Design, Synthesis, and Molecular Docking Study of Novel 3-Cyanopyridine Derivatives for the Anti-Cancer Drug Target Survivin Protein
Copyright© Bentham Science Publishers; For any queries, please email at epubbenthamscience.net..
Survivin is an important member of the antiapoptotic protein family and controls the cell's life cycle. Overexpression of survivin in tumor cells leads to inhibition of apoptosis, thus contributing to cancer cell proliferation. The largest binding pocket in the survivin dimer was located in the BIR domain. The key to the efficacy of 3-cyanopyridines was their surface interaction with the survivin amino acid Ile74.
METHODS: Through the optimization of the 3-cyanopyridine, 29 new compounds with a 3- Cyanopyridine structure were designed, synthesized, and characterized by NMR, IR, and mass spectrometry. The antitumor activity of the compounds in vitro was detected by the MTT method.
RESULTS: In vitro anti-tumor experiments showed that some compounds exhibited good anti-cancer effects. The IC50 values of the compound 2-amino-6-(2,4-difluorophenyl)-4-(4-hydroxyphenyl) nicotinonitrile (10n) against human liver cancer (Huh7), human glioma (U251), and human melanoma (A375) cells were 5.9, 6.0 and 7.2 μM, respectively. The IC50 values of the compound 6-(2,4-difluorophenyl)- 4-(4-hydroxyphenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (9o) against Huh7, U251 and A375 cells were 2.4, 17.5 and 7.2 μM, respectively, which were better than those of 10- hydroxycamptothecin and 5-fluorouracil. Analysis of the results of molecular dynamics simulation established that the BIR domain is the optimal binding site on the survivin protein, and the fingerprints of the eight most active compounds and the molecular docking to the survivin protein are analyzed.
CONCLUSION: 3-Cyanopyridine is an excellent backbone for antitumor lead compounds, 10n and 9o, as derivatives of 3-Cyanopyridine are excellent survivin protein-targeting inhibitors worthy of further study. The key factor in inhibiting survivin protein through the action of amino acid Ile74.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:19 |
|---|---|
| Enthalten in: |
Medicinal chemistry (Shariqah (United Arab Emirates)) - 19(2023), 3 vom: 29., Seite 246-262 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Lu, Jia-Hao [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
3-cyanopyridine |
|---|
| Anmerkungen: |
Date Completed 10.03.2023 Date Revised 10.03.2023 published: Print Citation Status MEDLINE |
|---|
| doi: |
10.2174/1573406418666220829160820 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM345611241 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM345611241 | ||
| 003 | DE-627 | ||
| 005 | 20231226025446.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.2174/1573406418666220829160820 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1151.xml |
| 035 | |a (DE-627)NLM345611241 | ||
| 035 | |a (NLM)36043763 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Lu, Jia-Hao |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Design, Synthesis, and Molecular Docking Study of Novel 3-Cyanopyridine Derivatives for the Anti-Cancer Drug Target Survivin Protein |
| 264 | 1 | |c 2023 | |
| 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 10.03.2023 | ||
| 500 | |a Date Revised 10.03.2023 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright© Bentham Science Publishers; For any queries, please email at epubbenthamscience.net. | ||
| 520 | |a Survivin is an important member of the antiapoptotic protein family and controls the cell's life cycle. Overexpression of survivin in tumor cells leads to inhibition of apoptosis, thus contributing to cancer cell proliferation. The largest binding pocket in the survivin dimer was located in the BIR domain. The key to the efficacy of 3-cyanopyridines was their surface interaction with the survivin amino acid Ile74 | ||
| 520 | |a METHODS: Through the optimization of the 3-cyanopyridine, 29 new compounds with a 3- Cyanopyridine structure were designed, synthesized, and characterized by NMR, IR, and mass spectrometry. The antitumor activity of the compounds in vitro was detected by the MTT method | ||
| 520 | |a RESULTS: In vitro anti-tumor experiments showed that some compounds exhibited good anti-cancer effects. The IC50 values of the compound 2-amino-6-(2,4-difluorophenyl)-4-(4-hydroxyphenyl) nicotinonitrile (10n) against human liver cancer (Huh7), human glioma (U251), and human melanoma (A375) cells were 5.9, 6.0 and 7.2 μM, respectively. The IC50 values of the compound 6-(2,4-difluorophenyl)- 4-(4-hydroxyphenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (9o) against Huh7, U251 and A375 cells were 2.4, 17.5 and 7.2 μM, respectively, which were better than those of 10- hydroxycamptothecin and 5-fluorouracil. Analysis of the results of molecular dynamics simulation established that the BIR domain is the optimal binding site on the survivin protein, and the fingerprints of the eight most active compounds and the molecular docking to the survivin protein are analyzed | ||
| 520 | |a CONCLUSION: 3-Cyanopyridine is an excellent backbone for antitumor lead compounds, 10n and 9o, as derivatives of 3-Cyanopyridine are excellent survivin protein-targeting inhibitors worthy of further study. The key factor in inhibiting survivin protein through the action of amino acid Ile74 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Design and synthesis | |
| 650 | 4 | |a antitumor in vitro | |
| 650 | 4 | |a disease | |
| 650 | 4 | |a drugs | |
| 650 | 4 | |a molecular docking | |
| 650 | 4 | |a molecular dynamics | |
| 650 | 7 | |a 3-cyanopyridine |2 NLM | |
| 650 | 7 | |a X64V0K6260 |2 NLM | |
| 650 | 7 | |a Survivin |2 NLM | |
| 650 | 7 | |a Antineoplastic Agents |2 NLM | |
| 650 | 7 | |a Amino Acids |2 NLM | |
| 700 | 1 | |a Lai, Wu-Ji |e verfasserin |4 aut | |
| 700 | 1 | |a Jiang, Li-He |e verfasserin |4 aut | |
| 700 | 1 | |a Lei, Fu-Hou |e verfasserin |4 aut | |
| 700 | 1 | |a Shen, Li-Qun |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Ai-Qun |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Medicinal chemistry (Shariqah (United Arab Emirates)) |d 2005 |g 19(2023), 3 vom: 29., Seite 246-262 |w (DE-627)NLM163628467 |x 1875-6638 |7 nnns |
| 773 | 1 | 8 | |g volume:19 |g year:2023 |g number:3 |g day:29 |g pages:246-262 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.2174/1573406418666220829160820 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 19 |j 2023 |e 3 |b 29 |h 246-262 | ||