Background: Retinoblastoma is the most common malignant intraocular tumor in children. The current treatment gives a good vital prognostic but there are several drawbacks to the arsenal of "classical antitumoral" therapies. Photodynamic therapy (PDT) could be an exciting non-toxic and non-mutagenic alternative protocol.Method: In this paper, we report about the screening of the in vitro photocytotoxicity of hydrophenylporphyrins and chlorins and their glycoconjugated derivatives in a human retinoblastoma cell line (Y79) and for comparison in a colorectal adenocarcinoma cell line (HT29).Results: Despite lower photodynamic activity than that observed for hydroxylated photosensitizers, in particular Foscan (R) glycoconjugated derivatives display phototoxicity (IC50 2.4-0.05 mu M +/- 10%) against Y79 cells with examples of significant intrinsic cytotoxicity. Amongst them the triglucosyl porphyrin 10 is highly photocytotoxic (IC50 0.90 mu M +/- 10%) but is fully devoid of cytotoxicity (IC50 > 15 mu M). The photoactivity is highly modulated by the presence of a diethyleneglycol spacer between the chromophore and the glycoside (compounds 14-17, IC50 0.5, 0.6, 0.05 and 0.35 mu M +/- 10%) and by the anomeric configuration of the sugar (compound 15 and 17, IC50 0.6 and 0.05 mu M +/- 10% respectively). One of the main problems for the use of Foscan is its poor solubility which might be improved by glycoconjugation. Moreover Foscan has been shown to induce necrosis after PDT leading to a possible ulceration of surrounding tissues unsuitable for a conservative treatment. A preferential mitochondrial subcellular localization which has been previously reported for some glycoconjugated photosensitizers could enhance the contribution of apoptosis process.Conclusion: Tri-alpha-O-galactosyl porphyrin 16 is a better candidate than Foscan (R) for a clinical application of PDT for a conservative therapy of retinoblastoma. (C) 2007 Elsevier B.V. All rights reserved.

Asymmetrical glycoconjugated tetrapyrrolic macrocycles are under study as efficient sensitizers for photodynamic therapy (PDT). In this context, tri(meta-O-β-glucopyranosyloxyphenyl)chlorin [TPC(m-O-Glu)3] 2a/3a was found to be four times more photoactive in vitro than Foscan®. In a further study of this interesting glycoconjugate, its metabolism by cellular glycosidases in HT29 cells has to be explored. Cellular extracts of HT29 cells incubated with TPC(m-O-Glu)3 (24 h, 6 μM) were analyzed by MALDI-TOF mass spectrometry and high performance liquid chromatography (HPLC). In MALDI-TOF mass spectra, the presence of compounds distinct from TPC(m-O-Glu)3 (m/z 1151) were observed at m/z 989, 827 and 665 corresponding to the loss of one, two or three glucose units (162 u) and were be ascribed to TPC(m-OH)(m-O-Glu)2 2/3b,b′,b″, TPC(m-OH)2(m-O-Glu) 2/3c,c′,c″ and TPC(m-OH)3 isomers 2d/3d, respectively. The porphyrins resulting from chlorin oxidation TPP(m-O-Glu)3 4a, TPP(m-OH)(m-O-Glu)2 4b,b″, TPP(m-OH)2(m-O-Glu) 4c,c″ and TPP(m-OH)3 4d were also observed. The HPLC profile (λanal.=420 nm) showed eight peaks consistent with mass spectra. The kinetics of deglucosylation was studied from HPLC profiles between 1 and 48 h incubation. The concentration of triglucoconjugated and diglucoconjugated molecules was maximum around 3 and 8 h incubation, respectively, whereas, totally deglucosylated species appeared only after incubation for more than 10 h. The fully deglycosylated porphyrin TPP(m-OH)3 is the final metabolite, being observed at a concentration 15 times higher than that of the remaining TPC(m-O-Glu)3 2a/3a. Compared to the photobiological activity of the parent molecule [TPC(m-O-Glu)3], a three times higher TPP(m-OH)3 concentration was necessary to observe a similar in vitro photoactivity.

Glucoconjugated tri and tetra(meta-hydroxyphenyl)chlorins have been synthesized in order to explore how glucoconjugation of the macrocycle affects the photoactivity of the molecule. Internalization processes, photosensitizing efficacy of TPC(m-O-GluOH)3 and TPC(m-O-GluOH)4, in HT29 human adenocarcinoma cells have been compared to those of tetra(meta-hydroxyphenyl) chlorin (m-THPC, Foscan®). The tetra glucoconjugated chlorin, TPC(m-O-GluOH)4, was found to be poorly internalized and weakly photoactive. In contrast, the asymmetric and more amphiphilic compound TPC(m-O-GluOH)3, exhibited superior phototoxicity compared to m-THPC. Drug concentration, temperature and sodium azide effects indicated that TPC(m-O-GluOH)3 internalization partly proceeds via an active receptor-mediated endocytosis mechanism. Cellular uptake appeared as a saturable process and remained 30% lower than for mTHPC. However, a maximum phototoxicity in HT29 cells (survival fraction of 2±0.6%) were observed for concentration as low as 2μM. A 4-fold higher concentration of m-THPC was necessary to observe the same level of photoactivity. This higher phototoxicity has been correlated to a greater mitochondrial affinity. On the basis of these results, work is in progress to further evaluate the potential of glycosylated chlorins in photodynamic therapy (PDT).

The ladybug alkaloids 4 and 17 of the adaline series were synthesized via intramolecular Mannich reaction of the intermediate iminium-enols 13, generated from the corresponding 2-cyano-2′-alkyl-6- (propan-2-one ethylene ketal) piperidines 11 and 12.

Chemischer InformationsdienstVolume 4, Issue 13 Natural Products ChemInform Abstract: BESTANDTEILE AUS ABIES GRANDIS, STRUKTUR UND ABSOLUTE STEREOCHEMIE VON CYCLOGRANDISOLID UND EPICYCLOGRANDISOLID, NEUEN CYCLOPROPAN-TRITERPEN-LACTONEN J. P. KUTNEY, J. P. KUTNEYSearch for more papers by this authorD. S. GRIERSON, D. S. GRIERSONSearch for more papers by this authorG. D. KNOWLES, G. D. KNOWLESSearch for more papers by this authorN. D. WESTCOTT, N. D. WESTCOTTSearch for more papers by this authorI. H. ROGERS, I. H. ROGERSSearch for more papers by this author J. P. KUTNEY, J. P. KUTNEYSearch for more papers by this authorD. S. GRIERSON, D. S. GRIERSONSearch for more papers by this authorG. D. KNOWLES, G. D. KNOWLESSearch for more papers by this authorN. D. WESTCOTT, N. D. WESTCOTTSearch for more papers by this authorI. H. ROGERS, I. H. ROGERSSearch for more papers by this author First published: March 27, 1973 https://doi.org/10.1002/chin.197313463AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume4, Issue13March 27, 1973 RelatedInformation

The light petroleum extract of grand fir [Abies grandis (Dougl.) Lindl.] was found to contain two novel triterpene lactones. The first compound, named cyclograndisolide, was shown by chemical and spectroscopic considerations and finally confirmed by X-ray analysis to be (23 R)-3α-methoxy-9,19-cyclo-9β-lanost-24-ene-26,23-olide (6). The second component, epicyclograndisolide was isomeric with the first and was assigned as (23 S)-3α-methoxy-9,19-cyclo-9β-lanost-24-ene-26,23-olide (10).