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Bioconjugatable porphyrins bearing a compact swallowtail motif for water solubility.

ABSTRACT: A broad range of applications requires access to water-soluble, bioconjugatable porphyrins. Branched alkyl groups attached at the branching site to the porphyrin meso position are known to impart high organic solubility. Such "swallowtail" motifs bearing a polar group (hydroxy, dihydroxyphosphoryl, dihydroxyphosphoryloxy) at the terminus of each branch have now been incorporated at a meso site in trans-AB-porphyrins. The incorporation of the swallowtail motif relies on rational synthetic methods whereby a 1,9-bis(N-propylimino)dipyrromethane (bearing a bioconjugatable tether at the 5-position) is condensed with a dipyrromethane (bearing a protected 1,5-dihydroxypent-3-yl unit at the 5-position). The two hydroxy groups in the swallowtail motif of each of the resulting zinc porphyrins can be transformed to the corresponding diphosphate or diphosphonate product. A 4-(carboxymethyloxy)phenyl group provides the bioconjugatable tether. The six such porphyrins reported here are highly water-soluble (> or =20 mM at room temperature in water at pH 7) as determined by visual inspection, UV-vis absorption spectroscopy, or 1H NMR spectroscopy. Covalent attachment was carried out in aqueous solution with the unprotected porphyrin diphosphonate and a monoclonal antibody against the T-cell receptor CD3epsilon. The resulting conjugate performed comparably to a commercially available fluorescein isothiocyanate-labeled antibody with Jurkat cells in flow cytometry and fluorescence microscopy assays. Taken together, this work enables preparation of useful quantities of water-soluble, bioconjugatable porphyrins in a compact architecture for applications in the life sciences.

SUBMITTER: Borbas KE

PROVIDER: S-EPMC3072562 | biostudies-literature | 2006 May-Jun

REPOSITORIES: biostudies-literature

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Bioconjugatable porphyrins bearing a compact swallowtail motif for water solubility.

Borbas K Eszter KE Mroz Pawel P Hamblin Michael R MR Lindsey Jonathan S JS

Bioconjugate chemistry 20060501 3

A broad range of applications requires access to water-soluble, bioconjugatable porphyrins. Branched alkyl groups attached at the branching site to the porphyrin meso position are known to impart high organic solubility. Such "swallowtail" motifs bearing a polar group (hydroxy, dihydroxyphosphoryl, dihydroxyphosphoryloxy) at the terminus of each branch have now been incorporated at a meso site in trans-AB-porphyrins. The incorporation of the swallowtail motif relies on rational synthetic methods ...[more]

PMID: 16704201

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Project description:BACKGROUND: Porphyrin TMPyP4 (P4) and its C14H28-alkyl derivative (C14) are G-quadruplex binders and singlet oxygen (1O2) generators. In contrast, TMPyP2 (P2) produces 1O2 but it is not a G-quadruplex binder. As their photosensitizing activity is currently undefined, we report in this study their efficacy against a melanoma skin tumour and describe an in vitro mechanistic study which gives insights into their anticancer activity. METHODS: Uptake and antiproliferative activity of photoactivated P2, P4 and C14 have been investigated in murine melanoma B78-H1 cells by FACS, clonogenic and migration assays. Apoptosis was investigated by PARP-1 cleavage and annexin-propidium iodide assays. Biodistribution and in vivo anticancer activity were tested in melanoma tumour-bearing mice. Porphyrin binding and photocleavage of G-rich mRNA regions were investigated by electrophoresis and RT-PCR. Porphyrin effect on ERK pathway was explored by Western blots. RESULTS: Thanks to its higher lipophylicity C14 was taken up by murine melanoma B78-H1 cells up to 30-fold more efficiently than P4. When photoactivated (7.2 J/cm2) in B78-H1 melanoma cells, P4 and C14, but not control P2, caused a strong inhibition of metabolic activity, clonogenic growth and cell migration. Biodistribution studies on melanoma tumour-bearing mice showed that P4 and C14 localize in the tumour. Upon irradiation (660 nm, 193 J/cm2), P4 and C14 retarded tumour growth and increased the median survival time of the treated mice by ~50% (P <0.01 by ANOVA), whereas porphyrin P2 did not. The light-dependent mechanism mediated by P4 and C14 is likely due to the binding to and photocleavage of G-rich quadruplex-forming sequences within the 5'-untranslated regions of the mitogenic ras genes. This causes a decrease of RAS protein and inhibition of downstream ERK pathway, which stimulates proliferation. Annexin V/propidium iodide and PARP-1 cleavage assays showed that the porphyrins arrested tumour growth by apoptosis and necrosis. C14 also showed an intrinsic light-independent anticancer activity, as recently reported for G4-RNA binders. CONCLUSIONS: Porphyrins P4 and C14 impair the clonogenic growth and migration of B78-H1 melanoma cells and inhibit melanoma tumour growth in vivo. Evidence is provided that C14 acts through light-dependent (mRNA photocleavage) and light-independent (translation inhibition) mechanisms.

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Bioconjugatable porphyrins bearing a compact swallowtail motif for water solubility.

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Bioconjugatable porphyrins bearing a compact swallowtail motif for water solubility.

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