|Year : 2011 | Volume
| Issue : 2 | Page : 294-297
Photosensitizers for photodynamic therapy: One-pot heterogeneous catalytic transfer reduction of porphyrins
Amadeu F Brigas1, Ana M Rosa da Costa1, Arménio C Serra2, Catarina Pires1
1 CIQA and DQF, Faculty of Science and Technology, University of Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
2 Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal
|Date of Submission||08-Sep-2010|
|Date of Decision||15-Oct-2010|
|Date of Acceptance||27-Mar-2011|
|Date of Web Publication||12-May-2011|
Amadeu F Brigas
CIQA and DQF, Faculty of Science and Technology, University of Algarve, Campus de Gambelas, 8005-139 Faro
Source of Support: None, Conflict of Interest: None
| Abstract|| |
A number of new porphyrin-based photosensitizers have been developed for Photodynamic Therapy (PDT) in recent years. Chlorins, which are a reduced form of porphyrins, show better potential of application since they have a stronger absorption band on the red region of the visible spectrum and, hence, a deeper penetration into tissues. We found that by using heterogeneous catalytic transfer reduction (CTR), meso-tetraphenylporphyrin (TPP) could be hydrogenated, although in modest yields, to meso-tetraphenylchlorin (TPC) in a single reaction step. Best reaction conditions were attained using formic acid or sodium phosphinate/water as hydrogen donors, tetrahydrofuran (THF) or toluene as solvent and 10% palladium on charcoal as catalyst.
Keywords: Catalytic transfer reduction, hydrogenation, meso-tetraphenylchlorin, meso-tetraphenylporphyrin, photosensitizers
|How to cite this article:|
Brigas AF, Rosa da Costa AM, Serra AC, Pires C. Photosensitizers for photodynamic therapy: One-pot heterogeneous catalytic transfer reduction of porphyrins. J Pharm Bioall Sci 2011;3:294-7
|How to cite this URL:|
Brigas AF, Rosa da Costa AM, Serra AC, Pires C. Photosensitizers for photodynamic therapy: One-pot heterogeneous catalytic transfer reduction of porphyrins. J Pharm Bioall Sci [serial online] 2011 [cited 2019 May 21];3:294-7. Available from: http://www.jpbsonline.org/text.asp?2011/3/2/294/80770
Porphyrins have a variety of applications ,,, and, for this reason, their synthesis and modification is an expanding area. An example is the reduction of the pyrrole ring to produce chlorins and bacteriochlorins. ,,,,
Porphyrins and their reduced derivatives are the most popular photosensitizers for Photodynamic Therapy (PDT). A number of new porphyrin-based photosensitizers have been developed for PDT in recent years, including chlorins, bacteriochlorins and purpurins. , Porphyrins can be prepared in good yield from pyrrole-aldehyde condensation  and, therefore, the common method for chlorin synthesis is by diimide reduction proposed by Withlook in the sixties.  In spite of some recent advances, , this methodology presents some difficulties in product isolation and chlorins are generally obtained in moderate to poor yields. It would be convenient to find simpler procedures which originate better chlorin yields and at same time reduce the workup difficulties.
Catalytic transfer reduction in heterogeneous medium has proven to be an efficient method (specific and selective, under mild conditions) in the reduction of a variety of compounds. , We wish to report our efforts to achieve the transformation of a porphyrin (meso-tetraphenylporphyrin or TPP) 1 to the corresponding chlorin (meso-tetraphenylchlorin or TPC) 2 in a single step using catalytic transfer reduction (CTR) with 10% palladium on charcoal as catalyst and formic acid or sodium phosphinate as hydrogen donors [Scheme 1].
[Additional file 1]
| Material and Methods|| |
Reagents and equipment
Reagents were of reagent grade and solvents were of HPLC grade. TPC was purchased from Porphyrin Systems (Lübeck, Germany) and 10% palladium on charcoal was from Aldrich (St. Louis, MO, USA). TPP was synthesized by standard procedures from pyrrole and benzaldehyde  and was metallated by refluxing it (2 mg in 15 mL of dry dimethylformamide (DMF)) with 15 mg of anhydrous palladium(II) chloride for 30 min. , The catalyst was filtered off by Chromafil RC-20/25 disks (Machery-Nagel, Düren, Germany). Absorbances were measured on a UV-Vis spectrophotometer (Varian Cary 50 Bio) and reaction mixture analysis was carried on an HPLC (Agilent 1100) with RP-18 LiChrospher column (250×4 mm, 5 μm) and diode array UV-Vis detector and isocratic acetonitrile/THF (9:1, V/V) as eluent. Conversions were obtained from the peak areas at 419 nm in the HPLC chromatograms, after calibration using authentic samples of TPP and TPC. Retention times (tr ) were the following: chlorin 6.7 min, porphyrin 7.2 min, and Pd(II)-TPP 9.4 min.
Ten milliliters of 2.40 μm solution of TPP in THF was stirred at 25°C for 1 h, with the amounts of catalyst ranging from 27 to 750 mg. The catalyst was filtered and the solution absorbance was measured at 416 nm. The same procedure was repeated using toluene.
Catalytic transfer reduction with formic acid
As an example, 10 mL of 0.1 mM solution of TPP in toluene was stirred with 1 mL of 0.26 M toluene solution of formic acid, 0.4 mL of triethylamine and 50 mg of catalyst at 50°C. At intervals, samples were withdrawn, filtered and injected on the HPLC.
Catalytic transfer reduction with aqueous phosphinate
As an example, 10 mL of 0.1 mM solution of TPP in toluene and 5 mL of aqueous 5 mM solution of sodium phosphinate (25 eq) were refluxed in the presence of 50 mg of catalyst. Analysis was carried as previously.
| Results and Discussion|| |
Although CTR presents practical advantages, it requires very fine tuning of several experimental parameters - solvents, donors, catalysts - in order to render the process efficient. Key features in our approach are (i) the establishment of conditions to quantitatively analyze reaction progress with identification of side products, (ii) the study of adsorption isotherms, which are crucial in any heterogeneously catalyzed reaction, in order to predict which conditions are more likely to produce the best results, and (iii) screening and adjustment of hydrogen donors and other conditions to optimize yields.
UV/vis is broadly used to monitor the reaction progress in porphyrin chemistry, but mainly due to spectral similarities of the involved species, HPLC with diode array detection proved to be a more reliable quantitative methodology, with many reports on its application to the above compounds existing in the literature. ,,, Therefore, some efforts were devoted to the establishment of elution conditions.
In the measurement of the adsorption of porphyrins onto the catalyst, various solutions of known concentration of porphyrin were stirred with different amounts of the catalyst, under controlled conditions, and the decrease in porphyrin concentration was monitored by UV/vis [Figure 1].
|Figure 1: Linear plots of the Langmuir adsorption isotherms for THF (o) and toluene ( ) TPP solutions on 10% palladium over charcoal|
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Initial attempts to reduce TPP were made using formic acid as hydrogen donor and THF or toluene as solvents. Reaction proceeded reasonably fast, reaching a steady state in approximately 20 min. Conversions to the desired product TPC were below 40% [Figure 2] along with the formation of metalloporphyrin Pd(II)-TPP (not quantified) and trace amounts of bacteriochlorin and isobacteriochlorin. The metalloporphyrin is formed by complexation of Pd 2+ ions present on the catalyst, in spite of the reducing conditions, and was identified by comparison with an authentic sample. The latter compounds are due to reduction of the formed chlorin 2 , and were identified simply from their visible spectra characteristic bands. Although the preparation of an authentic sample of Pd(II)-TPC was attempted, the product of reaction between TPC and PdCl 2 exhibited the same tr and visible spectrum as Pd(II)-TPP, probably due to oxidation during the reflux and, therefore, the possibility of its formation cannot be discarded.
|Figure 2: Percent conversion (reduction) of TPP with time, in toluene, with formic acid (o) and with aqueous solution of sodium phosphinate ( )|
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In the second approach, a biphasic system consisting of a toluene solution of TPP and an aqueous solution of sodium phosphinate was used. Product distribution was found to be dependent on donor concentration: when 25 equivalents of the latter were used, the desired product TPC was obtained in nearly 40% yield; for other substrate:donor ratios (1:5, 1:15, 1:35, 1:50 and 1:100), an unidentified product was formed (tr = 4.9 min). In all cases, the metalloporphyrin was observed, but none of the other side products were obtained.
A plausible explanation for the stagnation of hydrogenation below 50% conversion is catalyst poisoning by the product, as although a double bond was reduced, most of the system responsible for the adsorption remained untouched, preventing product desorption.
Further work will be required to tackle this problem, but so far, it has been demonstrated that TPP could be reduced to TPC in a single step, although in moderate yields, using either (i) formic acid as hydrogen donor in a THF or toluene solution or (ii) a biphasic system of aqueous sodium phosphinate and toluene as solvent for the substrate, and 10% palladium on charcoal as catalyst.
| Acknowledgments|| |
We gratefully acknowledge FCT - Portugal for funding this work through CIQA, Centre for Research in Chemistry of Algarve. Thanks are also due to the Department of Chemistry and Pharmacy, Faculty of Science and Technology, University of Algarve, for technical support.
| References|| |
|1.||Cavaleiro JA, Neves MG, Tome AC, Silva AM, Faustino MA, Lacerda PS, et al. Porphyrin derivatives: Synthesis and potential applications. J Heterocycl Chem 2000;37:527-34. |
|2.||Dougherty TJ, Gomer CJ, Henderson BW, Jori G, Kessel D, Korbelik M, et al. Photodynamic therapy. J Natl Cancer Inst 1998;90:889-905. |
|3.||De Rosa FS, Bentley MV. Photodynamic therapy of skin cancers: Sensitizers, clinical studies and future directives. Pharm Res 2000;17:1447-55. |
|4.||Jasat A, Dolphin D, Expanded porphyrins and their heterologs. Chem Rev 1997;97;2267-340. |
|5.||Abraham RJ, Plant JE, Bedford GR. The nmr0 -spectra of the porphyrins. 24. The NMR-spectra of some tetraarylchlorins. Org Magn Reson 1983;21:745-56. |
|6.||Stolzenberg AM, Simerly SW, Steffey BD, Haymond GS. The synthesis, properties, and reactivities of free-base- and Zn(II)-N-methyl hydroporphyrin compounds. The unexpected selectivity of the direct methylation of free-base hydroporphyrin compounds. J Amer Chem Soc 1997;119;11843-54. |
|7.||Pineiro M, Carvalho AL, Pereira MM, Gonsalves AM, Arnaut LG, Formosinho SJ. Photoacoustic measurements of porphyrin triplet-state quantum yields and singlet-oxygen efficiencies. Chem Eur J 1998;4:2299-307. |
|8.||Galezowski M, Gryko DT. Recent advances in the synthesis of hydroporphyrins. Curr Org Chem 2007;11:1310-38. |
|9.||Crossley MJ, King LG. A new method for regiospecific deuteriation and reduction of 5,10,15,20-tetraphenylporphyrins - nucleophilic reaction of borohydride ion with 2-nitro-5,10,15,20-tetraphenylporphyrins. J Org Chem 1993;58:4370-5. |
|10.||Serra A, Pineiro M, Pereira N, Rocha Gonçalves A, Laranjo M, Abrantes M, et al. A look at clinical applications and developments of photodynamic therapy. Oncol Rev 2008;2:235-49. |
|11.||Shan XF, Wang TY, Li SY, Yang LY, Fu LM, Yang GQ, et al. Photophysical properties of diphenyl-2,3-dihydroxychlorin and diphenylchlorin. J Photochem Photobiol B 2006;82:140-5. |
|12.||Gonsalves AM, Serra AC, Pineiro M. The small stones of Coimbra in the huge tetrapyrrolic chemistry building. J Porphyrins Phthalocyanines 2009;13:429-45. |
|13.||Whitlock HW, Hanauer R, Oester MY, Bower BK. Diimide reduction of porphyrins. J Am Chem Soc 1969;91:7485-9. |
|14.||Nascimento BF, Gonsalves AM, Pineiro M. MnO2 instead of quinones as selective oxidant of tetrapyrrolic macrocycles. Inorg Chem Commun 2010;13:395-8. |
|15.||Serra AC, Gonsalves AM. Controlled porphyrinogen oxidation for the selective synthesis of meso-tetraarylchlorins. Tetrahedron Lett 2010;51:4192-4. |
|16.||Johnstone RA, Wilby AH, Entwistle ID. Heterogeneous catalytic transfer hydrogenation and its relation to other methods for reduction of organic-compounds. Chem Rev 1985;85:129-70. |
|17.||Brigas AF, Fonseca CS, Johnstone RA. Metal-assisted reactions, Part 31 : Adsorption isotherms and selective catalytic transfer reduction of aldehydes and ketones. J Mol Catal A Chem 2006;246:100-8. |
|18.||Falvo RE, Mink LM, Marsh DF. Microscale synthesis and H-1 NMR analysis of tetraphenylporphyrins. J Chem Ed 1999 76:237-9. |
|19.||Marsh DF, Mink LM. Microscale synthesis and electronic absorption spectroscopy of tetraphenylporphyrin H-2(TPP) and metalloporphyrins Zn-II(TPP) and N-II(TPP). J Chem Ed 1996;73:1188-90. |
|20.||Zhang JF, Wang H, Hou AX, Wang CF, Zhang HS. Behavior of new complexes of tetrakis(4-methoxylphenyl)porphyrin with heavy rare earth elements in reversed-phase high performance liquid chromatography. J Sep Sci 2004;27:1037-41. |
|21.||Kluska M, Mikus A, Ostrowski S. Influence of stationary phase selectivity on the HPLC separation of porphyrins. J Liq Chromatogr Related Technol 2006;29:263-72. |
|22.||Stefaniak M. HPLC separation of porphine, selected porphyrins, and their metal derivatives. Acta Chromatogr 2004;14:165-71. |
|23.||Spasojevic I, Menzeleev R, White PS, Fridovich I. Rotational isomers of N-alkylpyridylporphyrins and their metal complexes. HPLC separation, H-1 NMR and X-ray structural characterization, electrochemistry, and catalysis of O-2(center dot-) disproportionation. Inorg Chem 2002;41:5874-81. |
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