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Identification
and characterization of hypericin analogs that differ in tumor cell
toxicity.
Wills, Nick1,
Park, Jaehun1, Wen, Jin1,
Kesavan, Sarathy1, Kraus, George1,
Petrich, Jacob1 and Carpenter, Susan1
Iowa State University1
Abstract-
Hypericin has been shown to have potent light induced antiviral and
anti-tumor activity. To better understand the mechanisms of photo-induced
cytotoxicty, we constructed a series of hypericin analogs that varied
in the side chain moieties. The analogs were shown to differ in light
dependent cytotoxic activity as measured by MTT cell viability assay.
Further characterization of the analogs included measurements of percent
cell association, singlet oxygen production, and the molecular extinction
coefficient. Cell association was determined by spectraphotometric analysis
of cell free and cell associated extracts following incubation of cells
with analog. A markedly reduced cytotoxic activity was observed in cases
where cell association of the analog was found to be less than 50%,
indicating that cell association is required for activity. However,
among all analogs tested, there was no significant correlation between
cell association and cytotoxicity (R2=0.0686). Singlet oxygen
yield ranged from  =0.15
to 0.76, however
did not correlate well with cytotoxicity (R2=0.2077). Extinction
coefficients ranged from 450 to 44,000(M-1cm-1),and
there was no correlation with cytotoxicity. Moreover, comparative analysis
of cytotoxicity within subgroups of analogs having relatively similar
singlet oxygen yields or extinction coefficients failed to find a significant
correlation between cytotoxicity and either of these photophysical properties.
Together these data suggest that the cytotoxic activity of hypericin
is not likely due to a single major factor, but rather results from
a combination of factors whose roles may vary under different circumstances.
Keywords: hypericin,
analog, cytotoxicity, singlet oxygen
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