Expanded porphyrins as experimental anticancer agents and MRI contrast agents

Texaphyrins represent the vanguard of experimental anticancer drugs and also symbolize a well-known example of expanded porphyrins, a class of oligopyrrolic macrocycles with tumor localization properties and powerful metal chelating properties. Chapter 1 of this thesis describes the unique structural characteristics of this complex synthetic molecule along with the biological relevance and scientific justifications for studying its anticancer properties and powerful MRI contrast ability. This Chapter also serves to underscore the need to improve further and refine the efficacy of texaphyrins as compounds that may be applied in the struggle against cancer. Chapter 2 details the synthesis of bismuth(III) and lead(II)-texaphyrin complexes that could potentially find use as [alpha]-core emitters for radiotherapy. In principle, porphyrins would ostensibly appear to be ideal ligands for use in radiotherapy due to their tumor-localizing ability. However, Bi(III)- and Pb(II)-porphyrin complexes are extremely rare, most reflecting the vastly challenging synthesis of these compounds as well as their general lack of stability. These limitations provided an incentive for us to use texaphyrins as more versatile ligands to prepare and fully characterize stable bismuth(III) and lead(II) complexes. To be of interest in future medical applications, we needed to prepare these complexes quickly as compared to the relevant time scales set by the half-lives of the isotopes targeted for use in radiotherapy. This goal was successfully realized. As mentioned above, texaphyrin is able to form stable complexes with a large variety of metals particularly in the lanthanide series. Gadolinium(III) complexes of texaphyrin have been studied in considerable detail. Chapter 3 details the synthesis and conjugation methods used to develop a texaphyrin conjugated dual mode nanoparticle contrast agent. This project has been done in collaboration with the group of Prof. Jinwoo Cheon (Yonsei University, Seoul, Korea), who demonstrated fascinating results with the texaphyrin functionalized nanoparticles. Not only do these conjugates act as improved magnetic resonance contrast agents displaying enhanced signals in both the T1 and T2 MRI modes, but also serve to sensitize apoptotic hyperthermia. It is this latter, double effector feature, that has been most extensively studied to date. Chapter 4 of this dissertation describes work done in close collaboration with Dr. Natalie Barkey and Dr. David Morse (Moffitt Cancer Center, Tampa, FL) where a gadolinium texaphyrin complex was developed that is able to target the melanocortin 1 receptor (MC1R) when encapsulated in a micellar system. As detailed in this Chapter, these collaborateurs demonstrated that these gadolinium-texaphyrin micelles are able to target MC1R-expressing xenograft tumors in vivo. This work relied on the supply of a new set of texaphyrin derivatives that were prepared and characterized as part of this dissertation work Chapter 5 of this disseration introduces sapphyrins, another class of expanded porphyrins with tumor selectivity. This project is based on the hypothesis that a direct linkage of sapphyrin with an anticancer agent based on ruthenium(II) could improve the efficacy of both compounds. Since sapphyrins exhibit limited ability to form stable complexes with transition metals, an appended 1,10-phenanthroline unit was chosen as an efficient N-donor aromatic ligand for ruthenium(II). Therefore, extensive synthetic efforts were made to form this sapphyrin-1,10-phenanthroline construct in an effort to stabilize a mixed sapphyrin-metallo-phenanthroline complex. Finally, Chapter 6 of this dissertation demonstrates the author's efforts to synthesize a planar rosarin species. Non-aromatic and non-planar rosarins have been known for over two decades. Through structural modification of the compound, namely through linking of both [Beta] positions on the bipyrrole unit, a new planar rosarin species has been synthesized exhibiting Hückel antiaromaticity.