloxy)-10,10-dimethyl-5,10-dihydrodibenzo[b,e][1,4]azasiline is dissolved in ethanol and palladium on carbon (Pd/C) is added at 0-30° C. The system is vacuumed and filled with hydrogen (H2) gas. The mixture is stirred for 4-12 hours. The mixture is diluted with ethanol and filtered through celite. The solvent is evaporated and the mixture is purified by column chromatography.
  • Figure US20210252152A1-20210819-C00017
    • 10,10-dimethyl-5,10-dihydrodibenzo[b,e][1,4]azasiline-2,8-diol
  • 10,10-dimethyl-5,10-dihydrodibenzo[b,e][1,4]azasiline-2,8-diol is dissolved in DCM and an appropriate oxidant (DDQ, Dess-Martin, etc) is added at (−10)−25° C. The mixture is stirred for 2-12 hours and the mixture is diluted with dichloromethane (DCM) and filtered through celite. The residue is washed with water and the organic solvent is evaporated. The residue was purified by column chromatography to get the title compound of formula below.
  • Figure US20210252152A1-20210819-C00018
    • 8-hydroxy-10,10-dimethyldibenzo[b,e][1,4]azasilin-2(10H)-one The Synthesis of Resorufin-Based Photosensitizer of Formula Below:
  • Figure US20210252152A1-20210819-C00019
  • 10,10-dimethyl-5,10-dihydrodibenzo[b,e][1,4]azasiline-2,8-diol is dissolved in DCM. Pyridine is added and the mixture is cooled to (−20)−10° C. Trifilic anhydride is then added and the mixture is stirred for 1-4 hours. The mixture is diluted with DCM and washed with water. The organic solvent is evaporated and the product shown in below is attained.
  • Figure US20210252152A1-20210819-C00020
    • 10,10-dimethyl-5,10-dihydrodibenzo[b,e][1,4]azasiline-2,8-diyl bis(trifluoromethanesulfonate)
  • 10,10-dimethyl-5,10-dihydrodibenzo[b,e][1,4]azasiline-2,8-diyl bis(trifluoromethanesulfonate) is dissolved in toluene and Pd(OAc)2 and an appropriate ligand (Xantphos, DavePhos, XPhos, etc) is added. The system is purged with argon and the appropriate amine (in this example morpholine) is added. The mixture is stirred at 50-100° C. for 12-36 hours. The reaction was diluted with EtOAc and washed with water. The solvent was evaporated. The residue was treated with Et4NOH in MeOH the residue was purified by column chromatography.
  • Figure US20210252152A1-20210819-C00021
    • 10,10-dimethyl-8-morpholino-5,10-dihydrodibenzo[b,e][1,4]azasilin-2-ol
  • 10,10-dimethyl-8-morpholino-5,10-dihydrodibenzo[b,e][1,4]azasilin-2-ol was dissolved in DCM and an appropriate oxidant (DDQ, Dess-Martin, etc) was added at −10-25° C. The mixture was stirred for 2-12 hours and the mixture was diluted with DCM and filtered through Celite. The residue was washed with water and the organic solvent was evaporated. The residue was purified by column chromatography to get the title compound.
  • Figure US20210252152A1-20210819-C00022
    • 10,10-dimethyl-8-morpholinodibenzo[b,e][1,4]azasilin-2(10H)-one The Synthesis of Resorufin-Based Photosensitizer of Formula Below:
  • Figure US20210252152A1-20210819-C00023
  • 10,10-dimethyl-5,10-dihydrodibenzo[b,e][1,4]azasiline-2,8-diyl bis(trifluoromethanesulfonate) was dissolved in toluene and Pd(OAc)2 and an appropriate ligand (Xantphos, DavePhos, XPhos, etc) was added. The system was purged with argon and the appropriate amine (in this example dime was added. The mixture was stirred at 50-100° C. for 12-36 hours. The reaction was diluted with EtOAc and washed with water. The solvent was evaporated and the residue was purified by column chromatography.
  • Figure US20210252152A1-20210819-C00024
    • 10,10-dimethyl-8-morpholino-5,10-dihydrodibenzo[b,e][1,4]azasilin-2-ol
  • 10,10-dimethyl-8-morpholino-5,10-dihydrodibenzo[b,e][1,4]azasilin-2-ol was dissolved in DCM and an appropriate oxidant (DDQ, Dess-Martin, etc) was added at −10-25° C. The mixture was stirred for 2-12 hours and the mixture was diluted with DCM and filtered through Celite. The residue was washed with water and the organic solvent was evaporated. The residue was purified by column chromatography to get the title compound.
  • Figure US20210252152A1-20210819-C00025
    • 10,10-dimethyl-8-morpholinodibenzo[b,e][1,4]azasilin-2(10H)-one The Synthesis of Resorufin-Based Photosensitizer of Formula Below:
  • Figure US20210252152A1-20210819-C00026
  • N-benzyl-4-(benzyloxy)-N-(4-(benzyloxy)-2-bromophenyl)-2-bromoaniline was dissolved in Et20 and the mixture was cooled to −80 to −20° C. n-BuLi was added and the mixture was stirred for 1 hour. Then PPhCl2 was added and the mixture was gradually warmed to room temperature. H2O2 was added and the mixture was stirred for 1-3 hours. EtOAc was added and water was added the organic phase was separated. Solvent was evaporated and the residue purified by column chromatography to give the title compound.
  • Figure US20210252152A1-20210819-C00027
    • 5-benzyl-2,8-bis(benzyloxy)-10-phenyl-5H-phenophosphazinine 10-oxide
  • 5-benzyl-2,8-bis(benzyloxy)-10-phenyl-5H-phenophosphazinine 10-oxide was dissolved in Ethanol and Pd/C was added at 0-30° C. The system was vacuumed and filled with H2 gas. The mixture was stirred for 4-12 hours. The mixture was diluted with Ethanol and filtered through Celite. The solvent was evaporated and the mixture was purified by column chromatography.
  • Figure US20210252152A1-20210819-C00028
    • 2,8-dihydroxy-10-phenyl-5H-phenophosphazinine 10-oxide
  • 2,8-dihydroxy-10-phenyl-5H-phenophosphazinine 10-oxide was dissolved in DCM and an appropriate oxidant (DDQ, Dess-Martin, etc) was added at −10-25° C. The mixture was stirred for 2-12 hours and the mixture was diluted with DCM and filtered through Celite. The residue was washed with water and the organic solvent was evaporated. The residue was purified by column chromatography to get the title compound.
  • Figure US20210252152A1-20210819-C00029
    • 8-hydroxy-10-phenyl-2H-phenophosphazinin-2-one 10-oxide The Synthesis of Resorufin-Based Photosensitizer of Formula Below:
  • Figure US20210252152A1-20210819-C00030
  • 2,8-dihydroxy-10-phenyl-5H-phenophosphazinine 10-oxide was dissolved in DCM. Pyridine was added and the mixture was cooled to −20-10° C. Trifilic anhydride was then added and the mixture was stirred for 1-4 hours. The mixture was diluted with DCM and washed with water. The organic solvent was evaporated and the title product was attained.
  • Figure US20210252152A1-20210819-C00031
    • 10-oxido-10-phenyl-5H-phenophosphazinine-2,8-diyl bis(trifluoromethanesulfonate)
  • 10-oxido-10-phenyl-5H-phenophosphazinine-2,8-diyl bis(trifluoromethanesulfonate) was dissolved in toluene and Pd(OAc)2 and an appropriate ligand (Xantphos, DavePhos, XPhos, etc) was added. The system was purged with argon and the appropriate amine (in this example morpholine) was added. The mixture was stirred at 50-100° C. for 12-36 hours. The reaction was diluted with EtOAc and washed with water. The solvent was evaporated. The residue was treated with Et4NOH in MeOH the residue was purified by column chromatography.
  • Figure US20210252152A1-20210819-C00032
    • 2-hydroxy-8-morpholino-10-phenyl-5H-phenophosphazinine 10-oxide
  • 2-hydroxy-8-morpholino-10-phenyl-5H-phenophosphazinine 10-oxide was dissolved in DCM and an appropriate oxidant (DDQ, Dess-Martin, etc) was added at −10-25° C. The mixture was stirred for 2-12 hours and the mixture was diluted with DCM and filtered through Celite. The residue was washed with water and the organic solvent was evaporated. The residue was purified by column chromatography to get the title compound.
  • Figure US20210252152A1-20210819-C00033
    • 8-morpholino-10-phenyl-2H-phenophosphazinin-2-one 10-oxide
  • The synthesis of resorufin-based photosensitizer of formula below:
  • Figure US20210252152A1-20210819-C00034
  • 10-oxido-10-phenyl-5H-phenophosphazinine-2,8-diyl bis(trifluoromethanesulfonate) was dissolved in toluene and Pd(OAc)2 and an appropriate ligand (Xantphos, DavePhos, XPhos, etc) was added. The system was purged with argon and the appropriate amine (in this example morpholine) was added. The mixture was stirred at 50-100° C. for 12-36 hours. The reaction was diluted with EtOAc and washed with water. The solvent was evaporated. The residue was treated with Et4NOH in MeOH the residue was purified by column chromatography.
  • Figure US20210252152A1-20210819-C00035
    • 2,8-dimorpholino-10-phenyl-5H-phenophosphazinine 10-oxide
  • 2,8-dimorpholino-10-phenyl-5H-phenophosphazinine 10-oxide was dissolved in DCM and an appropriate oxidant (DDQ, Dess-Martin, etc) was added at −10-25° C. The mixture was stirred for 2-12 hours and the mixture was diluted with DCM and filtered through Celite. The residue was washed with water and the organic solvent was evaporated. The residue was purified by column chromatography to get the title compound.
  • Figure US20210252152A1-20210819-C00036
    • 4-(8-morpholino-10-oxido-10-phenyl-2H-phenophosphazinin-2-ylidene)morpholin-4-ium General Structure of Synthesized Resorufin-Based Photosensitizers
  • Figure US20210252152A1-20210819-C00037
    Figure US20210252152A1-20210819-C00038
    Figure US20210252152A1-20210819-C00039
    Figure US20210252152A1-20210819-C00040
    Figure US20210252152A1-20210819-C00041
    Figure US20210252152A1-20210819-C00042
    Figure US20210252152A1-20210819-C00043
    Figure US20210252152A1-20210819-C00044
    Figure US20210252152A1-20210819-C00045
    Figure US20210252152A1-20210819-C00046
    Figure US20210252152A1-20210819-C00047
    • Synthesized Compounds for Use in Photodynamic Therapy of Cancer:
  • Figure US20210252152A1-20210819-C00048
    Figure US20210252152A1-20210819-C00049
    Figure US20210252152A1-20210819-C00050
    Figure US20210252152A1-20210819-C00051
    Figure US20210252152A1-20210819-C00052
    Figure US20210252152A1-20210819-C00053
    Figure US20210252152A1-20210819-C00054
    Figure US20210252152A1-20210819-C00055
    Figure US20210252152A1-20210819-C00056
    Figure US20210252152A1-20210819-C00057
    Figure US20210252152A1-20210819-C00058
    Figure US20210252152A1-20210819-C00059
    Figure US20210252152A1-20210819-C00060
    Figure US20210252152A1-20210819-C00061
    Figure US20210252152A1-20210819-C00062
    Figure US20210252152A1-20210819-C00063
    Figure US20210252152A1-20210819-C00064
    Figure US20210252152A1-20210819-C00065
    Figure US20210252152A1-20210819-C00066
    Figure US20210252152A1-20210819-C00067
    Figure US20210252152A1-20210819-C00068
    Figure US20210252152A1-20210819-C00069
    Figure US20210252152A1-20210819-C00070
    Figure US20210252152A1-20210819-C00071
    Figure US20210252152A1-20210819-C00072
    Figure US20210252152A1-20210819-C00073
    Figure US20210252152A1-20210819-C00074
    Figure US20210252152A1-20210819-C00075
    Figure US20210252152A1-20210819-C00076
    Figure US20210252152A1-20210819-C00077
    Figure US20210252152A1-20210819-C00078
    Figure US20210252152A1-20210819-C00079
    Figure US20210252152A1-20210819-C00080
    Figure US20210252152A1-20210819-C00081
    Figure US20210252152A1-20210819-C00082
    Figure US20210252152A1-20210819-C00083
    Figure US20210252152A1-20210819-C00084
    Figure US20210252152A1-20210819-C00085
    Figure US20210252152A1-20210819-C00086
    Figure US20210252152A1-20210819-C00087
    Figure US20210252152A1-20210819-C00088
    Figure US20210252152A1-20210819-C00089
    Figure US20210252152A1-20210819-C00090
    Figure US20210252152A1-20210819-C00091
    Figure US20210252152A1-20210819-C00092
    Figure US20210252152A1-20210819-C00093
    Figure US20210252152A1-20210819-C00094
    Figure US20210252152A1-20210819-C00095
    Figure US20210252152A1-20210819-C00096
    Figure US20210252152A1-20210819-C00097
    Figure US20210252152A1-20210819-C00098
    Figure US20210252152A1-20210819-C00099
    Figure US20210252152A1-20210819-C00100
    Figure US20210252152A1-20210819-C00101
    Figure US20210252152A1-20210819-C00102
    • Synthesized Compounds for Use in Imaging of Cancer Cells:
  • Figure US20210252152A1-20210819-C00103
    Figure US20210252152A1-20210819-C00104
    Figure US20210252152A1-20210819-C00105
    Figure US20210252152A1-20210819-C00106
    Figure US20210252152A1-20210819-C00107
    Figure US20210252152A1-20210819-C00108
    Figure US20210252152A1-20210819-C00109
    Figure US20210252152A1-20210819-C00110
    Figure US20210252152A1-20210819-C00111
    Figure US20210252152A1-20210819-C00112
    Figure US20210252152A1-20210819-C00113
    Figure US20210252152A1-20210819-C00114
    Figure US20210252152A1-20210819-C00115
    Figure US20210252152A1-20210819-C00116
    Figure US20210252152A1-20210819-C00117
    Figure US20210252152A1-20210819-C00118
    Figure US20210252152A1-20210819-C00119
    Figure US20210252152A1-20210819-C00120
    Figure US20210252152A1-20210819-C00121
    Figure US20210252152A1-20210819-C00122
    Figure US20210252152A1-20210819-C00123
    Figure US20210252152A1-20210819-C00124
    Figure US20210252152A1-20210819-C00125
    Figure US20210252152A1-20210819-C00126
    Figure US20210252152A1-20210819-C00127
    Figure US20210252152A1-20210819-C00128
    Figure US20210252152A1-20210819-C00129
    Figure US20210252152A1-20210819-C00130

Claims (16)

What is claimed is:
1. A near-infrared (NIR) absorbing photosensitizer, comprising formula A or B;
Figure US20210252152A1-20210819-C00131
wherein,
Figure US20210252152A1-20210819-C00132
Figure US20210252152A1-20210819-C00133
Figure US20210252152A1-20210819-C00134
wherein,
R7=alkyl and aryl derivatives;
R8=H, Br, I, any alkyl and aryl derivatives;
R9=H, Br, I, any alkyl and aryl derivatives;
R10=H, Br, I, any alkyl and aryl derivatives;
R11=H, Br, I, any other possible alkyl and aryl derivatives;
R12=H, Br, I, any other possible alkyl and aryl derivatives;
R13=H, Br, I, any other possible alkyl and aryl derivatives;
R14=H, Br, I, any other possible alkyl and aryl derivatives; and
R15=H, Br, I, any other possible alkyl and aryl derivatives;
Figure US20210252152A1-20210819-C00135
wherein,
R7=alkyl and aryl derivatives;
R8=H, Br, I, any alkyl and aryl derivatives;
R9=H, Br, I, any alkyl and aryl derivatives;
R10=H, Br, I, any alkyl and aryl derivatives;
R11=H, Br, I, any other possible alkyl and aryl derivatives;
R12=H Br, I, any other possible alkyl and aryl derivatives;
R13=H, Br, I, any other possible alkyl and aryl derivatives;
R14=H, Br, I, any other possible alkyl and aryl derivatives; and
R15=H, Br, I, any other possible alkyl and aryl derivatives.
2. The NIR absorbing photosensitizer according to claim 1, comprising one selected from the group of
Figure US20210252152A1-20210819-C00136
Figure US20210252152A1-20210819-C00137
Figure US20210252152A1-20210819-C00138
Figure US20210252152A1-20210819-C00139
Figure US20210252152A1-20210819-C00140
Figure US20210252152A1-20210819-C00141
Figure US20210252152A1-20210819-C00142
Figure US20210252152A1-20210819-C00143
Figure US20210252152A1-20210819-C00144
Figure US20210252152A1-20210819-C00145
Figure US20210252152A1-20210819-C00146
Figure US20210252152A1-20210819-C00147
Figure US20210252152A1-20210819-C00148
Figure US20210252152A1-20210819-C00149
Figure US20210252152A1-20210819-C00150
Figure US20210252152A1-20210819-C00151
Figure US20210252152A1-20210819-C00152
Figure US20210252152A1-20210819-C00153
Figure US20210252152A1-20210819-C00154
Figure US20210252152A1-20210819-C00155
Figure US20210252152A1-20210819-C00156
Figure US20210252152A1-20210819-C00157
Figure US20210252152A1-20210819-C00158
Figure US20210252152A1-20210819-C00159
Figure US20210252152A1-20210819-C00160
3. A NIR absorbing photosensitizer, comprising formula C or D or E or F or G or H:
Figure US20210252152A1-20210819-C00161
wherein:
Figure US20210252152A1-20210819-C00162
wherein
R3=alkyl and aryl derivatives;
R4=—H, —Br, —I, alkyl and aryl derivatives;
R5=—H, —Br, —I, alkyl and aryl derivatives;
R6=—H, —Br, —I, alkyl and aryl derivatives;
R7=—H, —Br, —I, any other possible alkyl and aryl derivatives;
R8=—H, —Br, —I, any other possible alkyl and aryl derivatives;
R9= H, —Br, —I, any other possible alkyl and aryl derivatives;
R10==—H, —Br, —I, any other possible alkyl and aryl derivatives; and
R11=—H, —Br, —I, an other possible alkyl and aryl derivatives;
Figure US20210252152A1-20210819-C00163
wherein
R3=alkyl and aryl derivatives;
R4=—H, —Br, —I, alkyl and aryl derivatives;
R5=—H, —Br, —I, alkyl and aryl derivatives;
R6=—H, —Br, —I, alkyl and aryl derivatives;
R7=—H, —Br, —I, any other possible alkyl and aryl derivatives;
R8=—H, —Br, —I, any other possible alkyl and aryl derivatives;
R9=—H, —Br, —I, any other possible alkyl and aryl derivatives;
R10=—H, —Br, —I, any other possible alkyl and aryl derivatives; and
R11=—H, —Br, —I, any other possible alkyl and aryl derivatives;
Figure US20210252152A1-20210819-C00164
wherein:
Figure US20210252152A1-20210819-C00165
wherein
R3=alkyl and aryl derivatives;
R4=alkyl and aryl derivatives;
R5=alkyl and aryl derivatives;
R6=—H, —Br, —I, alkyl and aryl derivatives;
R7=—H, —Br, —I, any other possible alkyl and aryl derivatives;
R8=—H, —Br, —I, any other possible alkyl and aryl derivatives;
R9=—H, —Br, —I, any other possible alkyl and aryl derivatives;
R10=—H, —Br, —I, any other possible alkyl and aryl derivatives;
R11=—H, —Br, —I, any other possible alkyl and aryl derivatives;
R12=—H, —Br, —I, any other possible alkyl and aryl derivatives; and
R13=—H, —Br, —I, any other possible alkyl and aryl derivatives;
Figure US20210252152A1-20210819-C00166
wherein
R5 alkyl and aryl derivatives;
R6=—H, —Br, —I, alkyl and aryl derivatives;
R7=—H, —Br, —I, any other possible alkyl and aryl derivatives;
R8=—H, —Br, —I, any other possible alkyl and aryl derivatives;
R9=—H, —Br, —I, any other possible alkyl and aryl derivatives;
R10=—H, —Br, —I, any other possible alkyl and aryl derivatives;
R11=—H, —Br, —I, any other possible alkyl and aryl derivatives;
R12=—H, —Br, —I, any other possible alkyl and aryl derivatives; and
R13=—H, —Br, —I, any other possible alkyl and aryl derivatives;
Figure US20210252152A1-20210819-C00167
wherein;
Figure US20210252152A1-20210819-C00168
wherein
R3=alkyl and aryl derivatives;
R4=alkyl and aryl derivatives;
R5=alkyl and aryl derivatives;
R6=—H, —Br, —I, alkyl and aryl derivatives;
R7=—H, —Br, —I, any other possible alkyl and aryl derivatives;
R8=—H, —Br, —I, any other possible alkyl and aryl derivatives;
R9—H, —Br, —I, any other possible alkyl and aryl derivatives;
R10=—H, —Br, —I, any other possible alkyl and aryl derivatives;
R11=—H, —Br, —I, any other possible alkyl and aryl derivatives;
R12=—H, —Br, —I, any other possible alkyl and aryl derivatives; and
R13=—H, —Br, —I, any other possible alkyl and aryl derivatives;
Figure US20210252152A1-20210819-C00169
wherein
R5=alkyl and aryl derivatives;
R6=—H, —Br, —I, alkyl and aryl derivatives;
R7=—H, —Br, —I, any other possible alkyl and aryl derivatives;
R8=—H, —Br, —I, any other possible alkyl and aryl derivatives;
R9=—H, —Br, —I, any other possible alkyl and aryl derivatives;
R10=—H, —Br, —I, any other possible alkyl and aryl derivatives;
R11=—H, —Br, —I, any other possible alkyl and aryl derivatives;
R12=—H, —Br, —I, any other possible alkyl and aryl derivatives; and
R13=—H, —Br, —I, any other possible alkyl, and aryl derivatives;
Figure US20210252152A1-20210819-C00170
wherein;
Figure US20210252152A1-20210819-C00171
wherein
R2=alkyl and aryl derivatives;
R3=—H, —Br, —I, alkyl and aryl derivatives;
R4=—H, —Br, —I, any other possible alkyl and aryl derivatives;
R5=—H, —Br, —I, any other possible alkyl and aryl derivatives;
R6—H, —Br, —I, any other possible alkyl and aryl derivatives;
R7=—H, —Br, —I, any other possible alkyl and aryl derivatives;
R8=—H, —Br, —I, any other possible alkyl and aryl derivatives;
R9=—H, —Br, —I, any other possible alkyl and aryl derivatives; and
R10=—H, —Br, —I, any other possible alkyl and aryl derivatives
Figure US20210252152A1-20210819-C00172
wherein
R2=alkyl and aryl derivatives;
R3=—H, —Br, —I, alkyl and aryl derivatives;
R4=—Br, —I, any other possible alkyl and aryl derivatives;
R5=—H, —Br, —I, any other possible alkyl and aryl derivatives;
R6=—H, —Br, —I, any other possible alkyl and aryl derivatives;
R7=—H, —Br, —I, any other possible alkyl and aryl derivatives;
R8=—H, —Br, —I, any other possible alkyl and aryl derivatives;
R9=—H, —Br, —I, any other possible alkyl and aryl derivatives; and
R10=—H, —Br, —I, any other possible alkyl and aryl derivatives;
Figure US20210252152A1-20210819-C00173
wherein;
Figure US20210252152A1-20210819-C00174
wherein
R3=alkyl and aryl derivatives;
R4=alkyl and aryl derivatives;
R5=—H, —Br, —I, alkyl and aryl derivatives;
R6=—H, —Br, —I, alkyl and aryl derivatives;
R7=—H, —Br, —I, any other possible alkyl and aryl derivatives;
R8=—H, —Br, —I, any other possible alkyl and aryl derivatives;
R9=—H, —Br, —I, any other possible alkyl and aryl derivatives;
R10=—H, —Br, —I, any other possible alkyl and aryl derivatives;
R11=—H, —Br, —I, any other possible alkyl and aryl derivatives; and
R12=—H, —Br, —I, any other possible alkyl and aryl derivatives;
Figure US20210252152A1-20210819-C00175
wherein
R4=alkyl and aryl derivatives;
R5=—H, —Br, —I, alkyl and aryl derivatives;
R6=—H, —Br, —I, alkyl and aryl derivatives;
R7=—H, —Br, —I, any other possible alkyl and aryl derivatives;
R8=—H, —Br, —I, any other possible alkyl and aryl derivatives;
R9=—H, —Br, —I, any other possible alkyl and aryl derivatives;
R10=—H, —Br, —I, any other possible alkyl and aryl derivatives;
R11=—H, —Br, —I, any other possible alkyl and aryl derivatives; and
R12=—H, —Br, —I, any other possible alkyl and aryl derivatives;
Figure US20210252152A1-20210819-C00176
wherein;
Figure US20210252152A1-20210819-C00177
wherein
R3=alkyl and aryl derivatives;
R4=alkyl and aryl derivatives;
R5=—H, —Br, —I, alkyl and aryl derivatives;
R6=—H, —Br, —I, alkyl and aryl derivatives;
R7=—H, —Br, —I, any other possible alkyl and aryl derivatives;
R8=—H, —Br, —I, any other possible alkyl and aryl derivatives;
R9=—H, —Br, —I, any other possible alkyl and aryl derivatives;
R10=—H, —Br, —I, any other possible alkyl and aryl derivatives;
R11=—H, —Br, —I, any other possible alkyl and aryl derivatives; and
R12=—H, —Br, —I, any other possible alkyl and aryl derivatives;
Figure US20210252152A1-20210819-C00178
wherein
R4=alkyl and aryl derivatives;
R5=—H, —Br, —I, alkyl and aryl derivatives;
R6=—H, —Br, —I, alkyl and aryl derivatives;
R7=—H, —Br, —I, any other possible alkyl and aryl derivatives;
R8=—H, —Br, —I, any other possible alkyl and aryl derivatives;
R9=—H, —Br, —I, any other possible alkyl and aryl derivatives;
R10=H, —Br, —I, any other possible alkyl and aryl derivatives;
R11=H, —Br, —I, any other possible alkyl and aryl derivatives; and
R12=H, —Br, —I, any other possible alkyl and aryl derivatives.
4. The NIR absorbing photosensitizer according to claim 3, comprising one selected from the group of
Figure US20210252152A1-20210819-C00179
Figure US20210252152A1-20210819-C00180
Figure US20210252152A1-20210819-C00181
Figure US20210252152A1-20210819-C00182
Figure US20210252152A1-20210819-C00183
Figure US20210252152A1-20210819-C00184
Figure US20210252152A1-20210819-C00185
Figure US20210252152A1-20210819-C00186
Figure US20210252152A1-20210819-C00187
Figure US20210252152A1-20210819-C00188
Figure US20210252152A1-20210819-C00189
Figure US20210252152A1-20210819-C00190
Figure US20210252152A1-20210819-C00191
Figure US20210252152A1-20210819-C00192
Figure US20210252152A1-20210819-C00193
Figure US20210252152A1-20210819-C00194
Figure US20210252152A1-20210819-C00195
Figure US20210252152A1-20210819-C00196
Figure US20210252152A1-20210819-C00197
Figure US20210252152A1-20210819-C00198
Figure US20210252152A1-20210819-C00199
Figure US20210252152A1-20210819-C00200
Figure US20210252152A1-20210819-C00201
Figure US20210252152A1-20210819-C00202
Figure US20210252152A1-20210819-C00203
Figure US20210252152A1-20210819-C00204
Figure US20210252152A1-20210819-C00205
Figure US20210252152A1-20210819-C00206
Figure US20210252152A1-20210819-C00207
Figure US20210252152A1-20210819-C00208
Figure US20210252152A1-20210819-C00209
Figure US20210252152A1-20210819-C00210
Figure US20210252152A1-20210819-C00211
Figure US20210252152A1-20210819-C00212
Figure US20210252152A1-20210819-C00213
Figure US20210252152A1-20210819-C00214
Figure US20210252152A1-20210819-C00215
Figure US20210252152A1-20210819-C00216
5. The NIR absorbing photosensitizer according to claim 1, wherein the NIR absorbing photosensitizer is mitochondria targeted.
6. The NIR absorbing photosensitizer according to claim 1, wherein the NIR absorbing photosensitizer is water-soluble.
7. A method of using the compounds according to claim 1, wherein the compounds are used as a cytotoxic drug in a photodynamic therapy of a cancer.
8. The NIR absorbing photosensitizer according to claim 1, comprising formula I or J or K or L or M or N:
Figure US20210252152A1-20210819-C00217
wherein;
Figure US20210252152A1-20210819-C00218
wherein;
Figure US20210252152A1-20210819-C00219
wherein:
Figure US20210252152A1-20210819-C00220
wherein;
Figure US20210252152A1-20210819-C00221
wherein:
Figure US20210252152A1-20210819-C00222
Figure US20210252152A1-20210819-C00223
wherein;
Figure US20210252152A1-20210819-C00224
9. The NIR absorbing photosensitizer according to claim 8, comprising one selected from the group of
Figure US20210252152A1-20210819-C00225
Figure US20210252152A1-20210819-C00226
Figure US20210252152A1-20210819-C00227
Figure US20210252152A1-20210819-C00228
Figure US20210252152A1-20210819-C00229
Figure US20210252152A1-20210819-C00230
Figure US20210252152A1-20210819-C00231
Figure US20210252152A1-20210819-C00232
Figure US20210252152A1-20210819-C00233
Figure US20210252152A1-20210819-C00234
Figure US20210252152A1-20210819-C00235
Figure US20210252152A1-20210819-C00236
Figure US20210252152A1-20210819-C00237
Figure US20210252152A1-20210819-C00238
Figure US20210252152A1-20210819-C00239
Figure US20210252152A1-20210819-C00240
Figure US20210252152A1-20210819-C00241
Figure US20210252152A1-20210819-C00242
Figure US20210252152A1-20210819-C00243
Figure US20210252152A1-20210819-C00244
Figure US20210252152A1-20210819-C00245
Figure US20210252152A1-20210819-C00246
Figure US20210252152A1-20210819-C00247
Figure US20210252152A1-20210819-C00248
Figure US20210252152A1-20210819-C00249
Figure US20210252152A1-20210819-C00250
Figure US20210252152A1-20210819-C00251
Figure US20210252152A1-20210819-C00252
Figure US20210252152A1-20210819-C00253
Figure US20210252152A1-20210819-C00254
Figure US20210252152A1-20210819-C00255
Figure US20210252152A1-20210819-C00256
Figure US20210252152A1-20210819-C00257
10. A method of using the compounds for an imaging of cancer cells according to claim 9.
11. The NIR absorbing photosensitizer according to claim 2, wherein the NIR absorbing photosensitizer is mitochondria targeted.
12. The NIR absorbing photosensitizer according to claim 3, wherein the NIR absorbing photosensitizer is mitochondria targeted.
13. The NIR absorbing photosensitizer according to claim 4, wherein the NIR absorbing photosensitizer is mitochondria targeted.
14. The NIR absorbing photosensitizer according to claim 2, wherein the NIR absorbing photosensitizer is water-soluble.
15. The NIR absorbing photosensitizer according to claim 3, wherein the NIR absorbing photosensitizer is water-soluble.
16. The NIR absorbing photosensitizer according to claim 4, wherein the NIR absorbing photosensitizer is water-soluble.
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