Department of Chemistry

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Kazunori Koide

Professor

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1201 CHVRN
Chevron Science Center
219 Parkman Avenue

Pittsburgh, PA 15260
412-624-8767

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Research Overview

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. 

 

Awards

  • Merck Technology Collaboration Award (2014)
  • University of Pittsburgh Chancellor's Distinguished Research Award, 2009
  • University of Pittsburgh Innovator Award, 2008
  • Thieme Chemistry Journals Award, 2007
  • Merck Fellow of the Cancer Research Fund of the Damon Runyon-Walter Winchell Foundation, 1998-2000
  • Naito Foundation Fellowship, 1991-1992
  • University of Pittsburgh Innovator Award 2019

Publications

“Fluorometric study on the amine-catalysed Suzuki-Miyaura coupling,” Vinod, J.; Wanner, A.; James, E.; Koide, K. Nature Catalysis 2021, 4, 999-1001
“Scalable Birch reduction with lithium and ethylenediamine in tetrahydrofuran,” Burrows, J.; Kamo, S.; Koide, K. Science 2021, 374, 741-764
“Catalysis-Based Fluorometric Method for Trace Palladium Detection with Improved Convenience,” Williams, J. M.; Wanner, A. K.; Koide, K.  Org. Process Res. Dev. 2020, 24, 2941-2949
“Using Ligand-Accelerated Catalysis to Repurpose Fluorogenic Reactions for Platinum or Copper,” Pham.D; Deter.C.J; Reinard. M.C; Gibson. G.A.; Kiselyov. K.; Yu.W.; Sandulache. V.C.; St. Croix. C.M.; Kazunori. K. ACS Cent Sci 2020, 6, 1772-1788
“Fluorogenic Probe Using a Mislow‐Evans Rearrangement for Real‐Time Imaging of Hydrogen Peroxide,” Pham, D.; Basu, U.; Pohorilets, I.; St. Croix, C.; Watkins, S. C.; Koide, K. Angew. Chem. Int. Ed. 2020, 59, 17435-17441
“Total Synthesis of Meayamycin B,” Bressin, R. K.; Osman, S.; Pohorilets, I.; Basu, U.; & Koide, K. J. Org. Chem. 2020, 85, 4637-4647
“Methyl Scanning and Revised Binding Mode of 2-Pralidoxime, an Antidote for Nerve Agent Poisoning,” Gambino, A., Burnett, J. C., & Koide, K.  ACS Med. Chem. Lett. 2020, 11, 1893-1898
“Third-Generation Method for High-Throughput Quantification of Trace Palladium by Color or Fluorescence,” Lukomski, L., Pohorilets, I., & Koide, K. Org. Process Res. Dev. 2020, 24, 85-95
“Kinetic and Inverse Temperature Dependence of a Tsuji-Trost Reaction in Aqueous Buffer,” Pohorilets, I., Tracey, M. P., LeClaire, M. J., Moore, E. M., Lu, G., Liu, P., & Koide, K ACS Catal. 2019, 9, 11720
“Scalable Preparations of Methylated Ando-Type Horner-Wadsworth-Emmons Reagent,” Bressin, R. K., Driscoll, J. L., Wang, Y., & Koide, K. Org. Process Res. Dev. 2019, 23, 274-277
“Non-effervescent method for catalysis-based palladium detection with color or fluorescence,” Nieberding, M.; Tracey, M.P.; Koide, K. ACS Sens. 2017, 2, 1737-1743
“Synthesis of violaceic acid and related compounds through aryl triazene,” Ando, S.; Burrows, J.; Koide, K. Org. Lett. 2017, 19, 1116-1119
“Online sensing of palladium in flowing streams,” Bu, X. D.; Williams, M.; Jo, J.; Koide, K.; Welch, C. J. Chem. Commun. 2017, 53, 720-723
“A competitive and reversible deactivation approach to catalysis-based quantitative assays,” Koide, K.; Tracey, M. P.; Bu, X.; Jo, J.; Williams, M. J.; Welch, C. J. Nat. Commun. 2016, 7, Article Number 10691
“The SF3B1 inhibitor spliceostatin A (SSA) elicits apoptosis in Chronic Lymphocytic Leukemia cells through downregulation of Mcl-1,” Larrayoz, M.; Blakemore, S. J.; Dobson, R. C.; Blunt, M. D.; Rose-Zerilli, M. J.; Walewska, R.; Duncombe, A.; Oscier, D.; Koide, K.; Forconi, F.; Packham, G.; Yoshida, M.; Cragg, M. S.; Strefford, J. C.; Steele, A. J. Leukemia 2016, 30, 351–360
“Fluorometric imaging methods for palladium and platinum and the use of palladium for imaging biomolecules,” Tracey, M. P.; Pham, D.; Koide, K. Chem. Soc. Rev. 2015, 44, 4769–4791
“An siRNA screen identifies the U2 snRNP spliceosome as a host restriction factor for recombinant adeno-associated viruses,” Schreiber, C. A.; Sakuma, T.; Izumiya, Y.; Holditch, S. J.; Hickey, R. D.; Bressin, R. K.; Basu, U.; Koide, K.; Asokan, A.; Ikeda, Y. PLoS Pathog. 2015, 11, e1005082
“Time-insensitive fluorescent sensor for human serum albumin and its unusual red shift,” Smith, S. E.; Williams, J. M.; Ando, S.; Koide, K. Anal. Chem. 2014, 86, 2332–2336
“Palladium detection technologies for active pharmaceutical ingredients via cross-coupling,” Koide, K. Recent Trends in Cross Couplings; Colacot T. Ed. 2014
“Regulation of HPV16 E6 and MCL1 by SF3B1 inhibitor in head and neck cancer cells,” Gao, Y.; Trivedi, S.; Ferris, R. L., Koide, K. Sci. Rep. 2014, 4, 6098
“Chemical perturbation of Mcl-1 pre-mRNA splicing to induce apoptosis in cancer cells,” Gao, Y.; Koide, K., ACS Chem. Biol. 2013, 8, 895–900
“A high throughput method to detect palladium in ores,” Williams, J. M.; Koide, K. Ind. Eng. Chem. Res. 2013, 52, 8612–8615
“Rapid analysis of residual palladium in pharmaceutical development using a catalysis-based fluorometric method,” Bu, X., Koide, K., Carder, E.J., and Welch, C.J. Org. Process Res. Dev. 2013, 17, 108-113
“Comparison of splicing factor 3b inhibitors in human cells,” Gao, Y., Vogt, A., Forsyth, J., and Koide, K. ChemBioChem 2013, 14, 49-52
“SF3B1 haploinsufficiency leads to formation of ring sideroblasts in myelodysplastic syndromes,” Visconte, V., Rogers, H.J., Singh, J., Barnard, J., Bupathi, M., Traina, F., McMahon, J., Makishima, H., Szpurka, A., Jankowska A., Jerez, A., Sekeres, M.A., Saunthararajah, Y., Advani, A.S., Copelan, E., Koseki, H., Isono, K., Padgett, R.A., Osman, S., Koide, K., O'Keefe, C., Maciejewski, J.P., and Tiu, R.V. Blood 2012, 120, 3173-3186
“Diastereoselective synthesis of diketopiperazine bis-α,β-epoxides,” Ando, S., Grote, A. L., and Koide, K. J. Org. Chem. 2011, 76, 1155-1158
“Structural requirements for the antiproliferative activity of pre-mRNA splicing inhibitor FR901464,” Osman, S., Albert, B. J., Wang, Y., Li, M., Czaicki, N. L., Koide, K. Chem.-Eur. J. 2011, 17, 895–904
“Meayamycin inhibits pre-mRNA splicing and exhibits picomolar activity against multidrug resistant cells,” B. J. Albert, P. A. McPherson, K. O'Brien, N. L. Czaicki, V. DeStefino, S. Osman, M. Li, B. W. Day, P. J. Grabowski, M. Moore, A. Vogt, K. Koide Mol. Cancer Ther. 2009, 8, 2308-2318
“Specific fluorogenic probes for ozone in biological and atmospheric samples,” A. L. Garner, C. M. St. Croix, B. R. Pitt, G. D. Leikauf, S. Ando, and K. Koide Nature Chem. 2009, 1, 316-321