Towards the Rational Design of Photoinduced Electron Transfer (PET)-based Fluorescent Probes

Fluorescent probes act as valuable chemical tools to detect a variety of substances with exceptional sensitivity and selectivity. One desired property of an effective fluorescent probe is that it acts via a “turn-on” mechanism, in which fluorescence intensity increases upon interaction with the desired analyte. Photoinduced electron transfer (PET) is one of the many mechanisms that is used to modulate photophysical properties of fluorescent probes. In this mechanism, the fluorogenic probes are equipped with a motif that can suppress fluorescence. These probes can undergo a transformation upon interaction with a target molecule that restricts that moiety from quenching the fluorescence, resulting in a fluorescence enhancement. Various probes containing pendant aryl quenching moieties that undergo photoinduced electron transfer have been reported to have a direct correlation between the experimentally determined quantum yield of the probe and the highest occupied molecular orbital (EHOMO) of the corresponding PET quenching moiety. However, the systematic investigation of the relationship between PET-quenching and moieties other than aryl rings has been underdeveloped. By changing the electronics of heteroatom quenching moieties, systematic studies of factors which affect PET for common fluorophores, including coumarin based systems, can be reported. Through the synthesis of 7-MeO-coumarin probes with various quencher functionality, there exists a correlation between the quantum yield of these probes and the molecular orbital energy of the quenching moiety. This study aims to provide the scientific community with tools to design heteroatom PET-based fluorescent sensors a priori

Toward the Rational Design of Photo-induced Electron Transfer (PET)-Based Fluorescent Probes

Small molecule fluorescent probes are commonly used in imaging applications and sensors including detecting environmental analytes or elucidating biological phenomena. Many of these compounds function via a change in brightness occurring through photoinduced electron transfer (PeT). Although this concept is well understood, PeT-based probes are almost entirely developed via empirical methods. The current project focuses on synthesizing a series of naphthalene and coumarin-based fluorescent probes bearing carefully altered quenching moieties. The photophysical properties of these molecules will then be determined. Ultimately, this systematic investigation of structure-optical property relationship aims to provide the scientific community with a more rational means for creating these useful chemical tools

Functional dominance of CHIP-mutated hematopoietic stem cells in patients undergoing autologous transplantation

Clonal hematopoiesis of indeterminate potential (CHIP) is caused by recurrent somatic mutations leading to clonal blood cell expansion. However, direct evidence of the fitness of CHIP-mutated human hematopoietic stem cells (HSCs) in blood reconstitution is lacking. Because myeloablative treatment and transplantation enforce stress on HSCs, we followed 81 patients with solid tumors or lymphoid diseases undergoing autologous stem cell transplantation (ASCT) for the development of CHIP. We found a high incidence of CHIP (22%) after ASCT with a high mean variant allele frequency (VAF) of 10.7%. Most mutations were already present in the graft, albeit at lower VAFs, demonstrating a selective reconstitution advantage of mutated HSCs after ASCT. However, patients with CHIP mutations in DNA-damage response genes showed delayed neutrophil reconstitution. Thus, CHIP-mutated stem and progenitor cells largely gain on clone size upon ASCT-related blood reconstitution, leading to an increased future risk of CHIP-associated complications