Synthesis and characterization of substituted chlorins and bacteriochlorins suitable to be anchored to nanoparticles for application in PDT

Reduced analogues of porphyrins, such as dihydroporphyrins (i.e., chlorins) and tetrahydroporphyrins (i.e., bacteriochlorins) are gaining more and more attention in PDT, because of their photophysical and chemical properties. Their synthesis can be done by direct reduction of already preformed porphyrins, although this process is quite delicate, because the porphyrins have a higher intrinsic stability than their reduced derivatives. Cycloaddition reactions of one or two peripheral double bonds are another interesting alternative approach. In particular, Cavaleiro et al. described for the first time the reaction of porphyrins as dienophiles in a variety of Diels-Alder and 1,3 dipolar cycloaddition reactions (1). Through cycloaddition it is also possible to insert other functionalities (i.e, sugars), that can improve the solubility and the specificity of the photosensitizer toward a given cell type or other targets. Unfortunately good yields can be obtained only with porphyrins bearing strong electron withdrawing groups, like meso-tetrakis(pentafluorophenyl)porphyrin (TFPP), and they always produce mixtures of reduced compounds. TFPP is a versatile compound (2) that can react with a variety of nucleophiles by nucleophilic substitution, but this porphyrin is also quite expensive and of difficult purification if synthetized in the lab. Another way to activate a porphyrin ring towards cycloaddition is the introduction of a ??pyrrolic nitro group that selectively activates the adjacent double bond (3). In the framework of this area of research, we report here the synthesis by cycloaddition of several reduced porphyrin derivatives by taking advantage of the activating properties of ??pyrrolic nitro groups. Their modification in order to link them to convenient carriers (i.e., nanoparticles) for a better targeting in PDT is also reported.