Syntheses and preliminary in vivo photodynamic efficacy of benzoporphyrin derivatives from phylloerythrin and rhodoporphyrin XV methyl esters and aspartyl amides

Efficient approaches to the synthesis of methyl esters and aspartyl amides of so-called ring 'A'-benzoporphyrin derivatives from rhodoporphyrin XV dimethyl ester 10 and 3-vinylphylloerythrin methyl ester 22 are reported. The benzo-rings in the products are obtained by way of Diels-Alder (4+2) cyclizations which employ a dienophile and the vinyl and 2,3-double bonds in the starting materials as the diene. In the 3-vinyl-phylloerythrin series, the presence of the 13¹-keto-group in ring E inhibits the Diels-Alder reaction with dimethyl acetylenedicarboxylate, but with more reactive dienophiles, such as tetracyanoethylene, the Diels-Alder adduct was isolated in modest yield. Protection of the 13¹-keto-group as a ketal or thioketal afforded the intermediate benzoporphyrin adducts, which were rearranged to trans- and cis-isomers on reacting with triethylamine and 1,8-diazabiclo[5.4.0]undec-7-ene, respectively. Among the sensitizers tested so far, the benzoporphyrin derivative (cis-isomer) obtained from rhodoporphyrin XV di-tert-butyl aspartate showed the best in vivo photosensitizing activity in DBA/2 mice transplanted with SMT/F tumors.