Texaphyrin complexes

Metal-texaphyrin complexes such as 55 selectively accumulate in tumor cells (240) (see Section III). Complex 55 readily undergoes aone-electron reduction (Ei/2 = 0.08 V vs NHE), forming a free radical which is capable of damaging DNA. Because of the high electron affinity of 55, it may prolong the lifetime of HO- radicals formed by radiolysis of water. Complex 55 is now in phase II clinical trials for the treatment of brain tumors and lung, head, neck, and pancreatic cancer. 

Metal-texaphyrin complexes are readily taken up by tumor cells and have clinical potential as photosensitizers (see Section III) and... 

In the presence of anions such as phosphate and oxalate, the relaxivity of [Gd(Tex)]2+ is considerably reduced revealing that these anions compete with water for binding to the Gd3+ ion [167,171]. Most likely, texaphyrin complexes self-associate due to strong van der Waals interactions. UV-VIS studies suggest that the aggregates dissociate upon interaction with polyuronides (pectate, alginate), which probably act as polydentate polycarboxylate ligands for the [Gd(Tex)]2+ complexes [173]. 

Although structurally and spectrally similar, the differing redox and photophysical properties of the various lanthanide(III) texaphyrin complexes allow their use in such disparate areas as PDT, direct cancer treatment, and both X-ray and chemotherapy enhancement protocols. Both compounds 1 and 2 generate reactive oxygen species (ROS), albeit via mechanistically distinct pathways (vide infra). The ROS are thought to be responsible, at least in part, for the observed biological activity of MGd and MLu [22],... 

The cadmium(II) complex corresponding to 9 (M = Cd n = 2) was the first texaphyrin made [6], This aromatic expanded porphyrin was found to differ substantially from various porphyrin complexes and it was noted that its spectral and photophysical properties were such that it might prove useful as a PDT agent. However, it was also appreciated that the poor aqueous solubility and inherent toxicity of this particular metal complex would likely preclude its use in vivo [29-31], Nonetheless, the coordination chemistry of texaphyrins such as 9 was soon generalized to allow for the coordination of late first row transition metal (Mn(II), Co(II), Ni(II), Zn (II), Fe(III)) and trivalent lanthanide cations [26], This, in turn, opened up several possibilities for rational drag development. For instance, the Mn(II) texaphyrin complex was found to act as a peroxynitrite decomposition catalyst [32] and is being studied currently for possible use in treating amyotrophic lateral sclerosis. This work, which is outside the scope of this review, has recently been summarized by Crow [33],... 

One of the salient features of MGd is that it contains a highly paramagnetic Gd(III) center. This has provided the added benefit in clinical work of allowing neoplastic lesions to be imaged by MRI [9,28,48], These studies have also served to establish inter alia that MGd localizes well to tumors. In the case of MLu, which displays stronger fluorescence than MGd, localization in tumors and abnormal cells has repeatedly been demonstrated in experiments. The mechanisms by which this texaphyrin complex in... 

The structurally similar, but magnetically distinct, lanthanide(III) texaphyrin complexes, MLu and MGd both generate reactive oxygen species (ROS), albeit via different mechanisms. Photoirradiation of MLu causes excitation from the singlet ground state to the triplet state (Fig. 3). 

Young, S.W. et al. (1994) Preclinical evaluation of gadolinium(III) texaphyrin complex. A new paramagnetic contrast agent for magnetic resonance imaging, Invest Radiol. 29, 330-338. 

Geraldes, C.F. et al. (1995) Nuclear magnetic relaxation dispersion studies of water-soluble gadolinium(III)-texaphyrin complexes, J. Magn. Reson. Imag. 5, 725-729. 

The central hole or binding core in texaphyrins is roughly 20% larger than that of the porphyrins and accomplishes pentadentate binding [247]. In the course of the studies to exploit coordination behavior with lanthanide cations a serious of monoanionic texaphyrine complexes have been synthesized and fully characterized (Eq. 17, Table 20) [248],... 

Using a different metal salt, Cd(NOj)2, instead of CdClj oxidation reaction results in a slightly higher yield of the cadmium texaphyrin complex [60, 65]. However, upon purification, the product is obtained as a mixture of crystalline and non-crystalline solids. A single crystal X-ray diffraction study of the crystalline portion of the sample gave an unexpected result. The structure obtained (Fig. 20) revealed a six-coordinate pentagonal pyramidal cadmium (II) complex 156 (c.f. Scheme 20) where one of the two possible axial ligation sites is occupied by a benzimidazole [65]. The five donor atoms of the pentadentate texaphyrin macrocycle complete the coordination sphere about the cadmium with the cadmium... 

Support for the above conclusions was also obtained from an analysis of the Cd NMR and solid state MAS spectra of the five, six, and seven coordinate cadmium texaphyrin complexes 116, 156, and 157, respectively [70]. From the solid-state MAS results, a single tensor was observed for the five-coordinate complex 116 with a corresponding isotropic chemical shift of 194 ppm. The MAS spectrum of a complex prepared in the presence of pyridine, however, revealed two tensors, presumed to be due to a mixture of six and seven coordinate species. Based upon the isotropic chemical shifts and the symmetry of the tensors the six coordinate species was assigned to the isotropic shift at 188 ppm and the seven coordinate species assigned to the isotropic shift at 221 ppm. The MAS spectrum of the benzimidazole complex of cadmium texaphyrin consists of only a single... 

It was precisely this lack of activity towards non-polar substrates that provided an important motivation for the antibacterial and cell localization studies [94]. The cadmium texaphyrin 116 was investigated with regard to photo-activity against a strain of an antibiotic-resistant bacteria (S. aureus). The texaphyrin complex 116 proved to be an effective photosensitizer for the photoinactivation of S. aureus cells, being comparable but somewhat less active than hematoporphyrin at any given concentration tested. 

The first cell localization study, involving mononuclear cells, was carried out as a complement to the anti-viral photodynamic work. Here, the basic motivation for the study derived from the realization that HIV-1 replicates in human T-4 lymphocytes and that, as such, selective light-derived inactivation of such cells would be of benefit in possible photodynamic blood purification processes (see Sect. 12). Texaphyrin proved to be quite effective in the photodestruction of mononuclear cells. In fact it was found that the cadmium texaphyrin complex 116 is as effective on a per mole basis as the dihematoporphyrin ether (DHE) and slightly more so on a per photon basis. 

The final in vitro photodynamic studies involved the use of human cancer cells. Here, K562 leukemic cells of myelocutic origin were used. The texaphyrin complex 116 was very effective in the photo-eradication of K562 leukemic cells, being considerably more effective than hematoporphyrin under similar conditions. This suggests that the texaphyrin expanded porphyrins, as a class of photosensitizers, could have further application in the photo-kilUng of these and other cancer cells... 

The formation of a number of lanthanide texaphyrin complexes has been reported [95]. In all cases, metal insertion and oxidation proceeds smoothly (Scheme 16) [95]. The complexes demonstrate fair water solubility and good stability towards hydrolysis. Detailed kinetic studies of complex 147, for instance indicated that the half-life for decomplexation and/or decomposition of this complex is 37 days in a 1 1 mixture of MeOH H20 (pH7). Thus, it appears that gadolinium (III) complexes of texaphyrins could provide the basis for a new approach to paramagnetic MRI contrast reagent development [95]. 

Figure 3 Single crystal X-ray diffraction structure of the gadolinium texaphyrin complex PCI-0101 (2) (bis-nitrate form) showing the planar nature of the basic monoanionic texaphyrin macrocycle and the four putative inner sphere coordination sites for water (occupied by two apical methanol molecules and a bidentate nitrate anion in this structure). The Gd(III) ion is nine-coordinate and lies 0.60 A out of the plane through the five nitrogen atoms of the macrocycle. Most hydrogen atoms have been omitted for clarity. Thermal ellipsoids have been scaled to the 30% probability level. Reproduced from [22] with permission. 1993 American Chemical Society...

As alluded to above, metal complexes of a number of lanthanide and actinide texaphyrin complexes have also been prepared. In the case of Dy(III) texaphyrin 9.74, as in the case of the bis-pyridine cadmium complex 9.61b, the metal center sits directly within the mean plane of the macrocycle (Figure 9.1.12). This result stands in direct contrast to the highly labile, typically sandwich-type 2 1 or 3 2 complexes observed for porphyrin complexes with these larger metal cations. ... 

Figure 9.1.11 Single Crystal X-Ray Diffraction Structure of the Cadmium(II) Texaphyrin Complex 9.61b.

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