Synthetic bacteriochlorins bearing polar motifs (carboxylate, phosphonate, ammonium and a short PEG). Water-solubilization, bioconjugation, and photophysical properties

Abstract

Bacteriochlorins are potentially excellent chromophores for near-infrared (NIR) photochemical andspectroscopic studies yet the intrinsically hydrophobic macrocycle core has stymied work in aqueous media. Herein, a set of bacteriochlorins bearing distinct polar motifs is reported. The motifs include phosphonate (pH-dependent anionic, BC1), carboxylate (pH-dependent anionic, BC2), ammonium (permanently cationic) without (BC3) or with (BC4) a linker ester moiety, and tetraethyleneoxy (a short PEG, polar non-ionic, BC5). The groups are located at the 3,5-positions of each of two aryl groups at the bacteriochlorin 3,13-sites. Synthesis of the bacteriochlorins entails the Suzuki coupling of a common 3,13-dibromobacteriochlorin building block with a set of aryl boronates. Five factors were selected for comparisons among the polar motifs upon attachment to the bacteriochlorins: (1) synthesis yield and ease of purification, (2) amenability toward subsequent derivatization, (3) water-solubility, (4) full-width-at-halfmaximum (fwhm) of the long-wavelength (Q y ) absorption and fluorescence bands, singlet excited-state lifetime (t S ) and fluorescence quantum yield (F f ), and (5) stability in the dark or under illumination. Watersolubility was assessed by examination of the absorption spectra across a 1000-fold concentration range (B0.2-0.6 mM to B200-600 mM). With the exception of BC4, all displayed good aqueous solubility, photostability, and photophysical properties in aqueous solution (fwhm = 23-31 nm, F f = 0.10-0.16, t S = 1.9-2.7 ns). The modestly lower F f and t S values for the bacteriochlorins in aqueous versus organic (N,N-dimethylformamide) media are traced to an increased rate constant for excited-state internal conversion. Upon consideration of all factors, the ammonium (short linker) and short PEG groups were most attractive for solubilization of the bacteriochlorins in aqueous media. The studies prompted the synthesis of two water-soluble (ammonium-substituted) bacteriochlorins bearing N-hydroxysuccinimide esters. † Electronic supplementary information (ESI) available: Attempted synthesis of a phosphatidylcholine bacteriochlorin (BC6); mass spectrometry analysis for BC1-BC5, BC7, and BC8; and additional data concerning the photophysical properties of bacteriochlorins. See macrocycles can be incorporated with peptides to give selfassembled light-harvesting architectures. 25,26 The tetrapyrroles of present interest are bacteriochlorins, which absorb strongly in the near-infrared (NIR) region. A second objective -a spinoff thereof -aims to use hydrophilic bacteriochlorins in biomedical applications. A variety of bacteriochlorins with appended polar motifs has been previously prepared; representative members are shown in Chart 1. Compounds I, 27 II 27 and III 28 were derived by semisynthesis 29,30 from bacteriochlorophyll a; IV 13 by hydrogenation of the corresponding porphyrin; 31 and V-IX by de novo synthesis. 32,33 Methods of bacteriochlorin synthesis have been reviewed. 34,35 An attractive design element for...

Engineering of relevant photodynamic processes through structural modifications of metallotetrapyrrolic photosensitizers

“…Very large substituents, such as dendrimers, peptides and polymers, have also been considered in the design of novel photosensitizers for PDT. One of the design strategies that equips tetrapyrroles for solubilization in water recently explored was to shield the intrinsically hydrophobic faces of the tetrapyrrole π system from aqueous solution with appended polar motifs (phosphonate, carboxylate, ammonium and tetraethyleneoxy groups) and thereby suppress aggregation [124]. The resulting architecture contains a hydrophobic core and a hydrophilic exterior, which makes it similar to a micelle.…”

Bioconjugatable, PEGylated hydroporphyrins for photochemistry and photomedicine. Narrow-band, near-infrared-emitting bacteriochlorins

“…One objective has been to gain access to a palette of water-soluble, bioconjugatable, wavelength-tunable bacteriochlorins. 15 In energy sciences, such bacteriochlorins can be employed in light-harvesting architectures and as constituents of energy-transfer cascades. 16,17 In photomedicine, the bacteriochlorins are effective in photodynamic therapy 18,19 and in optical imaging.…”

“…31 On the other hand, achieving water solubility has proved quite challenging alone and has been even more daunting to accomplish while maintaining the other desired features of bioconjugation and wavelength tunability. 15 …”

“…Accordingly, we recently incorporated 3,5-disubstituted aryl groups located at the β-pyrrole positions wherein the 3,5-substituents are quite polar. 15 The substituents A–F are shown in Chart 2. The polar substituents are not thrust over the plane of the macrocycle as in the case for the 2,6-substitution pattern with chlorins, but still imparted a significant degree of aqueous solubility.…”

“…The common scaffold resulted in each bacteriochlorin exhibiting essentially the same spectral properties. 15 Among these various motifs, the PEG group was most attractive for aqueous solubilization and bioconjugation. The nonionic nature of the PEG facilitates handling – the PEG derivatives are soluble in both water and organic solvents, 32,33 but readily partition from water into dichloromethane thereby enabling partitioning of crude reaction mixtures.…”