Porphyrazines with annulated diazepine rings. 3.⊗ MgII Complex of 4-tert-Butylphenyl Substituted Tetra(1,4-diazepino)porphyrazine: Synthesis and Peculiar Effect of Solvent on Its Spectral Properties

5,7-Di(4-tert-butylphenyl)-6H-1,4-diazepine-2,3-dicarbonitrile, prepared by condensation of di(4-tert-butylbenzoyl) methane with diaminomaleodinitrile, affords upon template cyclotetramerization in the presence of magnesium(II) butoxide in n-butanol the MgII complex of octa-4-tert-butylphenyl substituted tetra(1,4-diazepino)porphyrazine. The strong solvent effect on its UV-Vis and 1H NMR spectral properties is rationalized in terms of dimerization occurring very likely due to intermolecular hydrogen bonding between diazepine nitrogen atoms and water molecules. The monomer is present exclusively only in diluted solutions of aprotic solvents such as dimethyl sulfoxide and dimethylformamide. Addition of water or methanol leads to dimerization. The dimer exists also in pyridine and tetrahydrofuran solutions, as well in benzene and dichloromethane containing residual water or alcohol. The UV-Vis spectrum of the monomer is typical for MgII porphyrazines and contains a single Q band at ca. 680 nm. In its 1H NMR spectrum the resonance of the CH2 protons is not observed at ambient temperatures but appear as a broad signal at 4.4-4.5 ppm above 100 °C, which is characteristic for rapid inversion of the 1,4-diazepine ring in the 6H form. The Q band of the dimer is split into two components (major at 640-645 nm and minor at 680-685 nm). The dimer gives two doublets of the diastereotopic CH2 protons (5.9-7.1 ppm for the equatorial and 4.8-6.1 ppm for the axial CH2 protons, depending on the solvent) with characteristic geminal splitting of ca. 11-12 Hz. Formation of the dimer hinders the inversion of diazepine rings and two sharp doublets are observed even above 100 °C. © ISUCT Publishing

Porphyrazines with annulated diazepine rings. 4. Synthesis and properties of Mg-II tetradiazepinoporphyrazine carrying exocyclic styryl fragments

A novel tetradiazepinoporphyrazine MgII complex bearing eight peripheral styryl substituents, [St(8)TDzPAMg(H2O)] (St = -CH=CHAr, where Ar = 4-methoxyphenyl) was prepared by template cyclotetramerization of the corresponding precursor - 5,7-distyryl substituted diazepino-2,3- dicarbonitrile - in the presence of Mg-II butoxide in n-butanol. UV-visible and H-1 NMR spectral data indicate that the complex is strongly aggregated in non-coordinating solvents (dichloromethane, chloroform, benzene), it is dimeric in pyridine, whereas it is predominantly monomeric in dimethylsulfoxide and dimethylformamide. The fluorescence response is high for solutions in which the monomeric form is prevalent, but it is strongly quenched as the content of the dimer is increased. Evidence was obtained that dimerization occurs due to intermolecular hydrogen bonding between acidic CH2 groups in the diazepine ring (6H form) of one molecule with meso- and/or diazepine N atoms of another molecule, dimerization being also contributed by the presence of chlatrated water. In the presence of fluoride anions the dimer is destroyed with formation of the monomeric species, which is changed to the 1H form upon heating, as indicated by H-1 NMR spectra

Synthesis of Chlorin-(Arylamino)quinazoline Hybrids as Models for Multifunctional Drug Development

A series of multifunctional conjugates each consisting of a fluorescent chlorin photosensitizer and an (arylamino)quinazoline-based epidermal growth factor receptor/vascular endothelial growth factor receptor ligand, potentially useful in site-selective photodynamic antitumor therapy, were prepared and their photochemical properties were investigated

Reactions of glutathionylcobalamin with nitroxyl and its donor, Angeli’s salt

We investigated the reaction between glutathionylcobalamin (GSCbl), a tight complex of cobalamin with glutathione (GSH), and nitroxyl (HNO) produced upon decomposition of Angeli’s salt using ultraviolet-visible spectroscopy and 1H NMR. The reaction in neutral and alkaline media leads to formation of nitrosylcobalamin (NOCbl). Simulation of the kinetic traces using the ChemMech program package suggested that the mechanism of the process involves complexation between HNO and GSCbl and further decomposition of the complex into the products. The complex participates in an acid-base equilibrium (pKa = 8.9), and the deprotonated form decomposes to NOCbl more rapidly than the protonated species. At pH 7.4, the reaction of HNO with GSCbl proceeds ca.103-times more slowly than with free GSH. GSCbl can react directly with the monoprotonated anion of Angeli’s salt (HN2O3−) to produce nitrocobalamin (NO2Cbl). The reaction between GSCbl and HN2O3− is insignificant in an alkaline medium and is accelerated upon acidification of the medium. The critical step of the process is the complexation between GSCbl and HN2O3−. The produced complex is involved in an acid-base equilibrium (pKa = 8.1): the protonated form can be transformed to NO2Cbl and GSNHO−, whereas the deprotonated species decompose to initial reactants.</p

Transurethral Resection of Non-Muscle Invasive Bladder Tumors Combined with Fluorescence Diagnosis and Photodynamic Therapy with Chlorin e6-Type Photosensitizers

Bladder cancer is a common disease with a high recurrence rate. In order to improve the treatment of superficial bladder tumors, we evaluated the efficacy and safety of transurethral resection (TURB) followed by fluorescence diagnosis (FD) and photodynamic therapy (PDT) with chlorin e6 photosensitizers (PSs), viz. &ldquo;Fotoran e6&rdquo; and &ldquo;Fotoditazin&rdquo;. It was found that both PSs generated singlet oxygen and revealed moderate affinity toward the lipid-like compartment. Between November 2018 and October 2020, 12 patients with verified non-muscle invasive bladder cancer (NMIBC) were treated by TURB combined with FD and PDT. Eight patients received &ldquo;Fotoran e6&rdquo; intravenously, while four patients received intravesical PSs. The patient ages were between 31 and 79 years, with a median age of 64.5 years (mean 61.3 &plusmn; 14.2). The total light dose was 150 J/cm2 for the local irradiation of the tumor bed with a red light at the &lambda; = 660 nm wavelength, and 10&ndash;25 J/cm2 were additionally delivered for diffuse irradiation of the entire bladder mucosa. At the median follow-up period of 24 months (mean 24.5 &plusmn; 5.4 months, range 16&ndash;35 months), 11 patients remained tumor-free. One 79-year-old patient developed a recurrence without progression to the muscle layer. This pilot study shows that the TURB + FD + PDT technique is an effective and safe option for the first-line treatment of superficial bladder tumors

A First-in-Class β-Glucuronidase Responsive Conjugate for Selective Dual Targeted and Photodynamic Therapy of Bladder Cancer

In this report, we present a novel prodrug strategy that can significantly improve the efficiency and selectivity of combined therapy for bladder cancer. Our approach involved the synthesis of a conjugate based on a chlorin-e6 photosensitizer and a derivative of the tyrosine kinase inhibitor cabozantinib, linked by a β-glucuronidase-responsive linker. Upon activation by β-glucuronidase, which is overproduced in various tumors and localized in lysosomes, this conjugate released both therapeutic modules within targeted cells. This activation was accompanied by the recovery of its fluorescence and the generation of reactive oxygen species. Investigation of photodynamic and dark toxicity in vitro revealed that the novel conjugate had an excellent safety profile and was able to inhibit tumor cells proliferation at submicromolar concentrations. Additionally, combined therapy effects were also observed in 3D models of tumor growth, demonstrating synergistic suppression through the activation of both photodynamic and targeted therapy