The design and synthesis of novel chalcogenopyrylium dyes for use as therapeutic sensitizers in photodynamic therapy

Photodynamic Therapy (PDT) has recently been developed as a chemotherapeutic treatment for cancer. PDT has been used in the treatment of cancers such as lung, bladder, esophageal, gastric and colon cancers. PDT employs a drug, known as a photosensitizer, which upon activation by light undergoes a chemical reaction that produces a cytotoxic agent in the tumor cell. The ideal photosensitizers for PDT are able to localize in and around the tumor mass, and are non-toxic to normal cells. Light activation must occur at wavelengths greater than 600 nm where light penetration into tissue is optimal. The ideal photosensitizer must be chemically efficient at producing the cytotoxic agent, allowing selective destruction of the tumor tissue, while leaving normal tissue intact. The objective of this dissertation is to design and synthesize novel clinical agents that will be useful as sensitizers for PDT. The sensitizers prepared are closely related in structure to lipophilic cationic dyes already tested for use in PDT; AA1 and Rhodamine 123. Although these dyes have been examined as sensitizers for PDT, they absorb light at wavelengths that are too short for optimal tissue penetration and are inefficient at producing cytotoxic agents. Our goal is to provide heavy atom analogs of these dyes by replacing oxygen or sulfur atoms with selenium and or tellurium. Introduction of heavy atoms increases the absorption wavelengths of the photosensitizers and the quantum yields for the generation of the cytotoxic agent singlet oxygen. Physical properties of the dyes were determined and promising candidates were tested in vitro against carcinoma cell lines. Structural modification of substituents increased water solubility and cellular uptake. Preparation of selenium and tellurium analogs of AA1 produced photosensitizers that are better suited for PDT.