Design, Synthesis and Evaluation of Prodigiosin Analogues as Chemotherapeutic Agents

We will investigate a new type of cancer treatment, based on a relatively unexplored structural scaffold of a naturally occurring molecule called prodigiosin. Prodigiosin was used in the USA from 1893 to 1963 as a (folklore) medicinal agent against various types of cancer. Under laboratory conditions prodigiosin shows excellent activity against cancer tissues, and lower affiliation for healthy tissue. However, the general toxicity of prodigiosin prevents its use as a modern drug for chemotherapy, and was the cause of its withdrawal from the therapeutic market by the Food and Drug Administration (FDA) in 1963. With previous financial support from CIHR more than thirty novel derivatives of prodigiosin were generated in Dr. Alison Thompson's chemistry research laboratory at Dalhousie University. This small library of prodigiosin derivatives generally retains the anti-cancer activity of prodigiosin itself, but exhibits significantly reduced toxicity (death) in healthy animals. This points to a differentiation between the way that "anti-cancer" and "toxicity/side-effects" are generated; a rare achievement. Furthermore, the derivatives show excellent stability (unlike prodigiosin), with respect to shelf-life. To create a chemotherapy drug using the prodigiosin backbone we need to increase its selectivity. The current proposal describes research efforts to enhance, and further understand, the effectiveness of chemotherapeutic agents based on the structural scaffold of prodigiosin. We will attach 'antenna' to the prodigiosin molecules, with the goal that the 'antenna' will guide the chemotherapy drug towards breast cancer sites, and away from healthy tissue. Ongoing collaborations with pathologists, biochemists, cancer biologists and with the National Cancer Institute (USA) will ensure that full evaluation of the compounds is achieved so that the research proceeds efficiently with minimum delay between synthesis, evaluation and potential medicinal advancement.