Photochemistry of ruthenium(II) complexes for use as photodynamic therapy agents

摘要

Cisplatin, cis-Pt(NH3)2Cl 2, is a widely used and very effect antitumor agent. Upon entering a cell it exchanges the two chloride ligands for water. This active species then binds DNA leading to cell death. Even though this drug is very successful, it has severe side effects, mainly due to its low selectivity for cancer cells and the thermal activation. Compounds that are activated by light, a field known a photodynamic therapy (PDT), is able to address some of these issues. Therefore, complexes that undergo light induced ligand exchange with water, in a manner similar to the thermal exchange of cisplatin, may be useful as PDT agents.;In chapter 3 a series of complexes [Ru(bpy)2(L)]2+ , where bpy = 2,2'-bipyridine and L = 3,6-dithiaoctane (bete, 3.1), 1,2-bis(phenylthio)ethane (bpte, 3.2), ethylenediamine (en, 3.3), and 1,2-dianilinoethane (dae, 3.4), were synthesized and their photochemistry was investigated. Photolysis experiments show that the bisthioether complexes are more easily photosubstituted than the diammine complexes. Electronic structure calculations show that the bisthioether complexes have greater bond elongation in the optimized excited state geometry, attributed to Ru--S pi-bonding character of the highest occupied molecular orbitals (HOMO), which is not present in the diammine complexes. The more efficient photoinduced ligand exchange of the complexes possessing thioether ligands results in binding of 3.1 and 3.2 to DNA upon irradiation.;The cation cis-[Ru(bpy)2(5CNU)2] 2+ (5CNU = 5-cyanouracil, 4.1) was synthesized and investigated for use as a potential dual-action photodynamic therapy agent. The complex undergoes efficient photoinduced 5CNU ligand exchange for solvent water molecules, thus simultaneously releasing biologically active 5CNU and generating [Ru(bpy) 2(H2O)2]2+. Since irradiation of the complexes in the PDT window of 600 -- 850 nm light is of importance, Chapter 5 focuses on at the complexes [Ru(tpy)(CH3CN)3] 2+ (5.1), [Ru(tpy)(CH3CN)2Cl] + (5.2), and [Ru(tpy)(5CNU)3] + (5.3), where tpy = 2,2':6',2''-terpyridine. The increase pi-conjugation and decrease symmetry produced by the tpy results in a red shift of the 1MLCT absorption. Complexes 5.1 -- 5.3 exhibit photointiated binding to DNA when irradiated with lambdairr > 395 nm light, as well as 5CNU dissociation. Notably, 5.2 is able to bind DNA when irradiated with lambda irr > 645 nm, well within the PDT window.;A novel method for caging protease inhibitors is described in chapter 6. The complex [Ru(bpy)2(6.1)2](PF6) 2 (6.2) was prepared from the nitrile-based peptidomimetic inhibitor Ac-Phe-NHCH2CN (6.1). Complex 6.2 shows excellent stability in aqueous solution in the dark and fast release of 6.1 upon irradiation with visible light. Due to binding to the Ru(II) center, 6.1 does not act as an inhibitor in complex 6.2. However, when 6.2 is irradiated, it releases 6.1 that inhibits the cysteine proteases papain and cathepsins B, K and L, up to two times more potently than 6.1 alone. Ratios for IC50 values for 6.2 range from 6:1 to 33:1 under dark vs. light conditions, against isolated enzymes and in human cell lysates, confirming a high level of photoinduced enzyme inhibition is obtained with this method.