Synthesis of 5,10,15-tris(trifluoromethyl)corrole Procedure A, with isolation of the bilane The oligomerization step: Sodium dithionite (3 g,15 mmol) and sodium hydrogen carbonate (3.5 g, 42 mmol) were suspended in aqueous acetonitrile solution (H2O:acetonitrile, 1:2, v/v, 30 mL) in a 250 mL three-necked flask placed in a preheated oil bath (45°C-50°C) fitted with a magnetic bar, thermometer, rubber septum and a reflux condenser connected to an oil bubbler. After increasing the bath temperature to 70°-80° C, a mixture of pyrrole (2.77 mL, 40 mmol) and halothane (3.20 mL, 30 mmol) was injected with a syringe through the septum. Noticeable gas evolution (CO2) occurred, as the yellow suspension was continually stirred and maintained at 70°-80° for 2h. Progress of the reaction was monitored by HPLC analysis. By the end of the reaction almost all inorganic salts were dissolved. After cooling to room temperature, water (50 mL) was added and the reaction mixture was extracted with diethyl ether (3×30 mL). The organic layer was washed with water and then dried over anhydrous Na2SO4. Gentle removal of the solvent on a rotary evaporator provided the oily crude mixture that was separated (silica gel column chromatography) by gradually increasing the amount of DCM (0-100%) in hexane. All the fractions were collected using Erlenmeyer flasks (50 mL) and small amounts from each were added to a test tube for reaction with DDQ, as only fractions containing the bilane become fluorescent upon that treatment. Dipyrromethane 1 was collected from 0-30% DCM/hexane fractions, tripyrromethane from the 30-90% DCM/hexane fractions and tetrapyrrane (bilane) from the 90-100% fractions. Pentapyrrane (a precursor of sapphyrin) was eluted the latest. All products except tripyrrane are liquids. The total amount of isolated tetrapyrrane was 1.5 g, 3 mmol (30% yield). General reaction conditions for oxidation by PIFA: Bilane (0.5 g, 0.9 mmol) was dissolved in DCM or acetonitrile or propionitrile (200 mL) and purged with Ar gas for 20 min. Then PIFA (1 g, 2.3 mmol) was
Heme-like metal-chelating macrocycles, including expanded and contracted porphyrins, are of everlasting interest as drug candidates for numerous diseases. Still, all reported corrole derivatives (and most other heme analogues) do not fulfill the most basic standards expected for oral drug administration: a combination of low molecular weight and reasonable water solubility. We now disclose a very straightforward synthetic method that relies on surprisingly facile trifluoromethyl hydrolysis for gaining access to a new class of corroles that do satisfy all druglikeness criteria. The relevance is briefly exemplified for the iron corroles by demonstrating the ability to affect their association with plasma proteins and their performance for catalase-like decomposition of hydrogen peroxide.
Heme-like metal-chelating macrocycles, including expanded and contracted porphyrins, are of everlasting interest as drug candidates for numerous diseases. Still, all reported corrole derivatives (and most other heme analogues) do not fulfill the most basic standards expected for oral drug administration: a combination of low molecular weight and reasonable water solubility. We now disclose a very straightforward synthetic method that relies on surprisingly facile trifluoromethyl hydrolysis for gaining access to a new class of corroles that do satisfy all druglikeness criteria. The relevance is briefly exemplified for the iron corroles by demonstrating the ability to affect their association with plasma proteins and their performance for catalase-like decomposition of hydrogen peroxide.
A nanoparticle-based system, composed of the gallium(III) complex of a minimally substituted corrole that is coated by transferrin as a targeting vehicle (3-Ga NPs), has been used for pre-clinical evaluation of its efficacy against human metastatic castration-resistant prostate cancer (mCRPC) tumor xenografts. All mice (N = 9) responded to a dose of 10 mg/kg, with a remarkable tumor growth inhibition of 400% following 2 weeks of treatment; Ames and hERG tests excluded potential concerns regarding mutagenicity and cardiotoxicity, respectively. Also demonstrated is the potential application of these 3-Ga NPs as sonodynamic agents for the preclinical treatment of pancreatic cancer. 10 mg/kg 3-Ga NPs combined with exposure to ultrasound waves (2 min of 1 MHz 0.1 w/cm 2 twice a week) induced up to 77% tumor shrinkage. Consistently, tumor/tissue distribution and serum levels of 3-Ga NPs in mice revealed high tumor specificity, favorable pharmacokinetics, fast absorption, slower redistribution, and very slow drug clearance.
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