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-alpha 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-alpha 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-alpha analogs were found to be more active than related chlorin e6 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-alpha analogs. The photosensitizers prepared from pyropheophorbide-alpha methyl ester and chlorin e6 trimethyl ester have long wavelength absorption at 660 nm (epsilon 45 000 to 50 000). Reduction of the carbonyl group in the pyropheophorbide-alpha to methylene (ring E) resulted in a blue shift to 648 nm (epsilon 38 000).