Sulfonium Salt Reagents for the Introduction of Deuterated Alkyl Groups in Drug Discovery |
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Authors: | Kazuho Ban Keisuke Imai Shuki Oyama Jin Tokunaga Yui Ikeda Dr Hiromasa Uchiyama Dr Kazunori Kadota Prof Dr Yuichi Tozuka Prof Dr Shuji Akai Dr Yoshinari Sawama |
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Institution: | 1. Graduate School of Pharmaceutical Sciences, Osaka University, 1-6, Yamada-oka, Suita, Osaka, 565-0871 Japan;2. Department of Formulation Design and Pharmaceutical Technology, Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094 Japan |
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Abstract: | The pharmacokinetics of pharmaceutical drugs can be improved by replacing C−H bonds with the more stable C−D bonds at the α-position to heteroatoms, which is a typical metabolic site for cytochrome P450 enzymes. However, the application of deuterated synthons is limited. Herein, we established a novel concept for preparing deuterated reagents for the successful synthesis of complex drug skeletons with deuterium atoms at the α-position to heteroatoms. (dn-Alkyl)diphenylsulfonium salts prepared from the corresponding nondeuterated forms using inexpensive and abundant D2O as the deuterium source with a base, were used as electrophilic alkylating reagents. Additionally, these deuterated sulfonium salts were efficiently transformed into dn-alkyl halides and a dn-alkyl azide as coupling reagents and a dn-alkyl amine as a nucleophile. Furthermore, liver microsomal metabolism studies revealed deuterium kinetic isotope effects (KIE) in 7-(d2-ethoxy)flavone. The present concept for the synthesis of deuterated reagents and the first demonstration of a KIE in a d2-ethoxy group will contribute to drug discovery research based on deuterium chemistry. |
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Keywords: | Alkylation Deuteration Heavy Drugs Kinetic Isotope Effect Sulfonium Salts |
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