Direct Synthesis of α- and β-2'-Deoxynucleosides with Stereodirecting Phosphine Oxide via Remote Participation
2'-Deoxynucleosides and analogues play a vital role in drug development, but their preparation remains a significant challenge. Previous studies have focused on β-2'-deoxynucleosides with the natural β-configuration. In fact, their isomeric α-2'-deoxynucleosides also exhibit diverse bioactivities and even better metabolic stability. Herein, we report that both α- and β-2'-deoxynucleosides can be prepared with high yields and stereoselectivity using a remote directing diphenylphosphinoyl (DPP) group. It is particularly efficient to prepare α-2'-deoxynucleosides with an easily accessible 3,5-di-ODPP donor. Instead of acting as a H-bond acceptor on a 2-(diphenylphosphinoyl)acetyl (DPPA) group in our previous studies for syn-facial O-glycosylation, the phosphine oxide moiety here acts as a remote participating group to enable highly antifacial N-glycosylation. This proposed remote participation mechanism is supported by our first characterization of an important 1,5-briged P-heterobicyclic intermediate via variable-temperature NMR spectroscopy. Interestingly, antiproliferative assays led to a α-2'-deoxynucleoside with IC50 values in the low micromole range against central nervous system tumor cell lines SH-SY5Y and LN229, whereas its β-anomer exhibited no inhibition at 100 μM. Furthermore, the DPP group significantly enhanced the antitumor activities by 10 times.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:146 |
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| Enthalten in: |
Journal of the American Chemical Society - 146(2024), 12 vom: 27. März, Seite 8768-8779 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Tang, Xintong [VerfasserIn] |
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| Links: |
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| Themen: |
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| Anmerkungen: |
Date Completed 28.03.2024 Date Revised 28.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/jacs.4c01780 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM369730208 |
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| 520 | |a 2'-Deoxynucleosides and analogues play a vital role in drug development, but their preparation remains a significant challenge. Previous studies have focused on β-2'-deoxynucleosides with the natural β-configuration. In fact, their isomeric α-2'-deoxynucleosides also exhibit diverse bioactivities and even better metabolic stability. Herein, we report that both α- and β-2'-deoxynucleosides can be prepared with high yields and stereoselectivity using a remote directing diphenylphosphinoyl (DPP) group. It is particularly efficient to prepare α-2'-deoxynucleosides with an easily accessible 3,5-di-ODPP donor. Instead of acting as a H-bond acceptor on a 2-(diphenylphosphinoyl)acetyl (DPPA) group in our previous studies for syn-facial O-glycosylation, the phosphine oxide moiety here acts as a remote participating group to enable highly antifacial N-glycosylation. This proposed remote participation mechanism is supported by our first characterization of an important 1,5-briged P-heterobicyclic intermediate via variable-temperature NMR spectroscopy. Interestingly, antiproliferative assays led to a α-2'-deoxynucleoside with IC50 values in the low micromole range against central nervous system tumor cell lines SH-SY5Y and LN229, whereas its β-anomer exhibited no inhibition at 100 μM. Furthermore, the DPP group significantly enhanced the antitumor activities by 10 times | ||
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| 700 | 1 | |a Wang, Yingjie |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Yetong |e verfasserin |4 aut | |
| 700 | 1 | |a Pan, Shuheng |e verfasserin |4 aut | |
| 700 | 1 | |a Che, Qianwei |e verfasserin |4 aut | |
| 700 | 1 | |a Sang, Jinpeng |e verfasserin |4 aut | |
| 700 | 1 | |a Gao, Ziming |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Weiting |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Yuanyuan |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Guolong |e verfasserin |4 aut | |
| 700 | 1 | |a Gao, Longwei |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Zhimei |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Xudong |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Ao |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Suyu |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Biao |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Peng |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Zhe |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Zhaolun |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Peng |e verfasserin |4 aut | |
| 700 | 1 | |a Xie, Weijia |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Haopeng |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Wei |e verfasserin |4 aut | |
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