A simple and efficient approach for the synthesis of fluorinated and nonfluorinated octaethylporphyrin-based benzochlorins with variable lipophilicity, their in vivo tumor uptake, and the preliminary in vitro photosensitizing efficacy

Starting from commercially available Ni(II)octaethylporphyrin (OEP), an eff icient approach for the preparation of a series of fluorinated and nonfluor inated benzochlorins with variable lipophicity has been developed. Their sp ectroscopic properties, preliminary in vitro photosensitizing efficacy, and tumor selectivity were determined. Our methodology provides a facile appro ach for the preparation of the free-base and the related Zn(II) benzochlori ns containing alkyl and alkyl ether side chains with variable carbon units. For the preparation of benzochlorins containing alkyl groups attached to t he exocyclic phenyl ring, the Ni(II) meso-(2-formylvinyl)octaethyl porphyri n 2 was reacted with various reagents such as (trifluoromethyl)trimethylsil ane (TMS-CF3) or the Grignard reagents of various fluorinated or nonfluorin ated alkyl halides. The corresponding intermediates 3, 6a-6e, and 8 obtaine d via intramolecular cyclization under acidic conditions afforded the relat ed benzochlorins 5, 7a-d, and 9 in good yields except for 7e which was obta ined in poor yield (11.4%). The alcohol 10 obtained by reacting porphyrin 2 with ethynylmagnesium chloride did not produce the expected acetylenic ben zochlorin; instead the corresponding acetyl derivative 11 was obtained as a major product, which under appropriate reaction conditions was converted i nto a series of alkyl ether derivatives 13a-13d. To obtain a benzochlorin b earing an ester functionality (1.5), porphyrin 2 was first reacted with eth yl acetate/LDA and the intermediate alcohol 14 was then cyclized with sulfu ric acid. Unlike most of the natural and synthetic chlorine, the Zn(II) com plexes of the benzochlorin analogues exhibited a significant bathochromic s hift (similar to 10 nm) in the electronic absorption spectra, and the long wavelength absorptions were observed in the range 671-677 nm (epsilon: 4327 0-50360). For investigating the in vitro efficacy of these analogues, Molt- 4 cells were used. At a concentration of 2.5 muM, and a light dose of 4 J/c m(2), all benzochlorins produced significant photosensitizing efficacy. The tumor (RIF) and muscle uptake in C3H mice of these photosensitizers was de termined by in vivo reflectance spectroscopy. These results indicate that i n this series increasing the length of the alkyl or alkyl ether carbon chai ns at the fused phenyl ring system produced a significant increase in tumor uptake.