Synthesis of Red‐Light‐Responsive Pheophorbide‐a Tryptamine Conjugated Photosensitizers for Photodynamic Therapy

Six methyl pheophorbide‐a derivatives were prepared by linking a tryptamine side chain at the C‐131, C‐152 and C‐173 positions of pheophorbide‐a. Prepared conjugates were characterized and evaluated for their photocytotoxicity against A549 cells. The conjugate 6 a with strong absorption at 413 nm (Soret band), 663–671 nm (Q bands) and comparable fluorescence quantum yield (0.26) was found to exhibit significant cytotoxicity (659 nM). Molecular integration of pheophorbide‐a and tryptamines showed synergistic effects as the most potent conjugate 6 a was identified with enhanced photocytotoxicity when compared to methyl pheophorbide‐a. The conjugate 6 a was smoothly taken up by A549 cells and exhibited intracellular localization predominantly to lysosome in the cytoplasm. Upon photoirradiation 6 a generated singlet oxygen to show potent cytotoxicity toward A549 cells. A molecular integration of pheophorbide‐a and tryptamine led to the identification of the potent and selective conjugate 6 a with significant photocytotoxicity (IC50=695 nM) toward A549 lung cancer cells. Conjugate 6a was found to be more potent than methyl pheophorbide‐a, making it a novel and potent photosensitizing agent suitable for further exploration in targeted delivery with lipophilic nanocarriers in photodynamic therapy.