Carbon-1 versus Carbon-3 Linkage of d-Galactose to Porphyrins: Synthesis, Uptake, and Photodynamic Efficiency

Abstract

The use of glycosylated compounds is actively pursued as a therapeutic strategy for cancer due to the overexpression of various types of sugar receptors and transporters on most cancer cells. Conjugation of saccharides to photosensitizers such as porphyrins provides a promising strategy to improve the selectivity and cell uptake of the photosensitizers, enhancing the overall photosensitizing efficacy. Most porphyrin-carbohydrate conjugates are linked via the carbon-1 position of the carbohydrate because this is the most synthetically accessible approach. Previous studies suggest that carbon-1 galactose derivatives show diminished binding since the hydroxyl group in the carbon-1 position of the sugar is a hydrogen bond acceptor in the galectin-1 sugar binding site. We therefore synthesized two isomeric porphyrin-galactose conjugates using click chemistry: one linked via the carbon-1 of the galactose and one linked via carbon-3. Free base and zinc analogs of both conjugates were synthesized. We assessed the uptake and photodynamic therapeutic (PDT) activity of the two conjugates in both monolayer and spheroidal cell cultures of four different cell lines. For both the monolayer and spheroid models, we observe that the uptake of both conjugates is proportional to the protein levels of galectin-1 and the uptake is suppressed after preincubation with an excess of thiogalactose, as measured by fluorescence spectroscopy. Compared to that of the carbon-1 conjugate, the uptake of the carbon-3 conjugate was greater in cell lines containing high expression levels of galectin-1. After photodynamic activation, MTT and lactate dehydrogenase assays demonstrated that the conjugates induce phototoxicity in both monolayers and spheroids of cancer cells.

Caveolin-1 Modulation Increases Efficacy of a Galacto-Conjugated Phthalocyanine in Bladder Cancer Cells Resistant to Photodynamic Therapy

“…22 Given that PDT highly depends on oxygen concentrations in the tumor tissues, cancer cells growing in three-dimensions are better biological models to screen photodynamic efficiency of PS. 33−35 We believe that based on our previous studies that successfully demonstrated the in vivo phototoxicity of porphyrinoids conjugated with dendritic units of the galactose sugar, [9][10][11][12]20,33 porphyrinoid and animal models are very similar. In this study, we extended our previous work on galactose-PS conjugates [9][10][11][12]20,33 and gained further insights into the specificity of PcGal 16 for bladder tumor tissues and the mechanism of PS intracellular accumulation.…”

Azides and Porphyrinoids: Synthetic Approaches and Applications. Part 1—Azides, Porphyrins and Corroles

“…These authors prepared carbon-1 and carbon-3-galactosyl porphyrin conjugates P60 and P61 (M = 2H or Zn) under CuAAC conditions and tested them towards four tumoral cell lines (monolayers or spheroids) containing high expression of galactin-1 protein ( Figure 6). The results pointed out that the uptake of the cabon-3 galactose porphyrin derivatives (P61) is higher than the carbon-1 galactose porphyrin derivatives (P60) probably due to the higher hydrophilicity and the binding recognition domain of galectin-1 protein by the available hydroxyl group at carbon-1 [44]. Using the same alkynyl porphyrinic precursor P26, Rajakumar and co-workers [45] and Rivera and co-workers [46] prepared different amphiphilic dendrimers by a convergent synthetic strategy also using click chemistry.…”

“…The obtained amphiphilic porphyrin-cyclodextrin conjugate P59 was used to prepare supramolecular nanoarchitectures to control drug delivery. Drain and co-workers also reported the synthesis of several porphyrin derivatives bearing carbohydrate moieties [44]. These authors prepared carbon-1 and carbon-3-galactosyl porphyrin conjugates P60 and P61 (M = 2H or Zn) under CuAAC conditions and tested them towards four tumoral cell lines (monolayers or spheroids) containing high expression of galactin-1 protein ( Figure 6).…”

Sonogashira cross-coupling as a key step in the synthesis of new glycoporphyrins

“…In this strategy we started with the synthesis of a porphyrin core first, followed by introduction of a glycal moiety via Sonogashira reaction. As a model porphyrin we chose (5,10,15,20)-tetrakis(4-bromophenyl)porphyrin ( 6) because it is bench-stable and smoothly available from 4-bromobenzaldehyde and pyrrole in Lindsey's conditions. 26 The glycal starting materials (Scheme 3, 7a-7c) were obtained from perbenzylated 2-iodo-D-glucal using the optimised conditions described in Table 1.…”

“…3 Especially intriguing are methods leading to glycoporphyrin hybrids, because these compounds may have a better solubility in polar solvents and they might exhibit an increased potential to aggregate nearby cancer cells. 4,5 However, the synthesis of new porphyrin-sugar hybrids suffers from an absence of general methodologies.…”