The synthesis of a novel series of quinazolines substituted at C4 by five-membered ring aminoheterocycles is reported. Their in vitro structure-activity relationships versus Aurora A and B serine-threonine kinases is discussed. Our results demonstrate that quinazolines with a substituted aminothiazole at C4 possess potent Aurora A and B inhibitory activity and excellent selectivity against a panel of various serine-threonine and tyrosine kinases, as exemplified by compound 46. We found also that the position and nature of the substituent on the thiazole play key roles in cellular potency. Compounds with an acetanilide substituent at C5' have the greatest cellular activity. The importance of the C5' position for substitution has been rationalized by ab initio molecular orbital calculations. Results show that the planar conformation with the sulfur of the thiazole next to the quinazoline N-3 is strongly favored over the other possible planar conformation. Compound 46 is a potent suppressor of the expression of phospho-histone H3 in tumor cells in vitro as well as in vivo, where 46, administered as its phosphate prodrug 54, suppresses the expression of phospho-histone H3 in subcutaneously implanted tumors in nude mice.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1021/jm050786h | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Synthesis of 2-Amino-quinazolin-4()-ones Using 2-Bromo--phenylbenzamide and Cyanamide Ullmann Cross-Coupling.
J Org Chem
December 2024
State Key Laboratory of High-efficiency Utilization of Coal and Green Chemical Engineering, College of Chemistry and Chemical Engineering, Ningxia University, Yinchuan 750001, China.
Article Synopsis
- A new method was developed to create 2-amino-3-substituted quinoline-4(3)-ones and -phenylbenzamide derivatives using inexpensive materials and a simple process.
- The synthesis involves Ullmann cross-coupling with cyanamide, 2-bromo-phenylbenzamide, copper iodide, and potassium tert-butoxide in dimethyl sulfoxide, all of which can be done under air conditions without ligands.
- Additionally, the research shows that other nucleophilic reagents like water and amines can also be used to produce 2-functionalized phenylbenzamides.
Dehydrogenative Coupling for Synthesis of Quinazolin-4(3H)-ones via Tandem Reaction using Ruthenium(II)-Phenyl-Azo-Naphthaldoxime: An Experimental and Theoretical Investigation.
Chem Asian J
November 2024
Department of Chemistry, St. Xavier's College (Autonomous), Kolkata, 700016, India.
The bidentate N, N, donor phenyl-azo-naphthaldoxime NpLH, 1 was used to synthesize the ruthenium(II) complex trans-[Ru(NpL)(CO)Cl(PPh)], 2. It has been characterized by SCXRD, electrochemical and spectral studies. Computational analysis indicates that the low-lying π*-LUMO of the complex has substantial azo-character of coordinated ligand.
View Article and Find Full Text PDFBioisosteric Replacement in the Search for Biologically Active Compounds: Design, Synthesis and Anti-Inflammatory Activity of Novel [1,2,4]triazino[2,3-c]quinazolines.
Pharmaceuticals (Basel)
October 2024
Department of Microbiology, Virology and Immunology, I. Horbachevsky Ternopil State Medical University, 46001 Ternopil, Ukraine.
Designing novel biologically active compounds with anti-inflammatory properties based on condensed quinazolines is a significant area of interest in modern medicinal chemistry. In the present study, we describe the development of promising new bioactive molecules through the bioisosteric replacement of a carbon atom with a sulfur atom in anti-inflammatory agents, specifically 3-methyl-2-oxo-2-[1,2,4]triazino[2,3-]quinazolin-6-yl)butanoate. Design and synthetic studies have led to the series of previously unknown substituted 2-[((3-R-2-oxo-2-[1,2,4]triazino[2,3-]quinazolin-6-yl)methyl)thio]carboxylic acids and their esters.
View Article and Find Full Text PDFRuthenium(II)-Catalyzed C-H/C-H (4+2) Annulation of 2-Aryl-N-heterocycles with Vinylene Carbonate.
Chem Asian J
November 2024
Department of Chemistry, Birla Institute of Technology and Science, Pilani, Pilani Campus, Pilani, Rajasthan, 333031, India.
A ruthenium(II)-catalyzed direct C-H/C-H (4+2) annulation of 2-aryl-N-heterocycles such as 2-aryl-4H-pyrido[1,2-a]pyrimidin-4-ones, 2-arylimidazo[1,2-a]pyridines, 2-aryl-2H-indazoles and 2-arylquinolin-4(1H)-ones with vinylene carbonate has been described. This one-pot cascade strategy provided the diversely substituted fused-polyheterocycles such as 7H-benzo[h]pyrido[2,1-b]quinazolin-7-ones, naphtho[1',2':4,5]imidazo[1,2-a]pyridines, indazolo[2,3-a]quinolines and benzo[c]acridin-7(12H)-ones in moderate to excellent yields. The developed protocol exhibited a broad substrate scope with good functional group tolerance and acid/base-free conditions.
View Article and Find Full Text PDFDesign, synthesis and anti-tumor evaluation of novel pyrimidine and quinazoline analogues.
Eur J Med Chem
January 2025
Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism and Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China. Electronic address:
Disrupting microtubule dynamics has emerged as a promising strategy for cancer therapy. Novel trimethoxyanilino-substituted pyrimidine and quinazoline derivatives were designed and synthesized to serve as potent microtubule-inhibiting agents with anti-proliferative activity. Compound 2k demonstrates high efficacy against B16-F10 cancer cells at low nanomolar concentrations, with an IC of 0.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!