Life science
Drug discovery, Functional material, Molecular imaging

Site-selective and multiple deuteration and application todrug discovery
Synthetic Medical Chemistry, Graduate School of Pharmaceutical Sciences
Associate Professor Yoshinari Sawama

https://researchmap.jp/sawama?lang=en

Professor Shuji Akai								https://researchmap.jp/shuji_akai?lang=en

英語バージョン
英語バージョン
英語バージョン

Life science

Abstract
Deuterium (D) is a non-radioactive and stable isotope of hydrogen (H). Deuterium-incorporated compounds have been widely utilized in various scientific application. We continuously developed
the deuteration methods of various organic compounds.
The phamacokinetics of pharmaceutical drugs can be improvedby replacing C-H bonds with more stable C-D bonds at the αposition of heteroatoms in the drugs, a typical metabolism site bycytochrome P450. However, the applicable deuterium-incorporated
synthetic synthons are crucially limited. We recently established thenovel concept to provide the breakthrough deuterated reagents,
which successfully realized to syntesize the complicated drug skeletons possessing deuterium atom at thier α-positions. dn-Alkyl diphenylsulfonium salts, prepared from the corresponding hydrogenforms using inexpensive and abundant D2O as a deuterium source
under basic conditions, played as electrophilic alkylating reagentsto enable the synthesis of various deuterated drugs.
Furthermore, PPh3 efficiently underwent the multiple deuteration at all aromatic C-H bonds using Ru/C and Ir/C co-catalysts in
2-PrOH and D2O. The Raman live-cell imaging of non-radioactive
and safe deuterium-incorporated Mito-Q, derived from deuterated
PPh3, was successfully accomplished.

▍ Background & Results
The replacement of C-H bonds with more stable C-D bonds at
metabolic sites of drugs can improve their phamacokinetics. The
commercially available d3-methyl sources (e.g., CD3OD) were frequently utilized for the syntheses of target materials including theapproved heavy drugs, deutetrabenazine and deucravacitinib.
Therefore, we recently developed the novel concept to prepare
breakthrough deuterium-incorporated reagents, i.e., dn-alkyl sulfonium salts, dn-alkyl halides and azide, and (d n-alkyl)amine, tointroduce dn-alkyl groups into drug candidates and such analogs,including the complicated skeletons.
On the other hand, Raman microscopy offers molecular imaging
of deuterated compounds in living cells using the specific signals ofmolecular stretching vibrations of C-D bonds, which are exhibitedin the cellular silent region (wavenumber range where Raman scattering of intracellular molecules such as proteins and lipids is notobserved). Namely, deuterium is functioned as an efficient tag oftarget material in Raman imaging analysis. However, numerous C-Dbonds in the target molecule are usually required due to the weak
Raman intensity of each C-D bond, which indicates the importanceto develop the direct and multiple H/D exchange reactions (deuteration) of a wide variety of organic compounds. Platinum group metal on carbon catalysts enabled the multiple deuteration of variousorganic compounds, including PPh3.

▍ Significance of the research and Future perspective
Although the utility of deuterated compounds is well recognized,
the difficulty in obtaining the desired deuterated substances isa problematic issue. We can synthesize various deuterated sub-stances using our original methods. We will promote their use invarious fields in the future.
Site-selective
deuteraton
Site-selective
Site-selectivedeuteraton
deuteraton

Fig. 1 Development of dn-alkyl reagents
Fig. 1 Developmentof dto
and application
drugreagents
discoveryn-alkyl
Fig. 1andDevelopmentofreagents
toddrug
discoveryn-alkylFig. 1 Developmentof application
dn-alkyl reagents
andapplication
to drug discovery
and application to drug discovery
Multiple deuteration
Multiple deuteration
Multiple deuteration

C-D bond’s signal
C-D bond’ssignal
Mito-Q-d15
C-D
bond’s signal
Mito-Q-d15

Mito-Q-d15

Green: 751 cm-1 Red: 2298 cm-1
Mito-Q-d15-12 mM
Cytochrome
Green:751 cm-1c Red: 2298 cm(mitochondriamarker)
Mito-Q-d15 2cmmM
Cytochrome-1
Green: 751ccm-1 Red: 2298
(mitochondriamarker)
Mito-Q-d 2 mM
CytochromecMerge（緑 + 赤）Merge（緑Merge+ 赤）Fig. 2 Live-cell Raman15imaging（緑 + 赤）Fig.
2 Live-cell
Raman
using
deuterium-tagdrugs
Fig.
2 Live-cell
Ramanimagingimaging
using deuterium-tagdrugs(mitochondria marker)

Fig. 2using
Live-cell
Raman imaging
deuterium-tagdrugs
using deuterium-tag drugs

Fig 3.
Synthetic
examplesof deuterated
Fig. 3 Synthetic
examplesof deuterated
compounds
using our original methods
Fig 3. Synthetic
examplescompounds
using ofourdeuterated
original methods
Fig 3.compounds
Synthetic examples
deuteratedusing ourof
original
methods
compounds using our original methods

P a t e n t
Tr e a t i s e

Akai, Shuji; Sawama, Yoshinari et al. Sulfonium salt reagents for introduction of deuterated alkyl groups in drug discovery. Angew. Chem. Int. Ed. 2023,
e202311058. doi: 10.1002/anie.202311058
Akai, Shuji; Sawama, Yoshinari et al. Multiple deuteration of triphenylphosphine and live-cell Raman imaging of deuterium-incorporated Mito-Q. Chem.
Commun. 2023, 59, 12100–12103. doi: 10.1039/D3CC04410F

URLK e y w o r d deuterium, heavy drug, organic chemistry, molecular imaging