Synthesis of Asymmetrically Meso-Substituted Porphyrins Bearing Amino Groups as Potential Cationic Photodynamic Agents

Novel asymmetrically meso-substituted porphyrins bearing amino groups have been synthesized as precursors of cationic photodynamic agents. The amphiphilic character of porphyrins was increased by the presence of a high lipophilic trifluoromethyl group. Different patterns were obtained from meso-4-[(3-N,N-dimethylaminopropoxy)phenyl]dipyrromethane 1, which was formed by the condensation of 4-(3-N,N-dimethylaminopropoxy)benzaldehyde with a large excess of pyrrole. This reaction takes place at high temperature with a yield of 59 %. To obtain porphyrins, dipyrromethane 1 was condensed with aldehydes in the presence of trifluoroacetic acid (TFA) under different conditions. First, 1 was reacts with 4-(3-N,N-dimethylaminopropoxy)benzaldehyde in dichloromethane catalyzed by TFA (~4 times TFA/1 molar ratio) to obtain 6.2 % of 5,10,15,20-tetrakis(4-[3-N,N-dimethylaminopropoxy]phenyl)porphyrin (A4-porphyrin). Under similar conditions, reaction of 1 with 4-(trifluoromethyl)benzaldehyde produces 5,15-di(4-[3-N,N-dimethylaminopropoxy]phenyl)-10,20-di(4-trifluoromethylphenyl)porphyrin (A2B2-porphyrin) with 4.8 % yield. Also, this procedure yields a mixture of porphyrins, which were formed due to acidolysis of 1. When minor amount of TFA was used in acetonitrile the yield of A2B2-porphyrin was very poor (~0.4 %). On the other hand, condensation of 1 with 4-trifluoromethylbenzaldehyde and 4-(3-N,N-dimethylaminopropoxy)benzaldehyde catalyzed by TFA (~2 times TFA/1 molar ratio) in acetonitrile yields 9.3 % of 5-(4-trifluoromethylphenyl)-10,15,20-tris(4-[3-N,N-dimethylaminopropoxy]phenyl) porphyrin (A3B-porphyrin). Also, A2B2 and A4 porphyrins were isolated with 6.0 and 2.0 %, respectively. Finally, exhaustive methylation of amino porphyrins produce cationic sensitizers (>94 % yields). In these porphyrins, the cationic centers are isolated from the porphyrin ring by a propoxy bridge, which also provides a higher mobility of the charge facilitating the interaction with the outer membrane of the Gram-negative bacteria. These amphiphilic cationic porphyrins are promising photosensitizers with potential applications in bacteria inactivation by photodynamic therapy.