Abstract-Synthetic methods to obtain selectively sulfonated metallo phthalocyanines are compared. Both condensation and direct sulfonation procedures lead to mixtures of mono-to tetrasulfonated products which are resolved by reverse phase liquid chromatography in buffered aqueous-methanol. The proportion of sulfonated derivatives is examined as a function of the starting reagents in the case of the condensation method. and as a function of the temperature and reaction time in the case of the direct sulfonation procedure. The number of sulfonate groups per phthalocyanine molecule is determined by oxidative degradation of the phthalocyanine ring followed by quantitative chromatographic analysis of the sulfophthalamide and phthalamide fragments.

A series of benzyl-substituted phthalonitriles, substituted at the 3-, 4-, and 4,5-positions, underwent varied condensations with phthalonitrile to give a series of protected (monohydroxy- and polyhydroxyphthalocyaninato)zinc(II) derivatives which were readily cleaved to give several hydroxyphthalocyanines (ZnPc) (phthalocyanine phenol analogues). Their efficacy as sensitizers for the photodynamic therapy (PDT) of cancer was evaluated on the EMT-6 mammary tumor cell line. In vitro, the 2-hydroxy ZnPc (32) was the most active, followed by the 2,3- and 2,9-dihydroxy ZnPc (39 and 45), with the 2,9,16-trihydroxy ZnPc (33) exhibiting the least activity. In vivo, the monohydroxy derivative 32 and the 2,3-dihydroxy derivative 39 were both efficient in inducing tumor necrosis at 1 micromol kg-1, but complete tumor regression was poor, even at 2 micromol/kg. In contrast, the 2,9-dihydroxy isomer 45, at 2 micromol kg-1, induced tumor necrosis in all animals treated, with 75% complete regression. These results underline the importance of the position of the substituents on the Pc macrocycle to optimize tumor response and confirm the PDT potential of the unsymmetrical Pcs bearing functional groups on adjacent benzene rings.

Among the second-generation photosensitizers (PS) developed for the treatment of neoplastic diseases by photodynamic therapy (PDT) (Kessel, 1996;Ochsner, 1997), metallo-phthalocyanines (MePc) have been proposed (Spikes, 1986;van Lier, 1990;Rosenthal, 1991) as an alternative to Photofrin (PII), the only PS currently approved for clinical use. Their stronger absorption in the red part of the spectrum (molar extinction coefficient, 2.5 × 10 5 M -1 cm -1 at 675 nm), where the depth of light penetration in tissues is twice that obtained at 630 nm with PII (Svaasand, 1984), together with their chemical homogeneity and their lower potential to induce cutaneous photosensitivity (Roberts et al, 1989;Tralau et al, 1989) are major advantages over PII.Unsubstituted MePc are not soluble in physiological solvents and their in vivo administration relies upon their incorporation into carriers, such as the liposomal formulation of ZnPc (Isele et al, 1995), or their chemical conversion into water-soluble dyes by the attachment of selected substituents onto the benzene rings of the macrocycle. An inverse relationship was related between the degree of substitution by sulphonato groups of MePc and their hydrophobicity and photodynamic activities, both at the cellular level and in tumour-bearing mice (Brasseur et al, 1987(Brasseur et al, , 1988Paquette et al, 1988;Berg et al, 1989;Chan et al, 1990Chan et al, , 1991Margaron et al, 1996a). The potential of the water-soluble aluminium sulphophthalocyanine (AlPcS) to generate activated oxygen species (Sharman et al, 1999) and to induce a photodynamic response in vivo has been widely evaluated, and a mixture of AlPcS bearing 2-4 sulphonato groups per Pc (Photosense) is used extensively and successfully in clinical PDT in Russia (Zharkova et al, 1994). Furthermore, the di-sulphonated derivative has been shown to induce tumour regression mainly via direct tumour cell kill rather than damage to the tumour vasculature, as observed for PII (Chan et al, 1996;Margaron et al, 1996b). The unsubstituted AlClPc has, however, attracted less attention even though it has been shown that this compound formulated as a Cremophor emulsion was preferentially retained by a gliosarcoma and was able to induce tumour necrosis in this model (Dereski et al, 1994). More recently, we demonstrated that the Cremophorformulated AlClPc was more effective in inducing tumour regression in EMT-6 tumour-bearing mice than the mono-through tetrasulphonated derivatives, while exerting relatively minor effects against normal tissues (Chan et al, 1997). The low dosage required together with the absence of systemic toxicity, even at much higher doses, renders the AlClPc Cremophor emulsion one of the most potent photosensitizer preparations currently available in terms of therapeutic window. However, Cremophor oil is known to induce unwanted side-effects in patients (Dye and Watkins, Summary The potential use of unsubstituted aluminium phthalocyanine (AlClPc) as a sensitizer for photodynamic therapy (PDT) of cancer has not been f...

Abstract— Sulfonated phthalocyanine and a series of its metal chelates in combination with red light irradiation led to the degradation of L‐tryptophan in oxygenated aqueous solution. The photoproducts and the rate of transformation of L‐tryptophan are compared with hematoporphyrin and rose bengal sensitized photooxidation. In all cases the primary photoproducts are characterized as cis and trans‐3a‐hydroperoxy‐l,2,3,3a,8,8a‐hexahydropyrrolo[2,3‐b]indole‐2‐carboxylic acid. Support for the involvement of singlet excited oxygen is obtained from azide inhibition and the formation of the specific singlet oxygen product with cholesterol. We observed the contribution of another pathway in the case of the manganese complex.