Harnessing endogenous carbon monoxide for cancer-selective drug synthesis

Abstract

Synthetic chemistry within living systems offers a transformative strategy for precision medicine by enabling the targeted generation of therapeutic agents directly at disease sites. Carbon monoxide (CO), an endogenous gasotransmitter upregulated in many cancer phenotypes, represents a unique yet underexploited chemical feedstock for such intracellular synthesis. However, the intrinsically low reactivity of CO necessitates transition-metal mediation, which is typically compromised by rapid deactivation by intracellular thiols such as glutathione (GSH). Here, we present a biocompatible albumin-palladacycle complex (APC) platform that harnesses endogenous CO for two distinct functions: the detection of CO levels and the in situ synthesis of cytotoxic phenanthridinone derivatives—a privileged scaffold found in potent poly(ADP-ribose) polymerase (PARP) and topoisomerase inhibitors. Central to this design is a coumarin anchor that directs the palladium center into the hydrophobic binding pocket of albumin, shielding it from thiol-mediated poisoning while facilitating cellular uptake via endocytosis. We demonstrate that this system effectively detects elevated CO in cancer cells and, in a parallel application, enables the in situ synthesis of pharmacologically active agents. Although the associated cytotoxicity is modest, the approach nonetheless suppresses cancer cell growth. This study considerably advances the proof of concept for “therapeutic in vivo synthetic chemistry,” in which disease-associated metabolites are repurposed as structural building blocks for both diagnostic and therapeutic applications. Carbon monoxide (CO), an endogenous gasotransmitter upregulated in many cancer phenotypes, represents a unique yet underexploited chemical feedstock for intracellular drug synthesis. Here, the authors present a biocompatible albumin palladacycle complex platform that harnesses endogenous CO for two distinct functions: the detection of CO levels and the in-situ synthesis of cytotoxic phenanthridinone derivatives containing scaffolds found in poly(ADP-ribose) polymerase and topoisomerase inhibitors.