Andrei N. Kozyrev

Syntheses of stable bacteriochlorophyll-a derivatives as potential photosensitizers for photodynamic therapy

New methods for conversion of unstable bacteriochlorophyll-a present in Rb. sphaeroides into stable bacteriochlorins are presented. Cyclic imide derivatives from related cyclic isoimide or amide analogs are obtained by intramolecular base catalyzed cyclization. Most of the new bacteriochlorins have long wavelength absorptions in the range of 796–822 nm. In preliminary screening, the isoimide analogs have shown promising in vivo photosensitizing activity for the treament of cancer by photodynamic therapy.

Photophysics of halogenated porphyrins

A series of free-base octaalkylporphyrins having halogen substituents at different sites on the nucleus has been examined by photophysical methods. In general, halogenation decreases the fluorescence yield and lifetime, increases triplet formation and decreases the resultant triplet lifetime. The magnitude of these effects, which increases in the order F < Cl < Br < I and is dependent on the site of halogenation (benzylic position of alkyl < β position of pyrrole < meso position) can be explained in terms of a modified spin–orbit coupling theory. Multiple halogenation at meso positions, however, can cause secondary effects, due to steric crowding (bromine) or electron redistribution (fluorine). Photophysical data derived from the full set of meso-fluorinated porphyrins can be described quantitatively in terms of combined spin–orbit coupling and electronic perturbation in which a fluorine substituent deactivates adjacent meso sites but activates the site opposite the substituent.

Effect of substituents in OsO4 reactions of metallochlorins regioselective synthesis of isobacteriochlorins and bacteriochlorins

A first regioselective synthesis of bacteriochlorin by hydroxylation of metallated chlorin with OsO4 is discussed. This is the first example for the preparation of metallobacteriochlorin. This methodology can also be used for the preparation of unsymmetrical isobacteriochlorins by introducing electron-withdawing substituent(s) at the adjacent position(s) of the reduced ring. The Zn(II) vic-dihydroxybacteriochlorin obtained from 2-formyl-purpurin methyl ester showed long wavelength absorption at 828 nm which seems to be associated with electronic interactions of the substituents with the π-system of the macrocycle.

Pyrazolinyl and cyclopropyl derivatives of protoporphyrin IX and chlorins related to chlorophyll a

Abstract Diazomethane reacts regioselectively with peripheral vinyl substituents of pyropheophorbide a and purpurin-18 N-methylimide to produce corresponding 1′-pyrazolinyl-substituted derivatives as a main product. Similarly, treatment of protoporphyrin IX gave a mixture of mono- and di-substituted pyrazolinyl analogs, which were isolated as individual products. Thermolytic decomposition of the pyrazolinyl derivatives produced cyclopropyl-substituted chlorins and porphyrins. 1,3-Dipolar cycloaddition mechanisms of the formation of 1′-pyrazolinyl derivatives are discussed.

Synthesis of Mono- and Di(oxopyri)porphyrins: A New Approach through Ring Enlargement with Diazomethane

A novel approach for porphyrin modification is provided by ring-enlargement reactions. Treatment of dioxochlorins (see scheme) and tetraoxobacteriochlorins with diazomethane results in formation of the corresponding mono- and di(oxopyri)porphyrins.

Syntheses and Spectroscopic Studies of Some Novel Porphyrin-Pyropheophorbide Dimers and Trimers with Fixed Distances

Abstract Syntheses and spectroscopic properties of pyropheophorbide-porphyrin dimers and a bis-pyropheophorbide-porphyrin trimer are described. Fluorescence spectroscopic data of the oligomers reveal that the macrocycles in the systems are only weakly coupled .

Sensitizers of second generation for photodynamic therapy of cancer based on chlorophyll and bacteriochlorophyll derivatives

Methods for preparation of chlorin sensitizers for PDT of cancer on the base of purple bacteria and blue-green algae have been elaborated. New bacteriochlorophyll a derivatives have been synthesized. Bacteriopurpurin and bacteriochlorin p6 have strong absorption at 818 and 770 nm respectively.

Synthesis, Photophysical and Electrochemistry of Near-IR Absorbing Bacteriochlorins Related to Bacteriochlorophyll a

A series of new bacteriochlorins was synthesized using 13(2)-oxo-bacteriopyropheophorbide a (derived from bacteriochlorophyll a) as a starting material, which on reacting with o-phenylenediamine and 1,10-diaminonaphthalene afforded highly conjugated annulated bacteriochlorins with fused quinoxaline, benzimidazole, and perimidine rings, respectively. The absorption spectra of these novel bacteriochlorins demonstrated remarkably red-shifted intense Q(y) absorption bands observed in the range of 816-850 nm with high molar extinction coefficients (89,900-136,800). Treatment of 13(2)-oxo-bacteriopyropheophorbide a methyl ester with diazomethane resulted in the formation of bacterioverdins containing a fused six-membered methoxy-substituted cyclohexenone (verdin) as an isomeric mixture. The pure isomers which exhibit long-wavelength absorptions in the near-IR region (865-890 nm) are highly stable at room temperature with high reactivity with O(2) at the triplet photoexcited state and favorable redox potential and could be potential candidates for use as photosensitizers in photodynamic therapy (PDT).

Syntheses of emeraldin and purpurin-18 analogs as target-specific photosensitizers for photodynamic therapy

Abstract Efficient syntheses and mechanisms of the formation of some novel porphyrins and chlorins with cyclic anhydride, imide and isoimide rings bearing various N-substituents as possible target-specific photosensitizers for photodynamic therapy are presented. Porphyrins with such cyclic ring systems are named as “emeraldins” due to their intense green color. This class of compounds show a unique reverse etio- type absorption spectra.

CHLOROPHYLL-A DERIVATIVES IN PHOTODYNAMIC THERAPY : EFFECT OF POSITION OF HEPTYL ETHER SIDE-CHAINS ON IN VIVO PHOTOSENSITIZING ACTIVITY

Abstract Syntheses and comparative in vivo photosensitizing efficacy of a series of chlorophyll-a derivatives with (1-heptyloxyethyl) substituents at various positions are discussed. Compared with Photofrin®, the n-heptyl ether analogues showed better in vivo sensitizing activity (DBA/2 mice transplanted with SMT/F tumors) as well as reduced skin phototoxicity. The Vilsmeier formylation of copper(II) methyl mesopyropheophorbide-a 11 did not produce the expected meso-formyl derivative 12 , but instead gave the α,β-unsaturated chloroformyl analogue 13 as the major product.