Selenium Atom-Polarization Effect Determines TrxR-Specific Recognition of Metallodrugs
Thioredoxin reductase (TrxR) is highly overexpressed in cancer cells to promote malignant tumor survival. Designing drugs that inhibit TrxR activity is a promising approach to achieve highly effective cancer chemotherapy. However, the selectivity of TrxR inhibitors continue to be a challenge for scientists. In this work, we demonstrate a new strategy to selectively inhibit TrxR through constructing electrophilic center -N-Se(δ+)-N- by using the polarization effect of the selenium atom. The constructed electrophilic center interacts noncovalently with the active motif of TrxR to avoid the interference of other residues in human tissues, thereby selectively inhibiting intracellular TrxR activity. Computational and experimental analysis confirms that the formed electrophilic selenium center preferred to attack the SeC residues in the redox active center of TrxR at the 498 site through strong noncovalent interactions. Both in vitro and in vivo experimental results confirmed that this strategy can significantly improve the anticancer effect. This study may provide a novel route to design highly effective and selective chemotherapeutic drugs.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2022 |
|---|---|
| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:144 |
|---|---|
| Enthalten in: |
Journal of the American Chemical Society - 144(2022), 45 vom: 16. Nov., Seite 20825-20833 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Chen, Mingkai [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Antioxidants |
|---|
| Anmerkungen: |
Date Completed 18.11.2022 Date Revised 01.12.2022 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1021/jacs.2c08802 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM348326637 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM348326637 | ||
| 003 | DE-627 | ||
| 005 | 20231226035918.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2022 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1021/jacs.2c08802 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1161.xml |
| 035 | |a (DE-627)NLM348326637 | ||
| 035 | |a (NLM)36318653 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Chen, Mingkai |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Selenium Atom-Polarization Effect Determines TrxR-Specific Recognition of Metallodrugs |
| 264 | 1 | |c 2022 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 18.11.2022 | ||
| 500 | |a Date Revised 01.12.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Thioredoxin reductase (TrxR) is highly overexpressed in cancer cells to promote malignant tumor survival. Designing drugs that inhibit TrxR activity is a promising approach to achieve highly effective cancer chemotherapy. However, the selectivity of TrxR inhibitors continue to be a challenge for scientists. In this work, we demonstrate a new strategy to selectively inhibit TrxR through constructing electrophilic center -N-Se(δ+)-N- by using the polarization effect of the selenium atom. The constructed electrophilic center interacts noncovalently with the active motif of TrxR to avoid the interference of other residues in human tissues, thereby selectively inhibiting intracellular TrxR activity. Computational and experimental analysis confirms that the formed electrophilic selenium center preferred to attack the SeC residues in the redox active center of TrxR at the 498 site through strong noncovalent interactions. Both in vitro and in vivo experimental results confirmed that this strategy can significantly improve the anticancer effect. This study may provide a novel route to design highly effective and selective chemotherapeutic drugs | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Thioredoxin-Disulfide Reductase |2 NLM | |
| 650 | 7 | |a EC 1.8.1.9 |2 NLM | |
| 650 | 7 | |a Selenium |2 NLM | |
| 650 | 7 | |a H6241UJ22B |2 NLM | |
| 650 | 7 | |a Antioxidants |2 NLM | |
| 700 | 1 | |a Cao, Wenqiang |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Junping |e verfasserin |4 aut | |
| 700 | 1 | |a Cai, Fei |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Liwen |e verfasserin |4 aut | |
| 700 | 1 | |a Ma, Li |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Tianfeng |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Journal of the American Chemical Society |d 1945 |g 144(2022), 45 vom: 16. Nov., Seite 20825-20833 |w (DE-627)NLM00000569X |x 1520-5126 |7 nnns |
| 773 | 1 | 8 | |g volume:144 |g year:2022 |g number:45 |g day:16 |g month:11 |g pages:20825-20833 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1021/jacs.2c08802 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 144 |j 2022 |e 45 |b 16 |c 11 |h 20825-20833 | ||