Synthesis and Characterization of New Cationic Porphyrins: Applications to Cancer Treatment and Chirality Sensing

Water-soluble cationic porphyrins such as H2T4, 5,10,15,20-tetra(N-methyl-4-pyridyl) 21H,23H have received considerable attention as telomerase inhibitors. Telomerase is selectively expressed in cancer cells, and is therefore an attractive target for the design of new anticancer drugs. H2T4 inhibits telomerase via stabilization of G-quadruplex DNA leading to apoptosis of cancer cells. The nature of porphyrin—G-quadruplex interactions is not fully understood, however. Greater potency and substantially higher selectivity of porphyrin-based telomerase inhibitors is highly desirable. The research in our laboratory focuses on the design, synthesis, and characterization of novel porphyrin-based antitumor drugs and their interaction with DNA.

The Synthesis of Novel b -alkyl-Substituted Cationic Porphyrins . The studies of G-quadruplex stabilization properties of various b-substituted porphyrins are limited. The analysis of their interaction with G-quadruplex DNA is important for biological and clinical applications, because naturally occurring porphyrins are mainly beta-substituted. In addition, beta-substituents exert stronger steric and electronic effects on the porphyrin ring than meso-substituents. It is very important to understand the molecular details of the interaction between beta-substituted porphyrins and human telomeric G-quadruplex structures (vs duplex DNA) in order to design drugs with high specificity toward G-quadruplexes. As a first step toward this goal we are working on the synthesis of beta-octamethyl, -octaethyl, and tetrakis ( beta, beta '-tetramethylene) tetra(N-methyl-4-pyridyl)-21H,23H-porphyrins (H2OMT4, H2OET4, and H2TC6T4) shown in Scheme 1. Although none of these porphyrins have been prepared before, the precedence in the literature exists for synthesis of related systems. This will be followed by a detailed characterization of porphyrins interaction with G-quadruplex DNA via a variety of spectroscopic and structural techniques. As these molecules are predicted to be nonplanar, the role of nonplanarity in the selectivity of porphyrins toward G-quadruplexes (over other DNA) can be thoroughly explored.

Investigating the Effect of the meso-Substituents on Porphyrins’ G-quadruplex Binding Properties. This is a collaborative project with Dr. Gianluca Azzellini from the University of São Paulo, Brazil. His lab provided us with the set of novel meso- substituted porphyrins (Scheme 2) that have electron rich and electron poor substituents. We are investigating the effect that the different meso-substituents have on the porphyrin—G-quadruplex DNA binding properties. The affinity and specificity of these porphyrins for various DNA structures (duplex, triplex, G-quadruplex) is being explored by CD, UV/Vis, NMR spectroscopies and X-ray crystallography.

Modification of Cationic Porphyrins via Lanthanide Addition for Chirality Sensing . Another important application of porphyrins (especially in combination with lanthanides) is in chirality sensing. Porphyrins could be used to detect chemical species in cells and correlate their biological activity with stereochemistry. However, poor resolution, weak binding and low selectivity of chiral probes toward specific biological substrates hinder these applications. Ln(III) porphyrinate b -diketonates (such as Gd(acac)T4, Scheme 3) offer suitable scaffolds for the chiral differentiation of various amino acids under physiological pH and sensitive CD probing of their chirality. While the influence of b -diketonate on chirality sensing has been thoroughly studied, there has been no systematic investigation of how the nature of the central metal ion or the identity of the porphyrin ring affects the supercomplexation with guests and subsequent sensing properties. Consequently, various di-, tri-, and tetra-(pyridinium-x-yl) (where x = 2, 3, and 4) meso-substituted porphyrins with Ln(acac) (Ln = Sm 3+, Yb 3+, Gd 3+, or Tb 3+) will be synthesized. The sensing efficiency of prepared lanthanide porphyrinates and the identity of biological substrates will be determined via liquid-liquid extraction experiments, followed by CD measurements. The binding of a chiral nonchromophoric guest to an achiral chromophoric host results in induced CD signal which reflects the chirality of the guest. Therefore, the chirality of guest molecules can be easily detected. In addition, guest molecules can be recovered. Using CD or NMR titrations, the binding affinities for guest molecules will be determined. The mechanism of chiral sensing will be investigated by NMR and X-ray crystallography. The results of structural and spectroscopic studies will be used to develop better porphyrin-based chiral sensors.


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Last Update: 6.15.08 David Marquardt '08

Created: 10.21.07 David Marquardt '08

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