Preparation and Evaluation of Pyropheophorbide a Derivatives

Photodynamic therapy (PDT) is an approved treatment for a wide range of diseases, especially for cancer.The essential elements in the treatment involve light source with appropriate wavelength, photosensitizing agents and oxygen in tissue. With minimally invasive ability, it attracts increasing attention and most of which centered in the development of efficient photosensitizers(PSs).
Several pyropheophorbide a derivatives, such as 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide (HPPH), with preferred properties have already progressed into clinical trial as potential photosensitizer (PS) candidates, inspired by which, this study used pyropheophytin a as starting material in the preparation of five derivatives of pyropheophorbide a, with four of them believed to be novel compounds, pyropheophorbide a 1-octadecanol ester (3a), pyropheophorbide a 2-methoxyphenol ester(3c),triglycine ester of 3a and 3c(6a and 6c).
Compounds synthesized in this work has been confirmed by 1H-NMR and MS. The UV-vis spectra, MSn, RP-HPLC and solubility measurement were also applied to compare the behavior of the five compounds. The three pyropheophorbide esters have identical maximum absorption wavelength (665 nm in red range). The pair of C-31 modified components also have identical absorption maxima (660 nm in red range). Although the three pyropheophorbide esters possess similar structures, their MSn dissociation behaviour shows several differences. For example, the loss of entire 2-methoxyl phenol group was observed in MS2 of the methoxyphenol ester, leaving a carbonyl residue on C-173 where an acid group remained in MS2 of the octadecanyl and cholesteryl esters.
RP-HPLC and TLC behavior gave consistent polarity trends for the five derivatives: (1) the triglycine derivatives exhibit greater polarity than the pheophorbide esters; (2) 3c and 6c are more polar than 3a and 6a, respectively; (3) pyropheophorbide a cholesterol ester (3b) demonstrated identical polarity behavior with 3a. The more polar compounds 6a and 6c exhibited greater solubility in the polar solvent methanol than 3a-c, and when increasing the solvent polarity (introducing 50% water), only 6c showed weak solubility.