Novel Thiazole-Fused [4,5-<i>g</i>] or [5,4-<i>g</i>]Quinazolin-8-ones and Their Quinazoline Analogues: Synthesis and Biological Evaluation
<b>Background/Objectives:</b> In connection with previous work on V-shaped polycyclic thiazolo[5,4-<i>f</i>]quinazolin-9-one and [5,4-<i>f</i>]quinazoline derivatives that can modulate the activity of various kinases, the synthesis of straight thiazole-fused [4,5-...
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2024-10-01
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| author | Nathan Broudic Alexandra Pacheco-Benichou Cécile Corbière Blandine Baratte Thomas Robert Stéphane Bach Hélène Solhi Rémy Le Guével Corinne Fruit Thierry Besson |
| author_facet | Nathan Broudic Alexandra Pacheco-Benichou Cécile Corbière Blandine Baratte Thomas Robert Stéphane Bach Hélène Solhi Rémy Le Guével Corinne Fruit Thierry Besson |
| author_sort | Nathan Broudic |
| collection | DOAJ |
| description | <b>Background/Objectives:</b> In connection with previous work on V-shaped polycyclic thiazolo[5,4-<i>f</i>]quinazolin-9-one and [5,4-<i>f</i>]quinazoline derivatives that can modulate the activity of various kinases, the synthesis of straight thiazole-fused [4,5-<i>g</i>] or [5,4-<i>g</i>]quinazolin-8-ones and quinazoline derivatives hitherto undescribed was envisioned. <b>Methods:</b> An innovative protocol allowed to obtain the target structures. The synthesis of inverted thiazolo[4,5-<i>h</i>] and [5,4-<i>h</i>]quinazolin-8-one derivatives was also explored with the aim of comparing biological results. The compounds obtained were tested against a representative panel of eight mammalian protein kinases of human origin: CDK9/CyclinT, Haspin, Pim-1, GSK-3β, CK-1ε, JAK3, CLK1 and DYRK1A. <b>Results and Conclusions:</b> The results obtained show that the novel linear thiazoloquinazolines are not kinase inhibitors. The cytotoxicity of these newly synthesized compounds was assessed against seven representative tumor cell lines (human cancers: Huh7-D12, Caco-2, HCT-116, MCF-7, MDA-MB-231, MDA-MB-468 and PC-3). The majority of these novel molecules proved capable of inhibiting the growth of the tested cells. The 7-Benzyl-8-oxo-7,8-dihydrothiazolo[5,4-<i>g</i>]quinazolinones <b>5b</b> and <b>6b</b> are the most potent, with IC<sub>50</sub> values in the micromolar range. None of these compounds showed toxicity against normal cells. A larger program of investigations will be launched to investigate the real potential interest of such compounds in anticancer applications. |
| format | Article |
| id | doaj-art-9fca41b7c93b4c3b930e5e47bdadcea3 |
| institution | OA Journals |
| issn | 1424-8247 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | MDPI AG |
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| series | Pharmaceuticals |
| spelling | doaj-art-9fca41b7c93b4c3b930e5e47bdadcea32025-08-20T01:53:57ZengMDPI AGPharmaceuticals1424-82472024-10-011711145210.3390/ph17111452Novel Thiazole-Fused [4,5-<i>g</i>] or [5,4-<i>g</i>]Quinazolin-8-ones and Their Quinazoline Analogues: Synthesis and Biological EvaluationNathan Broudic0Alexandra Pacheco-Benichou1Cécile Corbière2Blandine Baratte3Thomas Robert4Stéphane Bach5Hélène Solhi6Rémy Le Guével7Corinne Fruit8Thierry Besson9Univ Rouen Normandie, INSA Rouen Normandie, CNRS, COBRA UMR 6014, F-76000 Rouen, FranceUniv Rouen Normandie, INSA Rouen Normandie, CNRS, COBRA UMR 6014, F-76000 Rouen, FranceUniv Rouen Normandie, ABTE UR4651, F-76000 Rouen, FranceSorbonne Université, CNRS, UMR8227, Integrative Biology of Marine Models Laboratory (LBI2M), Station Biologique de Roscoff, F-29680 Roscoff, FranceSorbonne Université, CNRS, UMR8227, Integrative Biology of Marine Models Laboratory (LBI2M), Station Biologique de Roscoff, F-29680 Roscoff, FranceSorbonne Université, CNRS, UMR8227, Integrative Biology of Marine Models Laboratory (LBI2M), Station Biologique de Roscoff, F-29680 Roscoff, FranceUniv Rennes, Plateform ImPACcell, BIOSIT, F-35000 Rennes, FranceUniv Rennes, Plateform ImPACcell, BIOSIT, F-35000 Rennes, FranceUniv Rouen Normandie, INSA Rouen Normandie, CNRS, COBRA UMR 6014, F-76000 Rouen, FranceUniv Rouen Normandie, INSA Rouen Normandie, CNRS, COBRA UMR 6014, F-76000 Rouen, France<b>Background/Objectives:</b> In connection with previous work on V-shaped polycyclic thiazolo[5,4-<i>f</i>]quinazolin-9-one and [5,4-<i>f</i>]quinazoline derivatives that can modulate the activity of various kinases, the synthesis of straight thiazole-fused [4,5-<i>g</i>] or [5,4-<i>g</i>]quinazolin-8-ones and quinazoline derivatives hitherto undescribed was envisioned. <b>Methods:</b> An innovative protocol allowed to obtain the target structures. The synthesis of inverted thiazolo[4,5-<i>h</i>] and [5,4-<i>h</i>]quinazolin-8-one derivatives was also explored with the aim of comparing biological results. The compounds obtained were tested against a representative panel of eight mammalian protein kinases of human origin: CDK9/CyclinT, Haspin, Pim-1, GSK-3β, CK-1ε, JAK3, CLK1 and DYRK1A. <b>Results and Conclusions:</b> The results obtained show that the novel linear thiazoloquinazolines are not kinase inhibitors. The cytotoxicity of these newly synthesized compounds was assessed against seven representative tumor cell lines (human cancers: Huh7-D12, Caco-2, HCT-116, MCF-7, MDA-MB-231, MDA-MB-468 and PC-3). The majority of these novel molecules proved capable of inhibiting the growth of the tested cells. The 7-Benzyl-8-oxo-7,8-dihydrothiazolo[5,4-<i>g</i>]quinazolinones <b>5b</b> and <b>6b</b> are the most potent, with IC<sub>50</sub> values in the micromolar range. None of these compounds showed toxicity against normal cells. A larger program of investigations will be launched to investigate the real potential interest of such compounds in anticancer applications.https://www.mdpi.com/1424-8247/17/11/1452thiazoloquinazolinonesthiazoloquinazolines4,5-dichloro-1,2,3-dithiazolium chloridemicrowave-assisted chemistrycytotoxicitykinase inhibition |
| spellingShingle | Nathan Broudic Alexandra Pacheco-Benichou Cécile Corbière Blandine Baratte Thomas Robert Stéphane Bach Hélène Solhi Rémy Le Guével Corinne Fruit Thierry Besson Novel Thiazole-Fused [4,5-<i>g</i>] or [5,4-<i>g</i>]Quinazolin-8-ones and Their Quinazoline Analogues: Synthesis and Biological Evaluation Pharmaceuticals thiazoloquinazolinones thiazoloquinazolines 4,5-dichloro-1,2,3-dithiazolium chloride microwave-assisted chemistry cytotoxicity kinase inhibition |
| title | Novel Thiazole-Fused [4,5-<i>g</i>] or [5,4-<i>g</i>]Quinazolin-8-ones and Their Quinazoline Analogues: Synthesis and Biological Evaluation |
| title_full | Novel Thiazole-Fused [4,5-<i>g</i>] or [5,4-<i>g</i>]Quinazolin-8-ones and Their Quinazoline Analogues: Synthesis and Biological Evaluation |
| title_fullStr | Novel Thiazole-Fused [4,5-<i>g</i>] or [5,4-<i>g</i>]Quinazolin-8-ones and Their Quinazoline Analogues: Synthesis and Biological Evaluation |
| title_full_unstemmed | Novel Thiazole-Fused [4,5-<i>g</i>] or [5,4-<i>g</i>]Quinazolin-8-ones and Their Quinazoline Analogues: Synthesis and Biological Evaluation |
| title_short | Novel Thiazole-Fused [4,5-<i>g</i>] or [5,4-<i>g</i>]Quinazolin-8-ones and Their Quinazoline Analogues: Synthesis and Biological Evaluation |
| title_sort | novel thiazole fused 4 5 i g i or 5 4 i g i quinazolin 8 ones and their quinazoline analogues synthesis and biological evaluation |
| topic | thiazoloquinazolinones thiazoloquinazolines 4,5-dichloro-1,2,3-dithiazolium chloride microwave-assisted chemistry cytotoxicity kinase inhibition |
| url | https://www.mdpi.com/1424-8247/17/11/1452 |
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