| Title: |
Novel Thiazole-Fused [4,5-g] or [5,4-g]Quinazolin-8-ones and Their Quinazoline Analogues: Synthesis and Biological Evaluation |
| Authors: |
Broudic, Nathan; Pacheco-Benichou, Alexandra; Corbiere, Cecile; Baratte, Blandine; Robert, Thomas; Bach, Stéphane; Solhi, Hélène; Le Guével, Rémy; Fruit, Corinne; Besson, Thierry |
| Contributors: |
Chimie Organique et Bioorganique : Réactivité et Analyse (COBRA); Institut de Chimie Organique Fine (IRCOF); Université de Rouen Normandie (UNIROUEN); Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie); Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN); Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M); Université de Caen Normandie (UNICAEN); Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN); Normandie Université (NU)-Université Le Havre Normandie (ULH); Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN); Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie); Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie - CNRS Chimie (INC-CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN); Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN); Normandie Université (NU)-Institut de Chimie - CNRS Chimie (INC-CNRS)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS); Normandie Université (NU); Aliments Bioprocédés Toxicologie Environnements (ABTE); Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN); Station biologique de Roscoff = Roscoff Marine Station (SBR); Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS); Laboratoire de Biologie Intégrative des Modèles Marins (LBI2M); Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Station biologique de Roscoff = Roscoff Marine Station (SBR); Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS); Biosit : biologie, santé, innovation technologique (SFR UMS CNRS 3480 - INSERM 018); Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes (Biosit : Biologie - Santé - Innovation Technologique); Plate-forme ImPACcell (ImPACcell); Structure Fédérative de Recherche en Biologie et Santé de Rennes (Biosit : Biologie - Santé - Innovation Technologique); This work was partially supported by the European Regional Development Fund (ERDF), Labex SynOrg (ANR-11-LABX-0029), Carnot Institute I2C, and graduate school for research Xl-Chem (ANR-18-EURE-0020 XL CHEM).; ANR-11-LABX-0029,SYNORG,Synthèse Organique : des molécules au vivant(2011); ANR-18-EURE-0020,XL Chem,XLChem, Synthesizing our future(2018) |
| Source: |
ISSN: 1424-8247 ; Pharmaceuticals ; https://hal.science/hal-04783236 ; Pharmaceuticals, 2024, 17 (11), pp.1452. ⟨10.3390/ph17111452⟩. |
| Publisher Information: |
HAL CCSD; MDPI |
| Publication Year: |
2024 |
| Collection: |
Université de Rennes 1: Publications scientifiques (HAL) |
| Subject Terms: |
thiazoloquinazolinones; thiazoloquinazolines; 4,5-dichloro-1,2,3-dithiazolium chloride; microwave-assisted chemistry; cytotoxicity; kinase inhibition; DYRK1A kinase; [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology |
| Description: |
International audience ; Background/Objectives: In connection with previous work on V-shaped polycyclic thiazolo[5,4-f]quinazolin-9-one and [5,4-f]quinazoline derivatives that can modulate the activity of various kinases, the synthesis of straight thiazole-fused [4,5-g] or [5,4-g]quinazolin-8-ones and quinazoline derivatives hitherto undescribed was envisioned. Methods: An innovative protocol allowed to obtain the target structures. The synthesis of inverted thiazolo[4,5-h] and [5,4-h]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. Results and Conclusions: 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-g]quinazolinones 5b and 6b are the most potent, with IC50 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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.3390/ph17111452 |
| Availability: |
https://hal.science/hal-04783236; https://hal.science/hal-04783236v1/document; https://hal.science/hal-04783236v1/file/pharmaceuticals-17-01452.pdf; https://doi.org/10.3390/ph17111452 |
| Rights: |
http://creativecommons.org/licenses/by/ ; info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.C90253F3 |
| Database: |
BASE |