Kazunori Koide

Organic synthesis of natural products, new synthetic methods, and organic fluorescent sensors

Total Syntheses and Biological Studies of Natural Products

We are currently studying FR901464, a natural product that regulates cancer-related genes by novel mechanisms. This compound inhibits cancer proliferation at concentrations as low as 1 nM. To study FR901464, we completed a chemical total synthesis of this natural product. Combination of this powerful, stereocontrolled chemical synthesis and cell biology will provide insights into the molecular mechanisms of FR901464. More recently, we have developed an exceptionally active FR901464 analog (meayamycin) that inhibits tumor growth at 10 pM (analogouus to one pack of sugar (5 grams) at a coffee shop in 400 Olympic swimming pools).

Increased thermotolerance associated with tumors is a major problem in cancer radiotherapy and is mediated by heat shock proteins. Therefore, inhibitors of heat shock proteins are of great interest in medicine. Stresgenin B is a densely functionalized natural product that inhibits heat shock proteins. We have completed the total chemical synthesis of stresgenin B.

Development and Biological Applications of Fluorescent Probes

RNA - Systematic evolution of ligands by exponential enrichment (SELEX) allows for developing new RNA aptamers. Using this technique, we have developed a method to detect specific RNA by fluorescence.

Palladium - We combined the Tsuji-Trost reaction and a fluorogenic platform to create a catalysis-based fluorometric method to detect and quantify palladium at parts-per-billion levels (see the third box in the methodology section). The method has been implemented at pharmaceutical companies to expedite the drug production processes.

H₂O₂-We have developed a fluorogenic probe based on a Mislow-Evans rearrangement to detect endogenous hydrogen peroxide in live cells and a wound-healing zebrafish model in a spatiotemporal manner. Hydrogen peroxide is a critical intracellular molecule that mediates aging, tumor metastasis, tissue regeneration, inflammation, among others.

Platinum and Copper - Combinations of metals and ligands can exhibit unique reactivities. Using specific phosphines, we have developed catalysis-based fluorogenic probes for endogenous copper and exogenously added platinum (e.g., cisplatin, a widely used anticancer drug in the clinic).

New Synthetic Methods

1. We are developing a Birch reduction promoted by lithium and ethylenediamine in THF at ambient temperature. The method reduces arenes to form 1,4-cyclohexadienes. We are expanding the scope of the Birch reduction to synthesize previously inaccessible, increasingly functionalized organic molecules.
2. We developed a photo-induced radical reaction to add a formyl surrogate to electron-deficient alkenes.
3. Our highly selective and sensitive fluorometric method for palladium puts us in a unique position to study palladium catalysis, having led to identifying an exceptionally stable and active palladium pre-catalyst.