Agnieszka Mikus

1,3-DIPOLAR CYCLOADDITION REACTION IN PORPHYRIN SYSTEMS WITH FUNCTIONALIZED ALKYL NITRILE OXIDES : SYNTHESIS OF ISOXAZOLINE-FUSED CHLORINS

meso-Tetraphenylporphyrin reacts at higher temperature with unstable alkyl nitrile oxides (R-CNO) affording isoxazoline-fused chlorins according to dipolar (3+2)-cycloaddition pathway. The respective nitrile oxides were in situ generated from the corresponding functionalized nitroalkanes in the presence of base (NEt3, DABCO) and dehydrating agent (PhNCO, (Boc)2O). Substituent R bearing diverse of functionality allows synthesis of very attractive moieties which may be of potential use as sensitizers in photodynamic therapy. The products obtained are also suitable intermediates for further derivatization of porphyrins. In the past decade numerous investigations oriented towards the synthesis and utilization of chlorins and bacteriochlorins have been undertaken. These compounds may be considered as second generation photosensitizers in antitumor photodynamic therapy (PDT) 1 due to their characteristic strong absorption bands shifted to the red region of visible spectrum (630-780 nm). The attractive chlorin systems can be synthesized by various methods. 2 One of the approaches involves 1,3-dipolar cycloaddition reaction of peripheral β,β-double bonds of porphyrin moiety with some 1,3- dipoles. Among others, nitrile oxides could be used for this purpose. In the recent past we reported our preliminary results concerning this type of cycloaddition with the use of alkyl nitrile oxides, 3 generation of which is relatively difficult, and which are generally less stable 4 as compared to the aryl ones. It was one of the first three published works in which synthesis of fused porphyrin-isoxazoline derivatives was described. 3,5a,b Herein we report our further investigations oriented towards the synthesis of diversely functionalized chlorins. Studies on the scope and limitations of this derivatization method and exploring other possibilities of generation this type of alkyl nitrile oxides (and their applications in the above cycloaddition) were attempted. The previous reactions of meso-tetraphenylporphyrin (1) with an excess of alkyl nitrocompounds 2a-c, carried out in the presence of NEt3 and PhNCO in refluxing benzene (Mukaiyamas method 4a ), gave the expected isoxazoline-fused chlorins (3a-c) 3 (Scheme 1).

Synthesis of meso-TPP Revisited: Its “Green-Oriented” Optimization Under Controlled Microwave Heating

Abstract A practical and proecological improvement for synthesis of meso-tetraphenylporphyrin (meso-TPP) under microwave irradiation is described. A cyclocondensation reaction of benzaldehyde and pyrrole followed by oxidation of the porphyrinogen formed as an intermediate in a small amount of propionic acid at 120 °C (under controlled microwave heating) resulted in conversion to meso-TPP in a reasonable yield (ca. 30%) in preparative-scale experiments (300–500 mg). The influence of many parameters such as the concentration of reagents, catalyst, solvent, temperature, reaction time, and oxidant on the reaction yield was studied. The environmental motive in this improvement is reduction of solvent volume (ca. 250 times). Also, some toxic reagents were eliminated from the procedure.

Organometallic Nucleosides: Synthesis and Biological Evaluation of Substituted Dicobalt Hexacarbonyl 2′-Deoxy-5-oxopropynyluridines

Abstract Reactions of dicobalt octacarbonyl [Co2(CO)8] with 2′‐deoxy‐5‐oxopropynyluridines and related compounds gave dicobalt hexacarbonyl nucleoside complexes (83–31 %). The synthetic outcomes were confirmed by X‐ray structure determination of dicobalt hexacarbonyl 2′‐deoxy‐5‐(4‐hydroxybut‐1‐yn‐1‐yl)uridine, which exhibits intermolecular hydrogen bonding between a modified base and ribose. The electronic structure of this compound was characterized by the DFT calculations. The growth inhibition of HeLa and K562 cancer cell lines by organometallic nucleosides was examined and compared to that by alkynyl nucleoside precursors. Coordination of the dicobalt carbonyl moiety to the 2′‐deoxy‐5‐alkynyluridines led to a significant increase in the cytotoxic potency. The cobalt compounds displayed antiproliferative activities with median inhibitory values (IC50) in the range of 20 to 80 μm for the HeLa cell line and 18 to 30 μm for the K562 cell line. Coordination of an acetyl‐substituted cobalt nucleoside was expanded by using the 1,1‐bis(diphenylphosphino)methane (dppm) ligand, which exhibited cytotoxicity at comparable levels. The formation of reactive oxygen species in the presence of cobalt compounds was determined in K562 cells. The results indicate that the mechanism of action for most antiproliferative cobalt compounds may be related to the induction of oxidative stress.

Attempts of the Synthesis of Highly Functionalized Porphyrins at the β-Positions: Nitration of Exhaustively Substituted Moieties in the ’Eastern Half ’ and Mass-Spectral Study of the Reaction Products

MS investigations of the products obtained by electrophilic nitration of tetrasubstituted porphyrin complexes are described. Cu(II)-Porphyrinates, exhaustively derivatized at the so-called ’eastern half’ [dinitro-, bis(arylsulphonylmethyl-)], in the reaction with 33 % nitric acid (at r.t.; reaction time – ca. 5 h) resulted in the formation of a mixture of many polynitro-substituted products. They were identified by MS-ESI and IR methods and the mode of reactivity of the substrates was explained.

A fast and convenient method for analysis of collagen hydrolysis products Szybka i dogodna metoda analizy produktów hydrolizy kolagenu

Polypeptides produced by hydrolysis of collagen from minced animal hide and skin scraps were studied by mass spectrometry (MS) in conjunction with electrophoresis to det. their mol. mass. The degree of peptides ionisation was ca 50+. This allowed for observation of the large polypeptide chains with mass analyzers with a relatively low m/z range. The electrospray and atm. pressure photoionization techniques were used. The polypeptide fractions formed during the hydrolysis of collagen were easily identified. The mol. mass of the products was 28–82 kDa. Zaproponowano i zweryfikowano szybką i dogodną metode analizy polipeptydow wytwarzanych przez hydrolize kolagenu, ktorego źrodlem byly rozdrobnione skorki zwierzece. Badania metodą spektrometrii mas (MS), wspomagane danymi z rozdzialu elektroforetycznego, pozwolily stwierdzic, ze cząsteczki polipeptydow jonizują sie ok. 50-krotnie. Stosując techniki electrospray (ESI) i fotojonizacje pod ciśnieniem atmosferycznym (APPI), opracowano sposob identyfikacji frakcji peptydowych zarowno w trakcie hydrolizy, jak rowniez w gotowym produkcie. Znaleziono frakcje o masie cząsteczkowej 28–82 kDa. Wysoki stopien zjonizowania umozliwia obserwacje duzych cząsteczek z wykorzystaniem aparatow o stosunkowo niewielkim zakresie pomiaru masy (m/z), co jest niewątpliwą zaletą metody i czyni ją ogolnodostepną.

Synthesis of lutetium(III)–porphyrin complexes: old problems and new excellent conditions found

A convenient method for the preparation of very attractive and almost unknown lutetium(III)–porphyrins was developed. Systematic investigations involving a broad spectrum of solvents (DMF, TCB, imidazole, sulfolane, and a CHCl3/MeOH mixture), as well as studies concerning the influence of temperature and the reaction time on the yield, were performed. Under the optimized experimental conditions found within the study for [5,10,15,20-tetraphenylporphyrinato]lutetium(III) chloride (sulfolane, reflux, 0.5 h; 88% yield), the synthesis of some other more complex derivatives was demonstrated.

The First Example of Oxidative Nucleophilic Substitution of Hydrogen in meso-Aryl Ring of the 5,10,15,20-Tetraphenylporphyrin Derivatives

A synthesis of [2-nitro-5-(10,15,20-triphenylporphyrin-5-yl)-phenyl]phenyl-acetonitrile zinc complex by the reaction of the respective nitroporphyrin with the anion of benzyl cyanide, followed by addition of DDQ, is described. This is the first example of this type of process in the nitrophenyl side ring of meso-tetraarylporphyrin derivatives.

Influence of Stationary Phase Selectivity on the HPLC Separation of Porphyrins

Abstract The chromatographic conditions for the resolution and determination of {5‐[4‐nitro‐3‐(toluene‐4‐sulphonylmethyl)phenyl]‐10,15,20‐triphenylporphyrinato}zinc(II) and N,N‐dimethyl‐C‐{[2‐nitro‐5‐(10,15,20‐triphenylporphyrinato‐5‐yl) phenyl]methane‐sulphonamide}zinc(II) by HPLC are presented. These compounds have potential use in the treatment of cancer in the form of photodynamic therapy. Several stationary phases were taken into consideration, such as chemically bonded octadecyl (RP SG‐C18), octyl (RP SG‐C8), and an aryl stationary phase (RP SG‐NAF). The composition and type of mobile phase was also examined. The highest selectivity was observed when using the RP SG‐C18 stationary phase [usually regarded as a standard (reference) phase] with methanol/water as the mobile phase. The highest separation factor was seen using the aryl stationary phase SG‐NAF for an acetonitrile/water mobile phase.