Texaphyrins

As shown in Fig. 7.6, texaphyrins have a larger cavity than porphyrins so they can form complexes with lanthanide metals such as gadolinium (XCYTRIN ), that enhances the efficacy of treatment for certain brain tumours, and lutetium (LUTRIN ), used as a sensitizer for photodynamic therapy of recurrent breast cancer [17], Crucial to their success is the increased number of donor atoms available as the more lanthanide binding sites that a ligand can satisfy, the more stable the complex. 

The jury is still out on the clinical efficacy of texaphyrin-based therapeutics the commercialization of novel pharmaceutics requires careful negotiation through the minefield of clinical trials and the subsequent analysis of the data. Nevertheless this example should serve as an inspiration to chemists everywhere. 

A new type of complex with a different spectroscopic application is provided by the texaphyrins, compounds of extended porphyrins where the ring contains five donor nitrogens. These have attracted considerable interest because of their possible medicinal applications. 

---

Figure 9 Synthesis of a lutetium(III) texaphyrin derivative illustrated by the synthesis of (32) (trade name...

In spite of the heavy atom, compound (32) is sufficiently fluorescent for this to be used as an analytical tool to examine localization and pharmacokinetics. In EMT-6 murine tumors, (32) localizes initially on lysosomes, with selectivity for tumor over surrounding normal tissue, and with evidence for apoptotic cell kill.137 Fluorescence studies using a hamster cheek pouch model show a maximum emission in 2-3 h, with selectivity for the tumor (x 1.5 over normal tissue) after 24 h the photosensitizer is no longer detectable.138 Lutetium texaphyrin (32) has been compared... 

Sessler, J. L. Allen, W. E. Krai, V. A. Preparation of highly boronated derivatives of expanded porphyrins (texaphyrins) for potential use in boron neutron capture therapy and related applications. US Patent 5,955,586, 1999 Chem. Abstr. 1999, 131, 222611. 

Figure 1.17 The texaphyrin-gadolinium chelate structure used as a photosensitizer and MRI contrast agent in the detection and treatment of cancer.

Texaphyrins (i.e. metal-coordinating expanded porphyrins, Fig. 27) have recently been investigated as new drugs for applications in radioimaging and PDT (140). 

A water-solubilized texaphyrin based on gadolinium(III) (XCYTRIN ) is under current testing in a new Phase III clinical trial with the role to enhance the effects of radiation therapy for... 

Metal porphyrins as well as texaphyrin and phthalocyanin complexes are also featuring in the development of new photodynamic and sonodynamic therapeutic modes. 

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]. 

Another approach has been tackled with by Sessler et al. [37, 38] who described gadolinium(III) complexes with texaphyrins as potential MRI contrast agents. When the expanded porphyrin ring is subtituted by water solubilizing groups (Fig. 5), the chelate is sufficiently water soluble to be injected. It is... 

Sessler, J.L. and Miller, R.A. (2000) Texaphyrins new drugs with diverse clinical applications in radiation and photodynamic therapy, Biochem. Pharmacol. 59, 733-739. 

TEXAPHYRIN CONJUGATES. PROGRESS TOWARDS SECOND GENERATION DIAGNOSTIC AND THERAPEUTIC AGENTS... 

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 preparation of the basic texaphyrin ring starts from the diformyl tripyrrane fragment 5 (Scheme 1), an intermediate that in ton is prepared in three steps from the simple monomeric pyrroles 3 and 4. 

---