Fluorescent molecules to illuminate life: Simplified synthesis with formaldehyde

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A research team has recently made a breakthrough in synthesizing organic fluorophores more cost-effectively and atom-efficiently than ever before by using formaldehyde, the simplest carbon molecule. Their findings were published in Angewandte Chemie International Edition on Sept. 18.

Organic fluorophores, known for their ability to fluoresce by absorbing specific wavelengths of light, are widely employed in medical diagnostics and bioimaging, including cancer cell tracking and genetic analysis. However, the synthesis of trimethine cyanine (Cy3), a commonly used organic fluorophore, has traditionally involved a complex compound with a high molecular weight, leading to numerous byproducts and low atom efficiency.

To address this issue, the team utilized formaldehyde (HCHO)—a simple molecule made up of one carbon (C) atom, two hydrogen (H) atoms, and one oxygen (O) atom. While formaldehyde can become toxic by reacting with proteins and DNA in vivo, it serves as a valuable tool in organic synthesis for forming new carbon-carbon bonds.

By using formaldehyde instead of conventional complex compounds to add carbon into the molecular chain, a critical step in Cy3 synthesis, the team significantly reduced the molecular size required for the process, maximizing atomic efficiency. Additionally, they streamlined the traditional multi-step asymmetric Cy3 synthesis into a one-pot reaction, eliminating extra stages and boosting synthetic efficiency.

The team also explored whether their technique could be applied to cells and tissues, considering that certain amounts of formaldehyde are naturally produced in vivo during metabolism. In their analysis of rat small intestine tissue, they observed that the inflammation-induced group exhibited a weaker fluorescence signal compared to the normal group. This was attributed to relatively lower levels of formaldehyde during inflammation, which limited Cy3 synthesis. These findings demonstrate that the team's method is applicable not only to in vitro synthesis but also to in vivo environments.

The team was led by Professor Young-Tae Chang from the Department of Chemistry at POSTECH and Dr. Sun Hyeok Lee from the Basic Science Research Institute of POSTECH.

Professor Young-Tae Chang said, "This marks the first successful synthesis of Cy3 molecules using formaldehyde. Our method is not only cost-effective and highly atom-efficient, but it can also be utilized in vivo, expanding the potential applications of organic fluorophores in life sciences research and diagnostics."

More information: Sun Hyeok Lee et al, Atom Efficient Synthesis of Trimethine Cyanines Using Formaldehyde as a Single Carbon Source, Angewandte Chemie International Edition (2024). DOI: 10.1002/anie.202413121

Journal information: Angewandte Chemie International Edition

Provided by Pohang University of Science and Technology