In situ conversion of
bacteriochlorophyll-a, present in Rhodobacter sphaeroides (Rb. sphaeroides) gave bacteriopurpurin-18 in modest yield, which in a sequence of reactions was converted into two series of bacteriochlorins: bacteriopurpurinimide and bacteriopurpurin p6 with and without a fused
imide ring system, respectively. To determine the effect of overall lipophilicity in photosensitizing efficacy, these bacteriochlorins were independently reacted with HBr gas and subsequently treated with various alkyl
alcohols to afford the corresponding alkyl
ether derivatives as diastereomeric mixtures (the R- and S-isomers were obtained in almost equal ratios). Between the two series of bacteriochlorins, the bacteriopurpurinimides containing a fused
imide ring system were found to be more effective in vivo (C3H mice bearing RIF
tumors). To investigate the effect of the presence of the chiral center at position 3 of the most effective purpurinimide 9 [3(1'-heptyloxy)ethyl-3-deacetyl-bacteriopurpurin-18-N-hexylimide propyl
ester], the acetyl group was replaced with a hydroxymethyl substituent and converted into 3(1'-decyloxy)methyl-3-deacetyl-purpurin-18-N-hexylimide methyl
ester 26 with a similar lipophilicity. Interestingly, compared to 26, the bacteriopurpurinimide 9 was found to be more effective, suggesting that the chiral center at position 3 certainly plays an important role in photosensitizing activity. Among a series of alkyl
ether analogues, between the
PDT efficacy and the lipophilicity (log P and log D) calculated by computational methods (PALLAS program), a parabolic relationship was observed to some extent. However, it was limited to a particular series, e.g., compounds with similar log P values between bacteriopurpurinimides and
bacteriochlorin e6 did not produce similar in vivo efficacy. As expected, within a series, a linear relationship was observed between the log P values and the HPLC retention times of the
photosensitizers. Some of the mitochondrial localized
photosensitizers showed a significant peripheral
benzodiazepine binding (PBR) affinity. However, limited correlation between PBR binding affinity and in vivo
PDT efficacy was observed. Compared to the naturally occurring
bacteriochlorophyll-a, the bacteriopurpurinimides with fused
imide ring system showed higher in vitro/in vivo stability. In contrast to methyl
pyropheophorbide-a, the
ester functionalities in bacteriopurpurinimide did not convert into the corresponding
carboxylic acid by the
enzyme esterases.