Alkyl ether analogs of chlorophyll-a derivatives: Part 1. Synthesis, photophysical properties and photodynamic efficacy

The synthesis, preliminary in vivo biological activity, singlet oxygen and fluorescence yields of a series of alkyl ether derivatives of chlorophyll-a analogs are described. For short-chain carbon ethers (1-7 carbon units), it was observed that the biological activity increased by increasing the length of the carbon chain, being maximum in compounds with n- hexyl and n-heptyl chains. Related sensitizers prepared by reacting 2-(1- bromoethyl)-2-devinylpyropheophorbide-a with (sec)alcohols were found to be less effective. Under similar treatment conditions, photosensitizers containing cis- and trans- 3-hexenyl side chains were ineffective. Thus, both stereochemical and steric factors caused differences in sensitizing activity. In general, pyropheophorbide-a analogs were found to be more active than related chlorine, derivatives, in which the isocyclic ring (ring 'E') was cleaved. Related photosensitizers in the 9-deoxy- series were found to be as effective as the corresponding pyropheophorbide-a analogs. The photosensitizers prepared from pyropheophorhide-a methyl ester and chlorine₆ trimethyl ester have lung wavelength absorption at 660 nm (ε 45000 to 50000). Reduction of the carbonyl group in the pyrophenphorbide-a to methylene (ring E) resulted in a blue shift to 648 nm (ε 38000).