Radiosynthesis and biological evaluation of 166Ho labeled methoxylated porphyrins as possible therapeutic agents

¹⁶⁶Ho labeled 5,10,15,20-tetrakis(3,4-dimethoxyphenyl) porphyrin, and 5,10,15,20-tetrakis(3,4,5-trimethoxyphenyl) porphyrin ([¹⁶⁶Ho]–TDMPP and [¹⁶⁶Ho]–TTMPP respectively) were prepared with acceptable radiochemical purity and specific activities. Stability and partition coefficient of the complexes were determined in the final formulations and biodistribution studies in mouse demonstrated high accumulation of [¹⁶⁶Ho]–TDMPP in the lung and liver and less excretion through the kidney. while [¹⁶⁶Ho]–TTMPP was mostly excreted into intestines and kidneys while lungs were a minor accumulation site. In contrast to other reported radiolanthanide labeled porphyrins these two complexes showed less liver accumulation. Further investigation of their potential therapeutic properties is of interest.     

Preparation, nano purification, quality control and labeling optimization of [64Cu]-5,10,15,20-tetrakis (penta fluoro phenyl) porphyrin complex as a possible imaging agent

Cu-64 was produced via the ⁶⁸Zn (p,αn)⁶⁴Cu nuclear reaction (≈200 mCi, >95 % chemical yield at 180 μA for 1.1 h irradiation, (radionuclidic purity >96 %, copper-67 as impurity) followed by purification with amino functionalized nano magnetic oxide, Fe₃O₄ aiming to remove trace amount of heavy metal ions from aqueous media due to achieve ultra pure [⁶⁴Cu] CuCl₂ for labeling step. [⁶⁴Cu] labeled 5,10,15,20-tetrakis(penta fluoro phenyl) porphyrin ([⁶⁴Cu]-TFPP) was prepared using freshly prepared [⁶⁴Cu] CuCl₂ (Cu-64; T _1/2 = 12.7 h) and 5,10,15,20-tetrakis(penta fluoro phenyl)porphyrin (H₂TFPP) for 60 min at 100 °C under reflux condition (radiochemical purity: >97 % ITLC, >98 % HPLC, specific activity: 14–16 GBq/mmol). Stability of the complex was checked in final formulation and human serum for 24 h. The partition coefficient was calculated for the compound (log P = 0.73). The biodistribution of the labeled compound in vital organs of wild-type rats was studied using scarification studies and PET imaging up in 2 and 4 h after injection. A detailed comparative pharmacokinetic study performed for ⁶⁴Cu cation and [⁶⁴Cu]-TFPP. The complex is mostly washed out from the circulation through kidneys and liver and can be an interesting tumor imaging/targeting agent due to high specific uptake and rapid excretion through the urinary tract.     

Preparation and preliminary evaluation of [<Superscript>67</Superscript>Ga]-tetra phenyl porphyrin complexes as possible imaging agents

[⁶⁷Ga]labeled tetraphenyl porphyrin ([⁶⁷Ga]-TPP) was prepared using freshly prepared [⁶⁷Ga]GaCl₃ and tetraphenyl porphyrin (TPPH₂) for 30–60 min at 25 °C (radiochemical purity: >97 ± 1% ITLC, >98 ± 0.5% HPLC, specific activity: 13–14 GBq/mmol). Stability of the complex was checked in final formulation and human serum for 24 h. The partition coefficient was calculated for the compound (log P 1.89). The biodistribution of the labeled compound in vital organs of wild-type rats was studied using scarification studies and SPECT imaging up to 24 h. A detailed comparative pharmacokinetic study performed for ⁶⁷Ga cation and [⁶⁷Ga]-TPP. The complex is mostly washed out from the circulation through kidneys and can be an interesting tumor imaging/targeting agent due to low liver uptake and rapid excretion through the urinary tract.     

Production, nano-purification, radiolabeling and biodistribution study of [140Nd] 5,10,15,20-tetraphenylporphyrin complex as a possible imaging agent

[¹⁴⁰Nd] labeled 5,10,15,20-tetraphenylporphyrin ([¹⁴⁰Nd]-TPP) as a tumor–avid complex with a β-emitting radionuclide for evaluating its potential for target tumor therapy is reported. This complex was prepared using freshly prepared [¹⁴⁰Nd] NdCl₃ (purified by amino functionalized MCM-41 nano resin and commercial cation exchanger resins) and 5,10,15,20-tetraphenylporphyrin (H₂TPP).Stability of the complex was investigated in final formulation and human serum for 24 h and the partition coefficient was calculated. The biodistribution of the labeled compound in vital organs of Swiss mice bearing fibro sarcoma tumor was studied using scarification studies and positron emission tomography imaging up to 4 h.     

Fluorescent Arylphosphonic Acids: Synergic Interactions between Bone and the Fluorescent Core

Herein, we report the third generation of fluorescent probes (arylphosphonic acids) to target calcifications, particularly hydroxyapatite (HAP). In this study, we use highly conjugated porphyrin-based arylphosphonic acids and their diesters, namely 5,10,15,20-tetrakis[m-(diethoxyphosphoryl)phenyl]porphyrin ( m -H₈TPPA-OEt₈ ) and 5,10,15,20-tetrakis [m-phenylphosphonic acid]porphyrin ( m -H₈TPPA ), in comparison with their positional isomers 5,10,15,20-tetrakis[p-(diisopropoxyphosphoryl)phenyl]porphyrin ( p -H₈TPPA-iPr₈ ) and 5,10,15,20-tetrakis [p-phenylphosphonic acid]porphyrin ( p -H₈TPPA ), which have phosphonic acid units bonded to sp² carbon atoms of the fluorescent core. The conjugation of the fluorescent core is thus extended to the (HAP) through sp²-bonded −PO₃H₂ units, which generates increased fluorescence upon HAP binding. The resulting fluorescent probes are highly sensitive towards the HAP in rat bone sections. The designed probes are readily taken up by cells. Due to the lower reported toxicity of ( p -H₈TPPA ), these probes could find applications in monitoring bone resorption or adsorption, or imaging vascular or soft tissue calcifications for breast cancer diagnosis etc.     

Synthesis and spectrophotometric study of the acid-base and complexing properties of 2,3,7,8,12,13,17,18-Octaethyl-5,10,15,20-tetrakis(4-methoxyphenyl)porphyrin in acetonitrile

2,3,7,8,12,13,17,18-Octaethyl-5,10,15,20-tetrakis(4-methoxyphenyl)porphyrin has been synthesized, and its acid-base and complexing properties in the systems 1,8-diazabicyclo[5.4.0]undec-7-ene-acetonitrile, acetonitrile-Zn(OAc)₂, and 1,8-diazabicyclo[5.4.0]undec-7-ene-acetonitrile-Zn(OAc)₂ have been studied by spectrophotometry. Titration of 2,3,7,8,12,13,17,18-octaethyl-5,10,15,20-tetrakis(4-methoxyphenyl)porphyrin with 1,8-diazabicyclo[5.4.0]undec-7-ene is accompanied by successive deprotonation of the pyrrole nitrogen atoms with formation of the corresponding mono- and dianion. The overall acid dissociation constant of the title compound has been determined. The complexation of neutral and doubly deprotonated 2,3,7,8,12,13,17,18-octaethyl-5,10,15,20-tetrakis(4-methoxyphenyl)porphyrin with Zn(OAc)₂ has been studied, and kinetic parameters for the formation of the zinc complex according to the molecular and ionic mechanisms have been determined. Extra coordination of 1,8-diazabicyclo[5.4.0]undec-7-ene by the zinc complex of 2,3,7,8,12,13,17,18-octaethyl-5,10,15,20-tetrakis(4-methoxyphenyl)porphyrin.     

Synthesis of Novel Porphyrin Derivatives with Mesogenic Properties

Two novel porphyrin derivatives, 5,10,15,20-tetra(4-(N-octane-carboxamide)phenyl)porphyrin (4NC₈-TPP) and 5,10,15,20-tetra(4-(N-stearyl-carboxamide)phenyl)porphyrin (4NC₁₈-TPP), were synthesized. Their molecular structures were characterized by means of time-of-flight mass spectrometer (TOF-MS), nuclear magnetic resonance (NMR), and infrared spectra (IR). The thermal behavior and morphologies of 4NC₈-TPP and 4NC₁₈-TPP were examined by thermal gravity (TG), differential scanning calorimetry (DSC), x-ray diffraction (XRD), and polarizing optical microscope (POM). It was found that both 4NC₈-TPP and 4NC₁₈-TPP had mesogenic properties.     

Cellular uptake and photocytotoxicity of glycoconjugated chlorins in HeLa cells

Eight 5,10,15,20-tetrakis[3- or 4-(beta-D-glycopyranosyloxy)phenyl]chlorins were synthesized by means of the Whitlock method with diimide reduction and purified by reversed-phase thin layer chromatography (RP-TLC). All compounds were characterized by (1)H NMR spectroscopy, electron-spray ionization time-of-flight mass spectrometry (ESI-TOF MS), and UV-Vis spectroscopy. ESI-TOF MS could detect the 2H difference in molecular weight between a glycoconjugated chlorin and its corresponding porphyrin (i.e., 5,10,15,20-tetrakis[3- or 4-(beta-D-glycopyranosyloxy)phenyl]porphyrin). The cellular uptake of the eight chlorins was evaluated in HeLa cells. All glycoconjugated chlorins showed higher cellular uptake than tetraphenylporphyrin tetrasulfonic acid (TPPS), and 5,10,15,20-tetrakis[3-(beta-D-xylopyranosyloxy)phenyl]chlorin showed 50-fold higher uptake than TPPS. The photocytotoxicity of 5,10,15,20-tetrakis[3-(beta-D-glucopyranosyloxy)phenyl]chlorin, 5,10,15,20-tetrakis[3-(beta-D-xylopyranosyloxy)phenyl]chlorin and TPPS towards HeLa cells was examined at the concentration of 2x10(-7) M (mol/dm(3)). These photosensitizers had no cytotoxicity in the dark, but their photocytotoxicity decreased in the order of 5,10,15,20-tetrakis[3-(beta-D-glucopyranosyloxy)phenyl]chlorin>5,10,15,20-tetrakis[3-(beta-D-xylopyranosyloxy)phenyl]chlorin>TPPS. The results indicate that the photocytotoxicity is not related simply to cellular uptake.     

Development of 166Ho bleomycin as a possible therapeutic complex

Due to interesting therapeutic properties of ¹⁶⁶Ho and the antineoblastic antibiotic, bleomycin (BLM), ¹⁶⁶Ho-bleomycin (¹⁶⁶Ho-BLM) was developed as a possible therapeutic compound. ¹⁶⁶Ho chloride was obtained by thermal neutron irradiation (1 × 10¹³ n cm^?2 s^?1) of natural Ho(NO₃)₃ samples (specific activity = 3–5 GBq mg^?1), dissolved in acidic media. At optimized conditions (room temperature, 12 h, 0.15–0.3 mg bleomycin for 74 MBq ¹⁶⁶HoCl₃) a radiochemical purity of 94–97% was obtained as shown by ITLC and HPLC (specific activity, 700–740 GBq mmol^?1). Biodistribution studies of ¹⁶⁶Ho chloride and ¹⁶⁶Ho-BLM were performed in wild-type rats. The accumulation of the radiolabeled compound in lungs, liver and spleen demonstrates a similar pattern to the other radiolabeled bleomycins.     

New mixed rare earth double-decker complexes with octyloxynaphthyl-porphyrinato and phenylthio-naphthalocyaninato ligands – preparation and spectroscopic characterization

Eight new (porphyrinato)(naphthalocyaninato) rare earth(III) double-decker complexes M^III(TONPP)[Nc(PhS)₈] [M = La, Pr, Nd, Sm, Eu, Gd, Tb, and Dy; TONPP = 5,10,15,20-tetrakis(4-octyloxynaphthyl) porphyrin; Nc(PhS)₈ = 3,4,12,13,21,22,30,31-octa(phenylthio)-2,3-naphthalocyanine] have been prepared and characterized by spectroscopic methods. The UV–vis absorption spectra depend on the central rare earth ionic size, suggesting that all the transitions involve molecular orbitals with contribution from both porphyrin and naphthalocyanine ligands. The IR and Raman spectra of these double-decker compounds were systemically investigated, showing that the electron hole in these mixed double-deckers is mainly localized at the naphthalocyanine ring. Their sandwich nature was also characterized by MS, EA, and ¹H NMR techniques.     

Spectral properties and solution behavior of gold(III) coordination compounds with water-soluble porphyrins

Gold(III) coordination compounds with three water-soluble porphyrins―5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrin (H₂TSPP^4–), 5,10,15,20-tetrakis(4-N-methylpyridyl)porphyrin (H₂TMPyP⁴⁺), and 5,10,15,20-tetrakis(4-N,N,N-trimethylaminophenyl)porphyrin (H₂TTMAPP⁴⁺)―have been studied. Complex [Au(TTMAPP)]⁵⁺ has been prepared for the first time. The analysis of coordination-induced shifts of proton signals in NMR spectra and intensities of Q bands in absorption spectra indicates the high degree of bond covalence in the studied metal porphyrins and a partial transfer of electron density from porphyrin to gold ion. The cationic complexes [Au(TMPyP)]⁵⁺ and [Au(TTMAPP)]⁵⁺ in aqueous solutions has been found to exist in monomeric form, while anionic complex [Au(TSPP)]^3– undergoes dimerization upon growth of concentration and solution ionic strength. Equilibrium constant for dimerization has been calculated, the constant has been found to decrease when temperature rises. Thermodynamic parameters of dimerization process have been determined: ΔH° =–31.8 kJ/mol and ΔS° =–13.8 J/mol K.     

Methoxy-isoporphyrins of water-soluble porphyrins: synthesis,characterization and electrochemical properties

Abstract

Methoxy-isoporphyrins of zinc [5,10,15,20-tetrakis(4-sulfonatophenyl)]porphyrin, ZnTSPP (1a) and zinc [5,10,15,20-tetrakis(4-carboxyphenyl)]porphyrin, ZnTCPP (1b) have been synthesized and characterized using standard spectroscopic techniques (Uv-visible, ¹H NMR) , ESI-mass spectrometry and powder X-ray diffraction studies. The isoporphyrins [5-(methoxy)-5,10,15,20-tetrakis(4-sulfonatophenyl)-5H,15H-porphinato]zinc(II) (2a) and [5-(methoxy)-5,10,15,20-tetrakis(4-carboxyphenyl)-5H,21H-porphinato]zinc(II) (2b) are formed due to nucleophilic attack of the methanol to the zinc porphyrin dication. Ceric ammonium nitrate (CAN) was used to oxidize zinc porphyrin and to form zinc porphyrin dication. The electronic spectra of the isoporphyrin complexes 2a and 2b exhibit an intense peak at near IR region . Electrochemical measurements of the synthesized isoporphyrins showed a typical irreversible reduction peak at lower potential. S-containing nucleophiles, which work as reducing agents, convert the zinc isoporphyrins to their parent porphyrins, which supports the electrochemical observations. Their structural properties have been studied using powder X-ray diffraction. The luminescence properties of isoporphyrins were compared with the parent zinc porphyrins.     

Radiosynthesis and biodistribution studies of [62Zn/62Cu]–plerixafor complex as a novel in vivo PET generator for chemokine receptor imaging

In order to develop a possible C-X-C chemokine receptor type 4 (CXCR4) imaging agent for oncological scintigraphy, [⁶²Zn]labeled 1,1′-[1,4-phenylenebis(methylene)]bis-1,4,8,11-tetraazacyclotetradecane ([⁶²Zn]-AMD3100) was prepared using in-house made [⁶²Zn]ZnCl₂ and AMD-3100 for 1 h at 50 °C (radiochemical purity: >97 % ITLC, >96 % HPLC, specific activity: 20–22 GBq/mmol) in acetate buffer. The complex showed highly hydrophilic properties (log P = ?1.114). Stability of the complex was checked in presence of human serum (37 °C) and in final formulation for 1 day. The biodistribution of the labeled compound in vital organs of wild-type Sprague–Dawdley rats were determined and compared with that of free Zn²⁺ cation up to 6 h. Co-incidence imaging of the complex was consistent with the distribution data up to 3 h. The complex can be a possible in vivo generator compound for PET imaging in CXCR4 positive tumors.     

Preparation and the biodistribution study of [131I]-5,10,15,20-tetrakis(4-hydroxyphenyl)porphyrin and 5-(4-aminophenyl)-10,15,20-triphenylporphyrin

[¹³¹I]-5,10,15,20-tetrakis(4-hydroxyphenyl)porphyrin and [¹³¹I]-5-(4-aminophenyl)-10,15,20-triphenylporphyrin (¹³¹I-TPPOH and ¹³¹I-TPPNH₂) were prepared and their biodistribution properties were evaluated in normal Kunming (KM) mice and SMMC-7721 tumor-bearing BALB/c mice. The optimized labeling yields were 98 and 96 % for ¹³¹I-TPPOH and ¹³¹I-TPPNH₂, respectively. They were stable in vitro saline and in vivo. Both compounds had a specific affinity to liver and lung, and mainly metabolized through liver. They showed a time-dependent accumulation and retainable characteristics in SMMC-7721 tumor. These results supported their potential value for targeted tumor therapy agents.     

Synthesis of glycosylated porphyrins as neutral ionophores for a berberine-sensitive electrode

For preparing a berberine-sensitive electrode, 5,10,15,20-tetrakis[2-(2,3,4,6-tetraacetyl-β-D-glucopyranosyl)-1-O-phenyl]porphyrin (T(o-glu)PPH₂) was synthesized from the reaction of pyrrole with ortho-acetylglycosylated benzaldehyde by Lindsay’s method. The electrode based on T(o-glu)PPH₂ with an optimized membrane composition exhibits Nernstian response to berberine in the concentration range 2.4 × 10^–7–5.0 × 10^–3 mol L^–1, with a pH range from 3.9 to 10.2, and a fast response time of 30 s. The electrode shows fair selectivity towards berberine with respect to common co-existing species. T(o-glu)PPH₂ shows better potentiometric response characteristics comparing to chloro[5,10,15,20-tetrakis[2-(2,3,4,6-tetraacetyl-β-D-glucopyranosyl)-1-O-phenyl]-porphinato]-manganese (MnT(o-glu)PPCl) and better selectivity towards berberine than tetraphenylporphyrin (TPPH₂). The effect of the composition of the electrode membrane has been studied and the experimental conditions optimized. The contents of berberine in pharmaceutical tablets were determined by direct potentiometry and the results agreed with values obtained by the pharmacopoeia method. Received: 17 July 2000 / Revised: 18 September 2000 / Accepted: 23 October 2000     

Rational enhancement of the energy barrier of bis(tetrapyrrole) dysprosium SMMs via replacing atom of porphyrin core

With the coordination geometry of Dy^III being relatively fixed, oxygen and sulfur atoms were used to replace one porphyrin pyrrole nitrogen atom of sandwich complex [(Bu)₄N][Dy^III(Pc)(TBPP)] [Pc = dianion of phthalocyanine, TBPP = 5,10,15,20-tetrakis[(4-tert-butyl)phenyl]porphyrin]. The energy barrier of the compounds was enhanced three times, with the order of Dy^III(Pc)(STBPP) > Dy^III(Pc)(OTBPP) > [(Bu)₄N][Dy^III(Pc)(TBPP)] [STBPP = monoanion of 5,10,15,20-(4-tert-butyl)phenyl-21-thiaporphyrin, OTBPP = monoanion of 5,10,15,20-(4-tert-butyl)phenyl-21-oxaporphyrin]. Theoretical calculations offer reasonable explanations of such a significant enhancement. The energy barrier of 194 K for Dy^III(Pc)(STBPP) represents the highest one among all the bis(tetrapyrrole) dysprosium SMMs, providing a strategy to rationally enhance the anisotropy and energy barrier via atom replacement.     

Intramolecular C-N bond formation reactions catalyzed by ruthenium porphyrins: amidation of sulfamate esters and aziridination of unsaturated sulfonamides

Ruthenium porphyrins [Ru(F(20)-TPP)(CO)] (F(20)-TPP = 5,10,15,20-tetrakis(pentafluorophenyl)porphyrinato dianion) and [Ru(Por*)(CO)] (Por = 5,10,15,20-tetrakis[(1S,4R,5R,8S)-1,2,3,4,5,6,7,8-octahydro-1,4:5,8-dimethanoanthracen-9-yl]porphyrinato dianion) catalyzed intramolecular amidation of sulfamate esters p-X-C(6)H(4)(CH(2))(2)OSO(2)NH(2) (X = Cl, Me, MeO), XC(6)H(4)(CH(2))(3)OSO(2)NH(2) (X = p-F, p-MeO, m-MeO), and Ar(CH(2))(2)OSO(2)NH(2) (Ar = naphthalen-1-yl, naphthalen-2-yl) with PhI(OAc)(2) to afford the corresponding cyclic sulfamidates in up to 89% yield with up to 100% substrate conversion; up to 88% ee was attained in the asymmetric intramolecular amidation catalyzed by [Ru(Por)(CO)]. Reaction of [Ru(F(20)-TPP)(CO)] with PhI[double bond]NSO(2)OCH(2)CCl(3) (prepared by treating the sulfamate ester Cl(3)CCH(2)OSO(2)NH(2) with PhI(OAc)(2)) afforded a bis(imido)ruthenium(VI) porphyrin, [Ru(VI)(F(20)-TPP)(NSO(2)OCH(2)CCl(3))(2)], in 60% yield. A mechanism involving reactive imido ruthenium porphyrin intermediate was proposed for the ruthenium porphyrin-catalyzed intramolecular amidation of sulfamate esters. Complex [Ru(F(20)-TPP)(CO)] is an active catalyst for intramolecular aziridination of unsaturated sulfonamides with PhI(OAc)(2), producing corresponding bicyclic aziridines in up to 87% yield with up to 100% substrate conversion and high turnover (up to 2014).     

Synthesis of biomimetic heme precursors

Three kinds of biomimetic heme precursors have been prepared. The first type is based on tetra-aminoporphyrins: either 5,10,15,20-tetrakis (o-aminophenyl)porphyrin (various atropoisomers), or 5,15-bis(2′,6′-diaminophenyl)porphyrin. The second type is based on octa-aminoporphyrins: 5,10,15,20-tetrakis (2′,6′-diamino-4′-tert-butylphenyl)porphyrin. One example of “basket handle” porphyrin demonstrates selective discrimination between O₂ and CO with an M value [M=p_1/2(O₂)/p_1/2(CO)] of 105. This is similar to values reported for various natural hemoproteins. The third type is based on aminoporphyrin templates [5, 5,10- or 5,15- and 5,10,15-(2′,6′-dinitro,4′-tert-butylphenyl)porphyrins] which have been tested in asymmetric epoxidation.     

Catalytic activity and stability of anionic and cationic water soluble cobalt(II) tetraarylporphyrin complexes in the oxidation of 2-mercaptoethanol by molecular oxygen

The catalytic activity and stability of anionic cobalt(II) porphyrin complexes: 5,10,15,20-tetrakis(2,6-dichloro-3-sulfonatophenyl)porphyrinatocobalt(II), 5,10,15,20-tetrakis(2,4,6-trimethyl-3,5disulfonatophenyl)porphyrinatocobalt(II) and the cationic cobalt(II) porphyrin: 5,10,15,20-tetrakis[4-(diethylmethylammonio)phenyl]porphyrinatocobalt(II) tertraiodide have been investigated in the oxidation of 2-mercaptoethanol by dioxygen. All complexes were efficient catalysts for the auto-oxidation of 2-mercaptoethanol. The cationic cobalt(II) porphyrin has been found to be the most reactive catalyst. The rate of auto-oxidation of 2-mercaptoethanol catalysed by 5,10,15,20-tetrakis(2,4,6-trimethyl-3,5disulfonatophenyl)porphyrinatocobalt(II) has been found to increase with increasing the pH from 7 to 9 then decreased at higher pH. The rate constants of auto-oxidation reaction showed linear dependence on catalyst concentration and saturation kinetics in both 2-mercaptoethanol concentrations and dioxygen pressure. Anionic cobalt(II) porphyrin complexes showed higher stability than the cationic catalyst in repeat oxidation reactions. Immobilizing the anionic catalysts on ion exchange resin and supporting the cationic catalyst on clay mineral montmorillonite improved their stabilities towards oxidation.     

Synthesis,molecular structure,photophysical properties and spectroscopic characterization of new 1D-magnesium(II) porphyrin-based coordination polymer

Research on Chemical Intermediates - Chemical preparation, X-ray diffraction, spectral and photophysical studies were performed for H2TPBP (5,10,15,20-tetrakis[4 (benzoyloxy)phenyl] porphyrin),...