Six methyl pheophorbide-a derivatives were prepared by linking a tryptamine side chain at the C-13 1 , C-15 2 and C-17 3 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), 663671 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.
All the chemicals and solvents were purchased from commercial suppliers. Progress of reactions was monitored by thin layer chromatography (TLC). All the NMR spectra were recorded in CDCl 3 at 400 MHz for 1 H and 100 MHz for 13 C on Bruker Avance DPX-400MHz. Chemical shifts are reported in part per million (ppm) relative to CDCl 3 ( 13 C) as internal standards and coupling constants (J) are reported in Hz.. The HRMS was recorded on a JOEL-AccuTOF JMS-T100LC Mass spectrometer having a DART source. TLC analysis was carried out on aluminium sheets coated with silica gel and visualized under UV light. Yields refer to the quantities obtained after column chromatography.
To investigate and compare the pharmacokinetic profile and anti-cancer activity of fluorinated and iodinated photosensitizers (PSs), the 3-(1′-(o-fluorobenzyloxy)ethyl pyropheophorbide and the corresponding meta-(m-) and para (p-) fluorinated analogs (methyl esters and carboxylic acids) were synthesized. Replacing iodine with fluorine in PSs did not make any significant difference in fluorescence and singlet oxygen (a key cytotoxic agent) production. The nature of the delivery vehicle and tumor types showed a significant difference in uptake and long-term cure by photodynamic therapy (PDT), especially in the iodinated PS. An unexpected difference in the pharmacokinetic profiles of fluorinated vs. iodinated PSs was observed. At the same imaging parameters, the fluorinated PSs showed maximal tumor uptake at 2 h post injection of the PS, whereas the iodinated PS gave the highest uptake at 24 h post injection. Among all isomers, the m-fluoro PS showed the best in vivo anti-cancer activity in mice bearing U87 (brain) or bladder (UMUC3) tumors. A direct correlation between the tumor uptake and PDT efficacy was observed. The higher tumor uptake of m-fluoro PS at two hours post injection provides a solid rationale for developing the corresponding 18F-agent (half-life 110 min only) for positron imaging tomography (PET) of those cancers (e.g., bladder, prostate, kidney, pancreas, and brain) where 18F-FDG-PET shows limitations.
The 1,3‐dipolar cycloaddition reaction of azomethine ylides generated in situ by isatin and L‐proline to acrylonitrile and methyl acrylate in water affords a series of spirooxindolo pyrrolizidines in good yields.
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