Stable Bacteriochlorins Research Articles

Overcoming the challenges of infrared photosensitizers in photodynamic therapy: the making of redaporfin.

We offer a personal account of the discovery and development of a photosensitizer for photodynamic therapy (PDT) of cancer, from bench to bedside. We emphasize the more chemical aspects of drug discovery and drug development, namely the chemical landscape at the time of the discovery, the breakthrough in the field offered by stable bacteriochlorins, the challenges of synthesising a significant amount of the product with high purity for preclinical studies, the factors that relate molecular structure to pharmacology in PDT, the mechanistic interpretation of preclinical data and the management of unexpected results. Special attention is given to the implications of atropisomerism and immune responses in PDT.

Synthesis and photophysical characteristics of 2,3,12,13-tetraalkylbacteriochlorins

Tetraalkylbacteriochlorins, available upon acid-mediated self-condensation of α-ester stabilized dihydrodipyrrin-carboxaldehydes, provide valuable models of the naturally occurring bacteriochlorophylls.

Conversion of Bacteriochlorophyll-A to Bacteriopurpurin-18: A Useful Synthon for the Construction of Bioactive Agents for Photodynamic Therapy (PDT)

Bacteriochlorophyll-a 5 present in Rb. sphaeroides was converted into bacteriopurpurin-18 methyl ester 10 by following three different approaches and was used as a substrate for the preparation of a series of stable bacteriochlorins with long wavelength absorptions ranging from 760 to 824 nm. Bacteriopurpurin p 6 17, obtained by the base hydrolysis of 10, on reacting with L-aspartyl-di-tert -butyl ester in presence of EDCI and DMAP afforded the corresponding N-aspartyl-bacteriopurpurinimide 21 in high yield, possibly by the base-catalyzed intramolecular cyclization via the isoimide intermediate(s) 19 and 20. A possible mechanism for the formation of 10 and bacteriochlorin 15-glyoxilic acid trimethyl ester 8 from 5 via hydroxylactone 11 is also discussed. Among the compounds synthesized, the bacteriochlorin 21 containing a fused cyclic imide ring system was found to be the most stable in various solvents at room temperature and exhibited the longest wavelength absorption at 824 nm in dichloromethane.

De Novo Synthesis of Stable Tetrahydroporphyrinic Macrocycles: Bacteriochlorins and a Tetradehydrocorrin

[structures: see text] Bacteriochlorins (tetrahydroporphyrins) are attractive for diverse photochemical applications owing to their strong absorption in the near-infrared spectral region, as exemplified by the bacterial photosynthetic pigment bacteriochlorophyll a, yet often are labile toward dehydrogenation to give the chlorin. Tetradehydrocorrins (ring-contracted tetrahydroporphyrins) are attractive for studies of catalysis analogous to that of vitamin B12. An eight-step synthesis toward such tetrahydroporphyrinic macrocycles begins with p-tolualdehyde and proceeds to a dihydrodipyrrin-acetal (1) bearing a geminal dimethyl group and a p-tolyl substituent. Self-condensation of 1 in CH3CN containing BF3 x OEt2 at room temperature afforded a readily separable mixture of two free base bacteriochlorins and a free base B,D-tetradehydrocorrin. Each bacteriochlorin contains two geminal dimethyl groups to lock-in the bacteriochlorin hydrogenation level, p-tolyl substituents at opposing (2,12) beta-positions, and the absence (H-BC) or presence (MeO-BC) of a methoxy group at the 5- (meso) position. The B,D-tetradehydrocorrin (TDC) lies equidistant between the hydrogenation levels of corrin and corrole, is enantiomeric, and contains two geminal dimethyl groups, 2,12-di-p-tolyl substituents, and an acetal group at the pyrroline-pyrrole junction. Examination of the effect of the concentrations of 1 (2.5-50 mM) and BF3 x OEt2 (10-500 mM) revealed a different response surface for each of H-BC, MeO-BC, and TDC, enabling relatively selective preparation of a given macrocycle. The highest isolated yield of each was 49, 30, and 66%, respectively. The macrocycles are stable to routine handling in light and air. The bacteriochlorins display characteristic spectral features; for example, H-BC exhibits near-IR absorption (lambda(Qy) = 737 nm, epsilon(Qy) = 130,000 M(-1) cm(-1)) and emission (lambda(em) = 744 nm, phi(f) = 0.14). In summary, this simple entry to stable bacteriochlorins and tetradehydrocorrins should facilitate a wide variety of applications.

Photophysical and Electrochemical Properties of New Bacteriochlorins and Characterization of Radical Cation and Radical Anion Species

The synthesis, photophysical, and photochemical properties of a series of stable bacteriochlorins containing a fused six-member anhydride or an imide ring are discussed. The Qy band (a1u → egx transition) in the near-infrared region (NIR) lies between 788 and 831 nm depending upon the macrocycle substituents. Compounds with such a long-wavelength absorption are highly promising for their potential use in photodynamic therapy. Fluorescence maxima are also observed in the long-wavelength region of the spectrum, between 804 and 842 nm, and have lifetimes between 1.1 and 1.4 ns. The phosphorescence maxima are red-shifted to 840−870 nm. The triplet−triplet transient absorption spectra are observed to have maxima between 570 and 640 nm with lifetimes between 72 and 150 μs. The triplet excited states are efficiently quenched by oxygen to produce singlet oxygen. The quantum yields of the generated singlet oxygen were determined to be in the range of 0.33−0.55. The bacteriochlorin derivatives are easy to oxidize by one electron, and reversible half-wave potentials range between 0.65 and 0.82 V vs SCE in benzonitrile containing 0.1 M tetra-n-butylammonium perchlorate (TBAP). The second oxidation is irreversible and occurs at a rather constant potential of 1.17−1.22 V independent of the macrocycle substituents. The bacteriochlorin derivatives are also easy to reduce, and the reversible first and second one-electron reduction potentials range between −0.53 and −0.80 V and between −0.95 and −1.28 V vs SCE, respectively. Spectroelectrochemical measurements reveal the expected π radical cation and π radical anion marker bands of the bacteriochlorin derivatives. The electron spin resonance (ESR) spectra of the radical cations and radical anions produced by the chemical oxidation and reduction are reported, and the experimental and calculated spin densities are compared to each other.

Synthesis, Photophysical Properties, in Vivo Photosensitizing Efficacy, and Human Serum Albumin Binding Properties of Some Novel Bacteriochlorins

The synthesis, photophysical characteristics, in vivo photosensitizing efficacy, human serum albumin (HSA) binding properties, and skin phototoxicity of some stable bacteriochlorins were investigated. The novel bacteriochlorins, obtained from chlorophyll-a, have long-wavelength absorptions in the range lambda max = 734-758 nm. Preferential migration of ethyl over methyl substituents among ketobacteriochlorins obtained in the pinacol-pinacolone rearrangements of vic-dihydroxybacteriochlorins was confirmed by NOE studies. The bacteriochlorins show relatively low fluorescence quantum yields. Among all the bacteriochlorins the triplet states were quenched by ground state molecular oxygen in a relatively similar manner, yielding comparable singlet oxygen quantum yields. In preliminary in vivo studies (DBA/2 mice, transplanted with SMT/F tumors), ketobacteriochlorins were found to be more photodynamically active than the related vic-dihydroxy analogues. Replacement of the methyl ester functionalities with di-tert-butylaspartic acids enhanced the in vivo efficacy. Site specific human serum albumin (HSA) binding studies indicated a direct correlation between the ability of the compound to bind to the diazepam binding site (albumin site II) and the in vivo photosensitizing efficacy.

Synthesis of Novel Benzobacteriopurpurins by Diels-Alder Cycloaddition

Abstract A new class of stable bacteriochlorins, namely benzobacteriopurpurin bearing two exo-cyclic rings was synthesized by way of Diels-Alder cycloaddition of 8-vinyl-mesopurpurin-18 methyl ester with tetracyanoethylene (TCNE) and dimethyl acetylenedicarboxylate (DMAD). These novel bacteriochlorins have long wavelength absorptions in the range of 760 to 795 nm.

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.

Syntheses of new bacteriochlorins and their antitumor activity

Purpurin-18 methyl ester 1a was converted into a series of new bacteriochlorins 2b, 2c, 2f and 4b. These stable bacteriochlorins have strong long wavelength absorptions in the range of 760 to 816 nm, and were tested for in vivo photosensitizing activity using the standard screening system of DBA/2 mice bearing transplanted SMT/F tumors. In preliminary screening, among the photosensitizers tested so far, bacteriochlorins 2f and 4b have shown promising anti-tumor activity.