Dirk Kusch

Enantioselective synthesis of hematoporphyrin stereoisomers

Abstract The reduction of 3,8-diacetyl porphyrin 1 with borane-methyl sulfide complex, BMS, as stoichiometric reductant and methyloxazaborolidine 2 and ent- 2 as catalysts allows the enantioselective preparation of hematoporphyrin IX dimethyl ester stereoisomers.

How many molecules of a photosensitizer are necessary to photosensitize a tumor cell

Diglycosylated porphyrinoids were shown to stack at the outer cell membrane of tumor cells in vitro. Similar phototoxicities are acquired as with the non-glycosylated drugs at amounts of only 1% of that normally taken up of the non-glycosylated drugs. This means that a strict positioning of sensitizers at sensitive compartments may reduce the amount of sensitizer necessary to sensitize a tumor cell to about 106 molecules per cell. Similar numbers were seen only in erythrocytes and with immunoconjugates in ovarian cancer. This low amount facilitates photosensitizer transport against intratumoral pressure gradients.

Selective synthesis and photophysical properties of tailor-made chlorins for photodynamic therapy

Photodynamic therapy (PDT) is a promising approach for the treatment of cancer, and is presently being evaluated worldwide. PDT is based on the ability of photosensitizers to accumulate selectively in tumor tissue. On irradiation fluorescence of the sensitizer allows tumor localization. Singlet oxygen formed by sensitization causes tumor destruction. Hematoporphyrin derivatives and Photofrin IIR, at the present the only practically used sensitizers in PDT, absorb light only weakly ((epsilon) approximately equals 5.000 at (lambda) equals 620 nm). It has been shown that Photofrin IIR is a multicomponent mixture of different porphyrins with only a few therapeutically active components. In contrast to porphyrins, chlorins and azachlorins have ideal photophysical properties with strong absorption ((epsilon) approximately equals 50.000) in a spectral region ((lambda) equals 650 nm) where tissue transmits much better. Molecular properties of porphinoid structures, which are responsible for tumor uptake and tumor enrichment, are connected with lipophilicity and aggregation behavior. Therefore our aim was to synthesize well defined chlorins with lipophilic properties similar to those of the active fractions of Photofrin IIR.

Selective synthesis and characterization of chlorins as sensitizers for photodynamic therapy

Chlorin type sensitizers have ideal photophysical properties for an application in PDT. The basic chlorin framework of these sensitizers has to be modified by attachment of lipophilic and hydrophilic residues to achieve a good cell uptake and tumor enrichment. In the present study we describe the selective synthesis of amphiphilic chlorins starting from the readily accessible red blood pigment heme. The photophysical properties of the well defined synthetic chlorins are characterized by photophysical investigations. The kinetic of cell uptake, the localization in the cell and the photodynamic behavior of the amphiphilic sensitizers are demonstrated by incubation of A 375 cancer cell lines with structurally different chlorins.