Hydroporphyrins as Tumour Photosensitizers: Synthesis and Photophysical Studies of 2,3-Dihydro-5,15- di(3,5-dihydroxyphenyl) Porphyrin Yann Ferrand, a Ludovic Bourre´, b Ge´ rard Simonneaux, a, * Sonia Thibaut, b Fabrice Odobel, c Y. Lajat b and Thierry Patrice b, * a Laboratoire de Chimie Organome´tallique et Biologique, UMR CNRS 6509, Universite´ de Rennes 1, 35042 Rennes cedex, France b De´partement Laser, Neurochirurgie, CHU Nantes, 44480 Nantes, France c Laboratoire de Synthe`se Organique, UMR CNRS 6513, Universite´ de Nantes, 44322 Nantes cedex 3, France Received 22 October 2002; revised 6 December 2002; accepted 20 December 2002 Abstract—The synthesis and characterization of 2,3-dihydro-5,15-di(3,5-dihydroxyphenyl) porphyrin is reported. The phototoxicity on C6 cell lines and the pharmacokinetics are also reported as preliminary results showing a very high tumor to skin ratio and short retention time in tissues, and thus promising activity in photodynamic therapy. # 2003 Elsevier Science Ltd. All rights reserved. Recently, promising photosensitizers have been developed for photodynamic therapy. 1 Among these substances, certain hydroxysubstituted meso-tetraarylchlorins showed good activity. 2,3 However one problem with these mole- cules is the long retention time of the drug in normal tissues, more particularly in the skin because after injec- tion and treatment, the patient must be protected against sun during a period up to several days. A possible solu- tion is to use diphenylporphyrins instead of tetra- phenylporphyrins as precursors. This class of porphyrins was originally studied by several groups as models of the photosynthetic centre. 4 These compounds are stable and now relatively easy to prepare in high yields. We pos- tulated that (i), the diphenylporphyrin can be reduced in chlorin in order to show absorption in the red and (ii), the presence of two free meso positions will make easier the biotransformation in order to decrease pro- longed cutaneous photosensitivity, a major adverse effect associated with tetraphenyl porphyrin series and photofrin. On the basis of these criteria, we now report the synth- esis and the biophysical studies of these second genera- tion photosensitizers bearing only two phenyl groups on the meso position, a structural change which is accom- panied by a short retention time in tissues together with a promising activity. Cell uptake and photodynamic properties are compared to those of the structurally related meso-tetrahydroxyphenylchlorin (m-THPC), a drug which is one of the most potent photosensitizers discovered to date. 5 The condensation of dipyrrylmethane 1 with 3,5-di- methoxybenzaldehyde furnishes, upon oxidation with o-chloranil, 5,15-di(3,5-methoxyphenyl)porphyrin 2 in high yield (78%) under reaction conditions that ther- modynamically favors the formation of the intermediate porphyrinogen, as previously reported in the Lindsey method. 6 The porphyrin is then demethylated with boron tribromide in dichloromethane to give 3 (yield 75%). In the last step, diimide reduction of the diphenyl- porphyrin gives a mixture of the corresponding dihydro and tetrahydroporphyrins using the method of Whitlock et al. 7 Selective oxidation with o-chloranil removes the bacteriochlorin. Actually, reduction of the porphyrin gave first a mixture of tosylated inter- mediates 4 and after addition of HCl N/10, the tetra- hydroxy product 5 with the desired photophysical properties. Interestingly, the yield obtained for the chlorin is high (75%) and the formation of the corres- ponding porphyrin in the last step is not observed. Several attempts were made in order to isolate the 0960-894X/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0960-894X(03)00002-7 Bioorganic & Medicinal Chemistry Letters 13 (2003) 833–835 *Corresponding author. Tel.: +33-022-323-6285; fax: +33-022-323- 5637; e-mail: gerard.simonneaux@univ- rennes1.fr