Synthesis and photodynamic activity of unsymmetrical A3B tetraarylporphyrins functionalized with L-glutamate and their Zn(II) and Cu(II) metal complex derivatives

Four novel unsymmetrical A(3)B porphyrins 1, 2, 3 and 4 were synthesized following Lindsey procedure. Porphyrins 3 and 4 include one and three l-glutamate groups, respectively, and all porphyrins were metallated with Zn(II) (1a-4a) or Cu(II) (1b-4b). Porphyrins and metalloporphyrins presented values of singlet oxygen quantum yields (FD) ranging from 0.21 to 0.67. The tetraaryl derivatives in this study showed phototoxicity in SiHa cells with IC50 values ranging from < 0.01 to 6.56 +/- 0.11 mu M, the metalloporphyrin 4a showed the lowest IC50 value. Comparing the phototoxic activity between all porphyrins, functionalization of porphyrins with glutamate increased 100 times phototoxic activity (1 (IC50 4.81 +/- 0.34 mu M) vs. 3 (IC50 0.04 +/- 0.02 mu M) and 2 (IC50 5.19 +/- 0.42 mu M) vs. 4 (IC50 0.05 +/- 0.01 mu M)). This increased activity could be attributed to reduced hydrophobicity and increased FD, given by functionalization with l-glutamate. Metalloporphyrins 3a (IC50 0.04 +/- 0.01 mM) and 4a (IC50 < 0.01 mu M) presented the best values of phototoxic activity. Therefore, functionalization and zinc metalation increased the phototoxic activity. SiHa cells treated with porphyrins 3, 4, 3a and 4a at a final concentration of 10 mM, showed increased activity of caspase-3 enzyme compared to the negative control; indicating the induction of apoptosis. Differential gene expression pattern in SiHa cells was determined; treatments with metalloporphyrins 4a and 4b were performed, respectively, comparing the expression with untreated control. Treatments in both cases showed similar gene expression pattern in upregulated genes, since they share about 25 biological pathways and a large number of genes. According to the new photophysical properties related to the structural improvement and phototoxic activity, these molecules may have the potential application as photosensitizers in the photodynamic therapy. (C) 2016 Elsevier Masson SAS. All rights reserved.