Research

Based on a high degree of intellectual curiosity, the Iwabuchi Laboratory conducts research on the synthetic organic chemistry of fine chemicals to advance pharmaceutical sciences.
An important molecular function in pharmaceutical sciences is biological activity. Therefore, the Iwabuchi Laboratory investigates the synthesis of bioactive compounds (mainly natural products) as the main subject. We are also developing catalytic reactions that enable efficient synthesis of bioactive compounds and pharmaceuticals, and chemical biology research through the creation of molecular tools to clarify the mechanisms of activity of bioactive compounds and pharmaceuticals.
In catalytic reaction development, we are particularly interested in asymmetric catalysis. Precise control of the reaction space with original molecules is our important philosophy for this purpose. In the development of molecular tools, we aim to elucidate not only where and how compounds act, but also their changes over time (temporal control). To achieve these highly challenging spatial and temporal controls, we utilize not only experimental chemistry but also computational chemistry to efficiently carry out our research.

Development of Highly Selective Organic Synthesis Methodologies

東北大学大学院薬学研究科
分子制御化学講座 合成制御化学分野

Development of Highly Selective Organic Synthesis Methodologies

Many organic molecules with pharmaceutical functions have complex structures, and their synthesis requires the rational sequence of multi-step chemical reactions. With the help of numerous synthetic methodologies and reactants developed by predecessors, synthetic organic chemistry has made significant progress since the latter half of the last century, resulting in the development of excellent pharmaceuticals and the saving of many lives.
With the advancement of synthetic organic chemistry, the structures of pharmaceutical molecules have become more complex year by year, and the efficacy of pharmaceuticals has also improved remarkably. However, there are some diseases for which the development of effective drug therapies is still desperately needed. In order to synthesize the required organic molecules more precisely, rapidly, and elegantly, further development in synthetic organic chemistry is desirable.
In our laboratory, we are conducting research for the development of organic synthetic methods to support the synthesis of complex pharmaceutical molecules, based on the keywords of "molecular catalysis," "redox control," and "asymmetric synthesis."

  • ・Organocatalytic oxidation reactions
  • ・Oxidative molecular transformations using organocatalyst-metal hybrid catalysts
    →Chemoselective aerobic alcohol oxidation using nitroxyl radical/copper catalysis
    →Oxidative phenol coupling using nitroxyl radical/chromium catalysis
  • ・Asymmetric construction of nitrogen-containing tetrasubstituted carbon centers using chiral Rh(II) catalysis

Stereocontrolled Synthesis of Bioactive Natural Products

東北大学大学院薬学研究科
分子制御化学講座 合成制御化学分野

Stereocontrolled Synthesis of Bioactive Natural Products

In nature, there exist many organic compounds with complex structures and unique biological activities that are beyond human knowledge. Most of these compounds are produced by organisms that live in a world not directly related to humans, but as history has shown, these natural products are an irreplaceable resource that elucidates the mysteries of life phenomena and provides profound insights into drug discovery research.
In this laboratory, we conduct basic research to contribute to drug discovery by developing efficient synthetic methods for novel bioactive natural products with complex structures that are obtained on a small scale from nature, and by providing samples that enable detailed biological studies.

  • Synthesized natural products and pharmaceuticals (scince 2010)
  • ・Cytotrienin A (Angew. Chem. Int. Ed. 2023, e202303140, )
  • ・Rumphellclovane E (Org. Lett. 2022, 24, 7572)
  • ・(+)-Nemonapride (Chem. Pharm. Bull. 2017, 65, 22-24)
  • ・Heronamides A-C (Chem. Eur. J. 2016, 22, 8586-8595)
  • ・FD-891 (J. Antibiot 2016, 69, 287-293)
  • ・Turkiyenine (Proposed Structure) (Eur. J. Org. Chem 2016, , 270-273)
  • ・Irciniastatins A (Psymberin) and B (J. Org. Chem 2015, 80, 12333-12350)
  • ・(+)-Dubiusamine A (Org. Lett 2013, 15, 1788-1790)
  • ・Sundiversifolide (formal synthesis) (Org. Lett 2011, 13, 3620-3623)
  • ・Scabronine G (Org. Lett 2011, 13, 2864-2867)

Medicinal Chemistry based on precise functionalization of caged hydrocarbons

東北大学大学院薬学研究科
分子制御化学講座 合成制御化学分野

Medicinal Chemistry based on precise functionalization of caged hydrocarbons

Caged hydrocarbons have fascinated organic chemist with its structural elegance and wide range of studies have been conducted for a long time. These molecules generally have rigid and three-dimensional structure, therefore unique molecules in which position and direction of functional groups are defined can be obtained by precise functionalization. This feature would be advantageous for molecular design of medicines, which require appropriate interaction with biomolecules such as proteins.
Based on this consideration, our group perform research aimed to apply these molecules to medicinal chemistry. We focus two intriguing caged hydrocarbons, adamantane and cubane. We are tackling to expand a three-dimensional “chemical space” by development of methodology for functionalization and derivatization of these caged hydrocarbons.

<Adamantane: “A diamond in the rough” in medicine>
Adamantane, which is named from “diamond” (“adamas” in Greek) has a high stability and unique structure and its application to material and polymer sciences have been studied. This hydrocarbon also appears in medicine, such as amantadine (anti-influenza virus) and vildagliptin (anti-diabetes).
Our study focuses on development of synthetic methodology for concise access to various adamantane derivatives. For example, we have developed a novel method for chiral modification of adamantane (Tetrahedron Lett. 2002, 43, 4145.) and synthesis of various 1-aminoadamantane derivatives (Synthesis 2018, 50, 1820.). We are currently carrying out a drug discovery with these unique adamantane derivatives.

<Cubane: The die is cast to “escape from flatland”>
Cubane is one of the most unique caged hydrocarbons in the world. This cubic molecule was synthesized by Professor Eaton in 1964. Initial studies of this highly strained compound were focused on investigation of its unique physical properties and application of energetic materials. Recently, its medicinal uses as a “bioisostere of benzene ring” (this hypothesis was proposed by Professor Eaton) have been investigated. However, such studies are still limited due to difficulty of functionalization of cubane C–H bond.
We have recently developed a Pd-catalyzed C–H acetoxylation of cubane and showed that it can be applicable to a synthesis of cubane analogs of pharmaceutically relevant molecular scaffolds (Org. Lett. 2021, 23, 8717.). We now conduct the expansion of this methodology into introduction of various functional groups and its application to the synthesis of cubane-containing molecules. We believe this would provide a new principle of drug design in the field of medicinal chemistry.

Target identification and mechanism of action studies using chemically functionalized molecules

東北大学大学院薬学研究科
分子制御化学講座 合成制御化学分野

Target identification and mechanism of action studies using chemically functionalized molecules

Bioactive compounds exhibit biological activities against an organism by inhibiting or enhancing the functions of each target biomolecules. Depending on whether their pharmacological activities are beneficial or toxic, bioactive molecules are used as either medicines or poisons. Therefore, the target identification and mechanistic study for bioactive compounds are important issues in medical and pharmaceutical sciences.

In this direction, we develop and use functionalized molecules having "units that can be used for functional analysis and control" of bioactive compounds through chemical modifications.

“Biotin (upper left)” is a unit for target identifications. Using this unit, we have identified the target of TK-285 (Biochem. Pharmacol. 2021, 194, 114819). “Glutathione (upper right)” enhances the dissolution of poorly water-soluble compounds. We have developed a glutathione adduct, GO-Y140, as a prodrug for an anti-cancer curcumin analog, GO-Y030 (Org. Biomol. Chem. 2016, 14, 10683). Compounds having “alkyne-tag (bottom left)” can be specifically imaged in live cells by Raman microscopy. Bioactive molecules conjugated with "pomalidomide" (bottom right figure) induce degradation of their target proteins via the ubiquitin-proteasome system.

In addition to the above four examples, the development of new functionalized molecules and the analysis of biofunctions thereof is the subject of ongoing research in our laboratory.