1-substituted (Dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-ones endowed with dual DNA-PK/PI3-K inhibitory activity
Analogues of (dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one (NU7441), a potent inhibitor of DNA-dependent protein kinase (DNA-PK; IC50 = 42 ± 2 nM), have been synthesized in which water-solubilizing groups [NHCO(CH₂)nNR¹R², where n = 1 or 2 and the moiety R¹R²N was derived from a library of primary and secondary amines, e.g., morpholine] were placed at the 1-position. Several of the newly synthesized compounds exhibited high potency against DNA-PK and potentiated the cytotoxicity of ionizing radiation (IR) in vitro 10-fold or more (e.g., 2-(4-ethylpiperazin-1-yl)-N-(4-(2-morpholino-4-oxo-4H-chromen-8-yl)dibenzo[b,d]thio-phen-1-yl)acetamide, 39; DNA-PK IC₅₀ = 5.0 ± 1 nM, IR dose modification ratio = 13). Furthermore, 39 was shown to potentiate not only IR in vitro but also DNA-inducing cytotoxic anticancer agents, both in vitro and in vivo. Counter-screening against other members of the phosphatidylinositol 3-kinase (PI-3K) related kinase (PIKK) family unexpectedly revealed that some of the compounds were potent mixed DNA-PK and PI-3K inhibitors.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2013 |
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| Erschienen: |
2013 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:56 |
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| Enthalten in: |
Journal of medicinal chemistry - 56(2013), 16 vom: 22. Aug., Seite 6386-401 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Cano, Céline [VerfasserIn] |
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| Links: |
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| Themen: |
DNA-Activated Protein Kinase |
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| Anmerkungen: |
Date Completed 29.10.2013 Date Revised 10.02.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/jm400915j |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM229171761 |
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| 245 | 1 | 0 | |a 1-substituted (Dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-ones endowed with dual DNA-PK/PI3-K inhibitory activity |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Analogues of (dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one (NU7441), a potent inhibitor of DNA-dependent protein kinase (DNA-PK; IC50 = 42 ± 2 nM), have been synthesized in which water-solubilizing groups [NHCO(CH₂)nNR¹R², where n = 1 or 2 and the moiety R¹R²N was derived from a library of primary and secondary amines, e.g., morpholine] were placed at the 1-position. Several of the newly synthesized compounds exhibited high potency against DNA-PK and potentiated the cytotoxicity of ionizing radiation (IR) in vitro 10-fold or more (e.g., 2-(4-ethylpiperazin-1-yl)-N-(4-(2-morpholino-4-oxo-4H-chromen-8-yl)dibenzo[b,d]thio-phen-1-yl)acetamide, 39; DNA-PK IC₅₀ = 5.0 ± 1 nM, IR dose modification ratio = 13). Furthermore, 39 was shown to potentiate not only IR in vitro but also DNA-inducing cytotoxic anticancer agents, both in vitro and in vivo. Counter-screening against other members of the phosphatidylinositol 3-kinase (PI-3K) related kinase (PIKK) family unexpectedly revealed that some of the compounds were potent mixed DNA-PK and PI-3K inhibitors | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 7 | |a Phosphoinositide-3 Kinase Inhibitors |2 NLM | |
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| 700 | 1 | |a Saravanan, Kappusamy |e verfasserin |4 aut | |
| 700 | 1 | |a Bailey, Chris |e verfasserin |4 aut | |
| 700 | 1 | |a Bardos, Julia |e verfasserin |4 aut | |
| 700 | 1 | |a Curtin, Nicola J |e verfasserin |4 aut | |
| 700 | 1 | |a Frigerio, Mark |e verfasserin |4 aut | |
| 700 | 1 | |a Golding, Bernard T |e verfasserin |4 aut | |
| 700 | 1 | |a Hardcastle, Ian R |e verfasserin |4 aut | |
| 700 | 1 | |a Hummersone, Marc G |e verfasserin |4 aut | |
| 700 | 1 | |a Menear, Keith A |e verfasserin |4 aut | |
| 700 | 1 | |a Newell, David R |e verfasserin |4 aut | |
| 700 | 1 | |a Richardson, Caroline J |e verfasserin |4 aut | |
| 700 | 1 | |a Shea, K |e verfasserin |4 aut | |
| 700 | 1 | |a Smith, Graeme C M |e verfasserin |4 aut | |
| 700 | 1 | |a Thommes, Pia |e verfasserin |4 aut | |
| 700 | 1 | |a Ting, Attilla |e verfasserin |4 aut | |
| 700 | 1 | |a Griffin, Roger J |e verfasserin |4 aut | |
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