Coelenterazine Derivatives as Potential Drugs for Photodynamic Therapy ^†

Abstract

Cancer is one of the main leading causes of death worldwide, and its treatment is highly complex and known to cause serious side effects for patients. Photodynamic therapy (PDT) has gained a worldwide impact as a promising alternative strategy to overcome or minimize these potential side effects observed in conventional therapeutical approaches. This therapy is a minimally invasive treatment that combines a photosensitizer (PS), visible light, and molecular oxygen (³O₂). When excited, the PS interacts with ³O₂ to generate reactive oxygen species (ROS), mainly as singlet oxygen (¹O₂) which, in turn, induces cytotoxic effects in cancer cells. In a recent study led by our research group, coelenterazine (Clz) analogues have shown relevant cell-selective toxicity in different cancer cell lines, such as breast, liver, prostate, and neuroblastoma, without cytotoxic effects in the corresponding non-tumoral cells. Based on these results, this work aims to synthesize a new series of Clz-inspired PS derived from pyrazine scaffold, a common precursor for the synthesis of Clz and its structure-related analogues. Herein, we describe some methodological approaches for the synthesis of pyrazine-based precursors with high chemical yields and their chemical characterization for the assembly of Clz analogues. Currently, these compounds are being studied for the assembly of new PS with potential application for PDT.