Anthony Rice: Palladium Biladiene Complexes Bearing Aryl Groups Through Organometallic Cross-Couplings for Sensitization of Singlet Oxygen and Photodynamic Cancer Therapy

Photodynamic therapy (PDT), which involves the photoinduced sensitization of singlet oxygen (1O2) is an attractive treatment for certain types of cancer. The development of new photochemotherapeutic agents remains an important area of research. Macrocyclic tetrapyrrole compounds including porphyrins, phthalocyanines, chlorins and bacteriochlorins have been pursued as sensitizers of singlet oxygen for PDT applications but historically are difficult to prepare/purify and can also suffer from high non-specific dark toxicity, poor solubility in biological media and/or slow clearance from biological tissues. In response to these shortcomings, we have developed a series of novel linear tetrapyrrole architectures complexed to late transition metals as potential PDT agents. We find that these dimethylbiladiene (DMBil1) tetrapyrrole complexes can efficiently photosensitize generation of 1O2 oxygen upon irradiation with visible light, when metalated with palladium (Pd[DMBil1]). To extend the absorption profile of the Pd[DMBil1] platform, alkynyl-aryl groups have been conjugated to the periphery of the tetrapyrrole using Sonogashira methods. Derivatives of this type containing ancillary phenyl (PdDMBil–PE), naphthyl (PdDMBil–NE) and anthracenyl (DMBil–AE) groups have been prepared and characterized. A second derivative was synthesized utilizing an anthracene bridge to link the two dipyrrin units of the biladiene framework (Pd[DMBil2-AE). A third suite of derivatives was prepared using Heck coupling to extend conjugation through alkenes, rather than alkynes, while also altering the electronics of the aryl system to affect the photochemical properties of the biladiene platform (Pd[DMBil3–R]). Extension of the tetrapyrroles conjugation successfully redshifts the absorption of the Pd[DMBilX–Ar] family of biladienes further into the phototherapeutic window (i.e., 650–850 nm), which is the spectral range that most deeply penetrates epithelial tissues. Photochemical sensitization studies demonstrate that our series of new palladium biladiene complexes (Pd[DMBilX–Ar]) can sensitize the formation of 1O2 with quantum yields ranging from FD = 0.01 – 0.94 upon irradiation with light of l > 600 nm. The improved absorption properties of the Pd[DMBilX–Ar] complexes in the phototherapeutic window, together with their high 1O2 quantum yields highlight the promise of these compounds as potential agents for PDT and other photomedicine applications.

Anthony Rice is a fifth-year graduate student working in Joel Rosenthal’s lab and pursuing a doctorate in chemistry. Rice is from New Jersey and attended Notre Dame High School and Susquehanna University for undergraduate studies. At Susquehanna, Rice received a B.S. in chemistry while also being a four-year letter recipient for the men’s lacrosse team. Between undergraduate and graduate school, he worked in industry for nine months as a lab technician for a bioanalytical lab in Princeton, New Jersey. Rice has been a TA at UD and is working on a project developing and modifying molecular candidates for photosensitizers for photodynamic cancer therapies. Additionally, he is an author of two manuscripts published in “Inorganic Chemistry” with a few more manuscripts currently submitted or in preparation. After graduation, he is looking to get back into industry working in pharmaceuticals and the “business of science” realm in industry.