meso-Tetra(pentafluorophenyl)porphyrin as an Efficient Platform for Combinatorial Synthesis and the Selection of New Photodynamic Therapeutics using a Cancer Cell Line

Abstract

The four para fluoro groups on 5,10,15,3,4,5, ) are known to react with a variety of nucleophiles, but the reaction conditions for this substitution reaction depend on the nature of the nucleophiles, e.g. primary amines versus thiols. Glycosylated derivatives of this core porphyrin have been shown to be effective photodynamic agents in the induction of necrosis or apoptosis in several cancer cell lines. The present report demonstrates that TPPF 20 can be used as a core platform to efficiently generate a variety of solution phase combinatorial libraries. The focused combinatorial libraries have substituents that are chosen from a set of motifs known to bind biopolymers such as DNA, be taken up by cancer cells, or to render the compounds amphipathic. Incubation of a breast cancer cell line with these solution phase libraries, followed by cell lyses and extraction, affords a selection assay. MALDI mass spectrometry of the extracts allows identification of the molecules taken up by the cells. Cell binding assays of the winning compounds synthesized directly, indicate that both glycosylation and amphipathicity are key properties since neither tetraglycosylated porphyrins nor those with four polar groups are selected to the same extent. In addition, photodynamic efficacy was evaluated.

Highly Fluorous Porphyrins as Model Compounds for Molecule Interferometry

“…This para-fluorine substitution reaction in pentafluorophenyl moieties is not limited to porphyrin systems. [12][13][14] The first example for the fourfold substitution reaction of TPPF 20 with a nucleophile was reported by Kadish et al [15] Examples with non-fluorous alcohols, [16][17][18] amines, [16,17] or thiols [16,19] as well as the introduction of fluorous nucleophiles -namely alcohols [20] and thiols [21,22] are also known.…”

Chemical Synthesis and Medicinal Applications of Glycoporphyrins

“…[215] Note: all are Beta isomers (apart from mannose which is alpha) unless stated as alpha (or beta for mannose) or a mixture of the two. pyridiniumyl)}porphyrin [190] .…”

“…From the series conjugates with the most promising PDT efficacy were identified by in vitro analysis. The viable derivatives (341-363) were subject to direct synthesis and further testing [215] .…”

“…The concentration dependent behavior of this effect indicates the possible use of glycosylated sapphyrins as fluorescent phosphate anion sensors. Several examples of mono-, di-and triglycosylated fluorophenyl corroles were synthesized via combinatorial approaches with a total of 24 products [215] . An example of a deprotected mono-glycosylated calix [4]pyrrole derivative was synthesized by Drašer et al via C-glycosyl linkage to the meso-positions of oligopyrrole.…”

“…This caused the release of free calcium, followed by release of cytochrome c from the mitochondria, caspase 3 activation, PARP cleavage and chromation condensation; all of which are indicative of the apoptosis cascade process [346] . A similar range of thio-glycosylated derivatives (341-363) synthesized by combinatorial synthesis was evaluated against human breast cancer cells MDA-MB-231 and those prospective derivatives analyzed for PDT [215] . Metalloporphyrins are used less frequently in PDT, the high fluorescence of the free bases often provides a good, additional analytical tool.…”