The photochemistry and photobiology of rhodium(III) polypyridyl complexes and psoralen pro-drugs

Deborah Lee Terrian, Purdue University

Abstract

A "second generation" photoactive analog of cisplatin, cis-dichloro(1,10-phenanthroline)(9,10-phenanthrenequinone diimine) rhodium (III) chloride (PHIPHEN), was prepared and studied as a potential anti-tumor agent and virucide. The compound was prepared to improve upon a previously studied photoactivated complex, cis-dichlorobis(1,10-phenanthroline) rhodium (III) chloride (BISPHEN). PHIPHEN was found to covalently bind to calf thymus DNA upon irradiation. NO binding was observed in the absence of light. Comparable efficiencies for binding of PHIPHEN and BISPHEN to DNA were measured. K$\sb{\rm eq}$ for PHIPHEN and DNA was determined to be $\rm 3.7\times 10\sp4\ M\sp{-1}.$ In cell culture studies, liposomes were required to deliver BISPHEN into KB cells. However, even then BISPHEN was not very phototoxic. Intracellular incorporation of PHIPHEN occurred without the need for liposomes and led to substantial photosensitized cell killing (70-90% drug sensitized cell death). Typical drug concentrations (50 $\mu$g/mL) caused minimal cell death in the absence of light ($<$10%). In viral studies using bacteriophage $\phi$6, four logs of photosensitized virus inactivation were observed. Cell culture studies were also done on psoralen pro-drugs, (Z)-3-(5-(4,6-dimethoxy)benzofuranyl) propenoic acid (pre-5-MOP) and (Z)-3-(5-(6,7-dimethoxy)benzofuranyl) propenoic acid (pre-8-MOP). These compounds photocyclize to 5-methoxypsoralen (5-MOP) and 8-methoxypsoralen (8-MOP), respectively. Both pro-drugs were found to be phototoxic to KB cells, with pre-5-MOP the more effective of the two. The mechanism of the photocyclization was studied using aryl substituted cinnamic acids. A reaction involving photoinitiated intramolecular nucleophilic displacement best accommodates the data.

Degree

Ph.D.

Advisors

Morrison, Purdue University.

Subject Area

Biochemistry|Organic chemistry

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